Protein kinases

FIELD OF THE INVENTION

The present invention relates to novel kinase polypeptides, nucleotide sequences encoding the novel kinase polypeptides, as well as various products and methods useful for the diagnosis and treatment of various kinase-related diseases and conditions.

BACKGROUND OF THE INVENTION

The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be or to describe prior art to the invention.

Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins, which enables regulation of the activity of mature proteins by altering their structure and function.

Protein phosphorylation plays a pivotal role in biological signal transduction. Among the biological functions controlled by protein phosphorylation are the following: cell division; differentiation and death (apoptosis); cell motility and cytoskeletal structure; control of DNA replication, transcription, splicing and translation; protein translocation events from the endoplasmic reticulum and Golgi apparatus to the membrane and extracellular space; protein nuclear import and export; regulation of metabolic reactions, etc. Abnormal protein phosphorylation is widely recognized to be causally linked to the etiology of many diseases including cancer as well as immunologic, neuronal and metabolic disorders.

The most common phospho-acceptor amino acid residues are serine, threonine and tyrosine. Phosphorylation in histidine has also been observed in bacteria. The presence of a phosphate moeity modulates protein function in multiple ways. A common mechanism includes changes in the catalytic properties (V_maxand K_m) of an enzyme leading to its activation or inactivation. A second widely recognized mechanism involves promoting protein-protein interactions. An example of this is the tyrosine autophosphorylation of the ligand-activated EGF receptor tyrosine kinase. This event triggers the high-affinity binding to the phosphotyrosine residue on the receptor's C-terminal intracellular domain to the SH2 motif of the adaptor molecule Grb2. Grb2 in turn binds through its SH3 motif to a second adaptor molecule, such as SHC. The formation of this ternary complex acivates the signaling events that are responsible for the biological effects of EGF. Serine and threonine phosphorylation events have also being recently recognized to exert their biological function through protein-protein interaction events mediated by the high-affinity binding of phosphoserine and phosphothreonine to WW motifs present in a large variety of proteins (Lu, P. J. et al. (1999) Science 283:1325-1328). A third important outcome of protein phosphorylation is changes in the subcellular localization of the substrate. As an example, nuclear import and export events in a large diversity of proteins are regulated by protein phosphorylation (Drier E. A. et al. (1999) Genes Dev 13: 556-568).

Protein kinases are one of the largest families of eukaryotic proteins with several hundred known members. These proteins share a 250-300 amino acid domain that can be subdivided into 12 distinct subdomains that comprise the common catalytic core structure. These conserved protein motifs have recently been exploited using PCR-based and bioinformatic strategies leading to a significant expansion of the known kinases. Multiple alignment of the sequences in the catalytic domain of protein kinases and subsequent parsimony analysis permits their segregation into a dendrogram reflecting the relatedness of their catalytic domains (FIG. 1). In this manner, related kinases are clustered into distinct branches or subfamilies including: tyrosine kinases, cyclic-nucleotide-dependent kinases, calcium/calmodulin kinases, cyclin-dependent kinases and MAP-kinases, serine-threonine kinase receptors, and several other less defined subfamilies.

We have recently completed a systematic analysis of the protein kinases present in C. elegans, the multicellular organism whose entire DNA sequence has been determined. We identified 473 unique kinase profiles including 398 full-length conventional kinases, and 20 additional proteins that may function as atypical protein kinases. (Plowman G. D. et al. (1999), Proc. Natl. Acad. Sci. 96:13603-13610).

Using parsimony analysis, the protein kinases may be divided into 4 major groups: AGC, CAMK, CMGC and tyrosine kinases. In addition, there are a number of minor yet distinct families, including the STE and casein kinase 1, families related to worm- or fungal-specific kinases, and a family designated “other” to represent several smaller families. In addition, we designate an “atypical” family to represent protein kinases whose catalytic domain has little or no primary sequence homology to conventional kinases, including the A6 kinases and PI3 kinases.

The AGC kinases are basic amino acid-directed enzymes that phosphorylate residues found proximal to Arg and Lys. Examples of this group are the cyclic nucleotide-dependent kinases, G protein kinases, NDR or DBF2 and the ribosomal S6 kinases.

The CAMK group kinases are also basic amino acid-directed kinases. They include the Ca2+/calmodulin-regulated and AMP-dependent protein kinases, myosin light chain kinases, checkpoint 2 kinases (CHK2) and EMK-related protein kinases. The EMK family of STK are involved in the control of cell polarity, micotubule stability and cancer. One member of the EMK family, C-TAK1 has been reported to control entry into mitosis by activating Cdc25C which in turn dephosphorylates Cdc2.

CMGC group kinases are “proline-directed” enzymes phosphorylating residues that exist in a proline-rich context. They include the cyclin-dependent kinases (CDKs), mitogen-activated kinases (MAPKs), GSK3s and CLKs. Most CMGC kinases have larger-than-average kinase domains owing to the presence of insertions within subdomains X and XI.

The tyrosine kinase group encompass both cytoplasmic (i.e. src) as well as transmembrane receptor tyrosine kinases (i.e. EGF receptor). These kinases play a pivotal role in the signal transduction processes that mediate cell proliferation, differentiation and apoptotis.

Group members that define smaller, yet distinct phylogenetic branches of conventional kinases include the elongation factor 2 kinases (EIFKs); homologues of the yeast sterile family kinases (STE) which refers to 3 classes of kinases which lie sequentially upstream of the MAPKs; mixed lineage kinases (MLKs); Lim-domain containing kinases (LIMKs); Calcium-calmodulin kinase kinases (CAMKK), dual-specific tyrosine kinases (DYRK), integrin receptor associated kinase (IRAK); testis-specific kinases (TSK); UNC-51 related kinases (UNC); several families that are close homologues to worm (C26C2.1, YQ09, ZC581.9, YFL033c, C24A 1.3), Drosophila (SLOB), or yeast (YDOD_sp, YGR262_sc) kinases, and others that are “unique” and don't cluster into any obvious family.

SUMMARY OF THE INVENTION

Through a search of the EST database for homologies to the conserved catalytic kinase domain of protein kinases, hundreds of mammalian members of known and previously unidentified protein kinase families and groups have been identified as part of the present invention. Multiple alignment and parsimony analysis of the catalytic domain reveals that approximately half of these protein kinases cluster into 10 known groups, with the other half perhaps defining novel groups. Classification in this manner has proven highly accurate not only in predicting motifs present in the remaining non-catalytic portion of each protein, but also in their regulation, substrates, and signaling pathways. The present invention includes the partial or complete sequence of new protein kinases, their classification, predicted or deduced protein structure, and a strategy for elucidating their biologic and therapeutic relevance.

Thus, a first aspect of the invention features an isolated, enriched, or purified nucleic acid molecule encoding a kinase polypeptide selected from the group consisting SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242.

By “isolated” in reference to nucleic acid is meant a polymer of nucleotides conjugated to each other, including DNA and RNA, that is isolated from a natural source or that is synthesized. The isolated nucleic acid of the present invention is unique in the sense that it is not found in a pure or separated state in nature. Use of the term “isolated” indicates that a naturally occurring sequence has been removed from its normal cellular (ie., chromosomal) environment. Thus, the sequence may be in a cell-free solution or placed in a different cellular environment. The term does not imply that the sequence is the only nucleotide chain present, but that it is essentially free (about 90-95% pure at least) of non-nucleotide material naturally associated with it, and thus is distinguished from isolated chromosomes.

By the use of the term “enriched” in reference to nucleic acid is meant that the specific DNA or RNA sequence constitutes a significantly higher fraction (2-5 fold) of the total DNA or RNA present in the cells or solution of interest than in normal or diseased cells or in the cells from which the sequence was taken. This could be caused by a person by preferential reduction in the amount of other DNA or RNA present, or by a preferential increase in the amount of the specific DNA or RNA sequence, or by a combination of the two. However, it should be noted that enriched does not imply that there are no other DNA or RNA sequences present, just that the relative amount of the sequence of interest has been significantly increased. The term “significant” is used to indicate that the level of increase is useful to the person making such an increase, and generally means an increase relative to other nucleic acids of about at least 2 fold, more preferably at least 5 to 10 fold or even more. The term also does not imply that there is no DNA or RNA from other sources. The other source DNA may, for example, comprise DNA from a yeast or bacterial genome, or a cloning vector such as pUC19. This term distinguishes from naturally occurring events, such as viral infection, or tumor type growths, in which the level of one mRNA may be naturally increased relative to other species of mRNA. That is, the term is meant to cover only those situations in which a person has intervened to elevate the proportion of the desired nucleic acid.

It is also advantageous for some purposes that a nucleotide sequence be in purified form The term “purified” in reference to nucleic acid does not require absolute purity (such as a homogeneous preparation). Instead, it represents an indication that the sequence is relatively more pure than in the natural environment (compared to the natural level this level should be at least 2-5 fold greater, e.g., in terms of mg/mL). Individual clones isolated from a cDNA library may be purified to electrophoretic homogeneity. The claimed DNA molecules obtained from these clones could be obtained directly from total DNA or from total RNA. The cDNA clones are not naturally occurring, but rather are preferably obtained via manipulation of a partially purified naturally occurring substance (messenger RNA). The construction of a cDNA library from mRNA involves the creation of a synthetic substance (cDNA) and pure individual cDNA clones can be isolated from the synthetic library by clonal selection of the cells carrying the cDNA library. Thus, the process which includes the construction of a cDNA library from mRNA and isolation of distinct cDNA clones yields an approximately 10⁶-fold purification of the native message. Thus, purification of at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated.

By a “kinase polypeptide” is meant 10 (preferably 20, more preferably 40, most preferably 75) or more contiguous amino acids set forth in an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122,SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or functional derivatives thereof as described herein. For sequences for which the full-length sequence is not given, the remaining sequences can be determined using methods well-known to those in the art and are intended to be included in the invention. In certain aspects, polypeptides of 100, 200, 300 or more amino acids are preferred. The kinase polypeptide can be encoded by a full-length nucleic acid sequence or any portion of the full-length nucleic acid sequence, so long as a functional activity of the polypeptide is retained. By “functional” domain is meant any region of the polypeptide that may play a regulatory or catalytic role as predicted from amino acid sequence homology to other proteins or by the presence of amino acid sequences that may give rise to specific structural conformations (i.e., coiled-coils). For some purposes, polypeptide domains are preferred, including, but not limited to, N-terminal, catalytic/kinase and C-terminal.

The amino acid sequence will be substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO: 125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 or portions of or the entire corresponding full-length amino acid sequences.

By “identity” is meant a property of sequences that measures their similarity or relationship. Identity is measured by dividing the number of identical residues between two sequences (either full-length or a defined domain) by the total number of residues in the known sequence, or the domain of the known sequence, and multiplying the product by 100. Thus, two copies of exactly the same sequence have 100% identity, but sequences that are less highly conserved, and have replacements and substitutions, have a lower degree of identity. “Gaps” are spaces in an alignment that can result from aligning a novel sequence with a known sequence when the novel sequence has additions or deletions of amino acids in comparison with the known sequence. These gaps do not factor into the assessment of % identity using the sbove calculation.

Those skilled in the art will recognize that several computer programs are also available for determining sequence identity using standard parameters, for example, Blast (Altschul, et al. (1997) Nucleic Acids Res. 25:3389-3402), Blast2 (Altschul, et al. (1990) J. Mol. Biol. 215:403-410), and Smith-Waterman (Smith, et al. (1981) J. Mol. Biol. 147:195-197).

In preferred embodiments, the invention features isolated, enriched, or purified nucleic acid molecules encoding a kinase polypeptide comprising a nucleotide sequence that: (a) encodes a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to the sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242; () is the complement of the nucleotide sequence of (a); (c) hybridizes under highly stringent conditions to the nucleotide molecule of (a) and encodes a naturally occurring kinase polypeptide; (d) encodes a kinase polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof. A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ D) NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to the sequence of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, except that it lacks one or more, but not all, of a domain selected from the group consisting of an N-terminal domain, a catalytic domain, a C-terminal domain, a coiled-coil structure region, a proline-rich region, a spacer region, an insert, and a C-terminal tail; (e) is the complement of the nucleotide sequence of (d); (f) encodes a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof (The domain demarcations of the polypeptides of the invention are indicated in Table 2 by reference to the kinase domain.) A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to the sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242; (b) is the complement of the nucleotide sequence of (a); (c) hybridizes under highly stringent conditions to the nucleotide molecule of (a) and encodes a naturally occurring kinase polypeptide; (d) encodes a kinase polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof. A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to a domain of a polypeptide selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ D) NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, where the domain is selected from the group consisting of an N-terminal domain, a catalytic domain, a C-terminal domain, a coiled-coil structure region, a proline-rich region, a spacer region, an insert, and a C-terminal tail; (g) is the complement of the nucleotide sequence of (f); (h) encodes a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to the sequence selected from-the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242; (b) is the complement of the nucleotide sequence of (a); (c) hybridizes under highly stringent conditions to the nucleotide molecule of (a) and encodes a naturally occurring kinase polypeptide; (d) encodes a kinase polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or fragments thereof A sequence that is substantially similar to a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 will have at least 75% identity (preferably 90%, more preferably at least 95% and most preferably 99-100%) to the sequence of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, except that it lacks one or more of the domains selected from the group consisting of a N-terminal domain, a catalytic domain, a C-terminal domain, a coiled-coil structure region, a proline-rich region, a spacer region, an insert, and a C-terminal tail; or (i) is the complement of the nucleotide sequence of (h). The domain demarcations of the polypeptides of the invention are indicated in Table 2 by reference to the kinase domain.

The term “complement” refers to two nucleotides that can form multiple favorable interactions with one another. For example, adenine is complementary to thymine as they can form two hydrogen bonds. Similarly, guanine and cytosine are complementary since they can form three hydrogen bonds. A nucleotide sequence is the complement of another nucleotide sequence if all of the nucleotides of the first sequence are complementary to all of the nucleotides of the second sequence.

The term “domain” refers to a region of a polypeptide that contains a particular function. For instance, N-terminal or C-terminal domains of signal transduction proteins can serve functions including, but not limited to, binding molecules that localize the signal transduction molecule to different regions of the cell or binding other signaling molecules directly responsible for propagating a particular cellular signal. Some domains can be expressed separately from the rest of the protein and function by themselves, while others must remain part of the intact protein to retain function. The latter are termed functional regions of proteins and also relate to domains.

The term “N-terminal domain” refers to the extracatalytic region located between the initiator methionine and the catalytic domain of the protein kinase. The N-terminal domain can be identified following a Smith-Waterman alignment of the protein sequence against the non-redundant protein database to define the N-terminal boundary of the catalytic domain. Depending on its length, the N-terminal domain may or may not play a regulatory role in kinase function. An example of a protein kinase whose N-terminal domain has been shown to play a regulatory role is PAK65, which contains a CRIB motif used for Cdc42 and rac binding (Burbelo, P. D. et al. (1995) J. Biol. Chem. 270, 29071-29074). The N-terminal domain of a protein kinase of the invention is that portion of the protein kinase to the amino-terminal side of the kinase domain where the kinase domain is identified in Table 2, herein. Further, in some cases, portions of the N-terminal domains of the protein kinases of the invention have not been identified since the entire sequence is not available. However, with the methods described herein, the full-length sequences of the kinases of the invention can be determined and using the approaches described herein the N-terminal domain can be identified.

The term “catalytic domain” or “kinase domain” refers to a region of the protein kinase that is typically 25-300 amino acids long and is responsible for carrying out the phosphate transfer reaction from a high-energy phosphate donor molecule such as ATP or GTP to itself (autophosphorylation) or to other proteins (exogenous phosphorylation). The catalytic domain of protein kinases is made up of 12 subdomains that contain highly conserved amino acid residues, and are responsible for proper polypeptide folding and for catalysis. The catalytic domain can be identified following a Smith-Waterman alignment of the protein sequence against the non-redundant protein database. The catalytic/kinase domains of the protein kinases of the invention are identified in Table 2, herein. Further, in some cases, the complete sequence of the catalytic/kinase domains of the protein kinases of the invention may not have been provided since the entire sequence is not available. However, with the methods described herein, the full-length sequences of the kinases of the invention can be determined, and using the approaches described herein, the catalytic/kinase domain can be identified.

The term “catalytic activity”, as used herein, defines the rate at which a kinase catalytic domain phosphorylates a substrate. Catalytic activity can be measured, for example, by determining the amount of a substrate converted to a phosphorylated product as a function of time. Catalytic activity can be measured by methods of the invention by holding time constant and determining the concentration of a phosphorylated substrate after a fixed period of time. Phosphorylation of a substrate occurs at the active-site of a protein kinase. The active-site is normally a cavity in which the substrate binds to the protein kinase and is phosphorylated.

The term “substrate” as used herein refers to a molecule phosphorylated by a kinase of the invention. Kinases phosphorylate substrates on serine/threonine or tyrosine amino acids. The molecule may be another protein or a polypeptide.

The term “C-terminal domain” refers to the region located between the catalytic domain and the carboxy-terminal amino acid residue of the protein kinase. The C-terminal domain can be identified by using a Smith-Waterman alignment of the protein sequence against the non-redundant protein database to define the C-terminal boundary of the catalytic domain or of any functional C-terminal extracatalytic domain. Depending on its length and amino acid composition, the C-terminal domain may or may not play a regulatory role in kinase function. An example of a protein kinase whose C-terminal domain may play a regulatory role is PAK3 which contains a heterotrimeric G_bsubunit-binding site near its C-terminus (Leeuw, T. el al. (1998) Nature, 391, 191-195). The C-terminal domain of a protein kinase of the invention is that portion of the protein kinase to the carboxy-terminal side of the kinase domain where the kinase domain is identified in Table 2, herein. In some cases, the C-terminal domains of the protein kinases of the invention have not been provided since the entire sequence is not available. However, with the methods described herein, the full-length sequences of the kinases of the invention can be determined, and using the approaches described herein, the C-terminal domain can be identified.

The term “signal transduction pathway” refers to the molecules that propagate an extracellular signal through the cell membrane to become an intracellular signal. This signal can then stimulate a cellular response. The polypeptide molecules involved in signal transduction processes are typically receptor and non-receptor protein tyrosine kinases, receptor and non-receptor protein phosphatases, SRC homology 2 and 3 domains, phosphotyrosine binding proteins (SRC homology 2 (SH2) and phosphotyrosine binding (PTB and PH) domain containing proteins), proline-rich binding proteins (SH3 domain containing proteins), nucleotide exchange factors, and transcription factors.

The term “coiled-coil structure region” as used herein, refers to a polypeptide sequence that has a high probability of adopting a coiled-coil structure as predicted by computer algorithms such as COILS (Lupas, A. (1996) Meth. Enzymology 266:513-525). Coiled-coils are formed by two or three amphipathic α-helices in parallel. Coiled-coils can bind to coiled-coil domains of other polypeptides resulting in homo- or heterodimers (Lupas, A. (1991) Science 252:1162-1164). Coiled-coil-dependent oligomerization has been shown to be necessary for protein function including catalytic activity of serine/threonine kinases (Roe, J. et al. (1997) J. Biol. Chem. 272:5838-5845). Coiled-coil regions in the proteins of the invention can be identified using these methods. They may be present as sub-domains of the N-terminal, kinase, or C-terminal domains of the polypeptides of the invention.

The term “proline-rich region” as used herein, refers to a region of a protein kinase whose proline content over a given amino acid length is higher than the average content of this amino acid found in proteins (i.e., >10%). Proline-rich regions are easily discernable by visual inspection of amino acid sequences and quantitated by standard computer sequence analysis programs such as the DNAStar program EditSeq. Proline-rich regions have been demonstrated to participate in regulatory protein -protein interactions. Among these interactions, those that are most relevant to this invention involve the “PxxP” proline rich motif found in certain protein kinases (i.e., human PAK1) and the SH3 domain of the adaptor molecule Nck (Galisteo, M. L. et al. (1996) J. Biol. Chem. 271:20997-21000). Other regulatory interactions involving “PxxP” proline-rich motifs include the WW domain (Sudol, M. (1996) Prog. Biophys. Mol. Bio. 65:113-132). Proline rich regions in the proteins of the invention can be identified using these methods. They may be present as sub-domains of the N-terminal, kinase, or C-terminal domains of the polypeptides of the invention.

The term “spacer region” as used herein, refers to a region of the protein kinase located between predicted functional domains. The spacer region has no detectable homology to any amino acid sequence in the database, and can be identified by using a Smith-Waterman alignment of the protein sequence against the non-redundant protein database to define the C— and N-terminal boundaries of the flanking functional domains. Spacer regions may or may not play a fundamental role in protein kinase function. Precedence for the regulatory role of spacer regions in kinase function is provided by the role of the src kinase spacer in inter-domain interactions (Xu, W. et al. (1997) Nature 385:595-602). Spacer regions in the proteins of the invention can be identified using these methods. They may be present as sub-domains of the N-terminal, kinase, or C-terminal domains of the polypeptides of the invention.

The term “insert” as used herein refers to a portion of a protein kinase that is absent from a close homolog. Inserts may or may not by the product alternative splicing of exons. Inserts can be identified by using a Smith-Waterman sequence alignment of the protein sequence against the non-redundant protein database, or by means of a multiple sequence alignment of homologous sequences using the DNAStar program Megalign. Inserts may play a functional role by presenting a new interface for protein-protein interactions, or by interfering with such interactions. Insert regions in the proteins of the invention can be identified using these methods. They may be present as sub-domains of the N-terminal, kinase, or C-terminal domains of the polypeptides of the invention.

The term “C-terminal tail” as used herein, refers to a C-terminal domain of a protein kinase, that by homology extends or protrudes past the C-terminal amino acid of its closest homolog. C-terminal tails can be identified by using a Smith-Waterman sequence alignment of the protein sequence against the non-redundant protein database, or by means of a multiple sequence alignment of homologous sequences using the DNAStar program Megalign. Depending on its length, a C-terminal tail may or may not play a regulatory role in kinase function. C-terminal tail regions in the proteins of the invention can be identified using these methods. They may be present as sub-domains of the N-terminal, kinase, or C-terminal domains of the polypeptides of the invention.

Various low or high stringency hybridization conditions may be used depending upon the specificity and selectivity desired. These conditions are well-known to those skilled in the art. Under stringent hybridization conditions only highly complementary nucleic acid sequences hybridize. Preferably, such conditions prevent hybridization of nucleic acids having more than 1 or 2 mismatches out of 20 contiguous nucleotides, more preferably, such conditions prevent hybridization of nucleic acids having more than 1 or 2 mismatches out of 50 contiguous nucleotides, most preferably, such conditions prevent hybridization of nucleic acids having more than 1 or 2 mismatches out of 100 contiguous nucleotides. In some instances, the conditions may prevent hybridization of nucleic acids having more than 5 mismatches in the fall-length sequence.

By stringent hybridization assay conditions is meant hybridization assay conditions at least as stringent as the following: hybridization in 50% formamide, 5×SSC, 50 mM NaH₂PO₄, pH 6.8, 0.5% SDS, 0.1 mg/mL sonicated salmon sperm DNA, and 5× Denhart solution at 42° C. overnight; washing with 2×SSC, 0.1% SDS at 45° C.; and washing with 0.2×SSC, 0. 1% SDS at 45° C. Under some of the most stringent hybridization assay conditions, the second wash can be done with 0.1×SSC at a temperature up to 70° C. (pg. 421, Berger et al. (1987) Guide to Molecular Cloning Techniques, Meth. Enzym. vol. 152, hereby incorporated by reference herein including any figures, tables, or drawings.). However, other applications may require the use of conditions falling between these sets of conditions. Methods of determining the conditions required to achieve desired hybridizations are well-known to those with ordinary skill in the art, and are based on several factors, including but not limited to, the sequences to be hybridized and the samples to be tested.

In other preferred embodiments, the invention features isolated, enriched, or purified nucleic acid molecules encoding kinase polypeptides, further comprising a vector or promoter effective to initiate transcription in a host cell. The invention also features recombinant nucleic acid, preferably in a cell or an organism. The recombinant nucleic acid may contain a sequence selected from the group consisting of those set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121, or a functional derivative thereof and a vector or a promoter effective to initiate transcription in a host cell. The recombinant nucleic acid can alternatively contain a transcriptional initiation region functional in a cell, a sequence complementary to an RNA sequence encoding a kinase polypeptide and a transcriptional termination region functional in a cell. Specific vectors and host cell combinations are discussed herein. The recombinant nucleic acid can also contain the full-length sequence encoding the protein kinase, or a domain, for example.

The term “vector” relates to a single or double-stranded circular nucleic acid molecule that can be transfected into cells and replicated within or independently of a cell genome. A circular double-stranded nucleic acid molecule can be cut and thereby linearized upon treatment with restriction enzymes. An assortment of nucleic acid vectors, restriction enzymes, and the knowledge of the nucleotide sequences cut by restriction enzymes are readily available to those skilled in the art. A nucleic acid molecule encoding a kinase can be inserted into a vector by cutting the vector with restriction enzymes and ligating the two pieces together.

The term “transfecting” defines a number of methods to insert a nucleic acid vector or other nucleic acid molecules into a cellular organism. These methods involve a variety of techniques, such as treating the cells with high concentrations of salt, an electric field, detergent, or DMSO to render the outer membrane or wall of the cells permeable to nucleic acid molecules of interest or use of various viral transduction strategies.

The term “promoter” as used herein, refers to nucleic acid sequence needed for gene sequence expression. Promoter regions vary from organism to organism, but are well known to persons skilled in the art for different organisms. For example, in prokaryotes, the promoter region contains both the promoter (which directs the initiation of RNA transcription) as well as the DNA sequences which, when transcribed into RNA, will signal synthesis initiation. Such regions will normally include those 5′-non-coding sequences involved with initiation of transcription and translation, such as the TATA box, capping sequence, CAAT sequence, and the like.

In preferred embodiments, the isolated nucleic acid comprises, consists essentially of, or consists of a nucleic acid sequence set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121, or the corresponding full-length sequence, encodes an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ 1ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, a functional derivative thereof, or at least 10, 20, 40, 50, 75, 100, 200, 300 or 500 contiguous amino acids of a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length sequences or derivatives thereof. The nucleic acid may be isolated from a natural source by cDNA cloning or by subtractive hybridization. The natural source may be mammalian, preferably human, blood, semen, or tissue, and the nucleic acid may be synthesized by the triester method or by using an automated DNA synthesizer.

The term “mammal” refers preferably to such organisms as mice, rats, rabbits, guinea pigs, sheep, and goats, more preferably to cats, dogs, monkeys, and apes, and most preferably to humans.

In yet other preferred embodiments, the nucleic acid is a conserved or unique region, for example those useful for: the design of hybridization probes to facilitate identification and cloning of additional polypeptides, the design of PCR probes to facilitate cloning of additional polypeptides, obtaining antibodies to polypeptide regions, and designing antisense oligonucleotides.

By “conserved nucleic acid regions”, are meant regions present on two or more nucleic acids encoding a kinase polypeptide, to which a particular nucleic acid sequence can hybridize under lower stringency conditions. Examples of lower stringency conditions suitable for screening for nucleic acid encoding kinase polypeptides are provided in Berger et al. (1987) Guide to Molecular Cloning Techniques, Meth. Enzym. vol. 152, hereby incorporated by reference herein in its entirety, including any drawings, figures, or tables. Preferably, conserved regions differ by no more than 5 out of 20 nucleotides, even more preferably 2 out of 20 nucleotides or most preferably 1 out of 20 nucleotides.

By “unique nucleic acid region” is meant a sequence present in a nucleic acid coding for a kinase polypeptide that is not present in a sequence coding for any other naturally occurring polypeptide. Such regions preferably encode 10 (preferably 25, more preferably 50, most preferably 75) or more contiguous amino acids selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242. Preferably, the nucleic acid probe encodes a kinase polypeptide that is a fragment of the protein encoded by an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequences. The nucleic acid probe contains a nucleotide base sequence that will hybridize to a sequence selected from the group consisting of those set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ D) NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121, or the corresponding full-length sequence, or a functional derivative thereof

In preferred embodiments, the nucleic acid probe hybridizes to nucleic acid encoding at least 6, 12, 75, 90, 105, 120, 150, 200, 250, 300 or 350 contiguous amino acids of a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137,.SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or functional derivatives thereof.

Methods for using the probes include detecting the presence or amount of kinase RNA in a sample by contacting the sample with a nucleic acid probe under conditions such that hybridization occurs and detecting the presence or amount of the probe bound to kinase RNA. The nucleic acid duplex formed between the probe and a nucleic acid sequence coding for a kinase polypeptide may be used in the identification of the sequence of the nucleic acid detected (Nelson et al., in Nonisotopic DNA Probe Techniques, Academic Press, San Diego, Kricka, ed., p. 275, 1992, hereby incorporated by reference herein in its entirety, including any drawings, figures, or tables). Kits for performing such methods may be constructed to include a container means having disposed therein a nucleic acid probe.

In a third aspect, the invention describes a recombinant cell or tissue comprising a nucleic acid molecule encoding a kinase polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242. In such cells, the nucleic acid may be under the control of the genomic regulatory elements, or may be under the control of exogenous regulatory elements including an exogenous promoter. By “exogenous” it is meant a promoter that is not normally coupled in vivo transcriptionally to the coding sequence for the kinase polypeptides.

The polypeptide is preferably a fragment of the protein encoded by an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence. By “fragment,” is meant an amino acid sequence present in a kinase polypeptide. Preferably, such a sequence comprises at least 10, 20, 40, 50, 75, 100, 200, or 300 contiguous amino acids a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO;170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or of the corresponding full-length amino acid sequence, or a functional derivative thereof.

In a fourth aspect, the invention features an isolated, enriched, or purified kinase polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242.

By “isolated” in reference to a polypeptide is meant a polymer of amino acids (2 or more amino acids) conjugated to each other, including polypeptides that are isolated from a natural source or that are synthesized. The isolated polypeptides of the present invention are unique in the sense that they are not found in a pure or separated state in nature. Use of the term “isolated” indicates that a naturally occurring sequence has been removed from its normal cellular environment. Thus, the sequence may be in a cell-free solution or placed in a different cellular environment. The term does not imply that the sequence is the only amino acid chain present, but that it is essentially free (about 90-95% pure at least) of non-amino acid material naturally associated with it.

By the use of the term “enriched” in reference to a polypeptide is meant that the specific amino acid sequence constitutes a significantly higher fraction (2-5 fold) of the total amino acid sequences present in the cells or solution of interest than in normal or diseased cells or in the cells from which the sequence was taken. This could be caused by a person by preferential reduction in the amount of other amino acid sequences present, or by a preferential increase in the amount of the specific amino acid sequence of interest, or by a combination of the two. However, it should be noted that enriched does not imply that there are no other amino acid sequences present, just that the relative amount of the sequence of interest has been significantly increased. The term significant here is used to indicate that the level of increase is useful to the person making such an increase, and generally means an increase relative to other amino acid sequences of about at least 2-fold, more preferably at least 5- to 10-fold or even more. The term also does not imply that there is no amino acid sequence from other sources. The other source of amino acid sequences may, for example, comprise amino acid sequence encoded by a yeast or bacterial genome, or a cloning vector such as pUC19. The term is meant to cover only those situations in which man has intervened to increase the proportion of the desired amino acid sequence.

It is also advantageous for some purposes that an amino acid sequence be in purified form. The term “purified” in reference to a polypeptide does not require absolute purity (such as a homogeneous preparation); instead, it represents an indication that the sequence is relatively purer than in the natural environment. Compared to the natural level this level should be at least 2-5 fold greater (e.g., in terms of mg/mL). Purification of at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. The substance is preferably free of contamination at a functionally significant level, for example 90%, 95%, or 99% pure.

In preferred embodiments, the kinase polypeptide is a fragment of the protein encoded by an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequences. Preferably, the kinase polypeptide contains at least 10, 20, 40, 50, 75, 100, 200, or 300 contiguous amino acids a sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or a functional derivative thereof.

In preferred embodiments, the kinase polypeptide comprises an amino acid sequence having (a) an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242; () an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, except that it lacks one or more, but not all, of a domain selected from the group consisting of an N-terminal domain, a catalytic domain, a C-terminal domain, a coiled-coil structure region, a proline-rich region, a spacer region, an insert, and a C-terminal tail; (c) an amino acid sequence of a domain of a polypeptide selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 where the domain is selected from the group consisting of an N-terminal domain, a catalytic domain, a C-terminal domain, a coiled-coil structure region, a proline-rich region, a spacer region, an insert, and a C-terminal tail; or (d) an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ II NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, except that it lacks one or more, but not all, of the domains selected from the group consisting of a C-terminal domain, a catalytic domain, an N-terminal domain, a spacer region, a proline-rich region, a coiled-coil structure region, an insert, and a C-terminal tail. (The domain demarcations of the polypeptides of the invention are indicated in Table 2 by reference to the kinase domain.)

The polypeptide can be isolated from a natural source by methods well-known in the art. The natural source may be mammalian, preferably human, blood, semen, or tissue, and the polypeptide may be synthesized using an automated polypeptide synthesizer. The isolated, enriched, or purified kinase polypeptide is preferably selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242A.

In some embodiments the invention includes a recombinant kinase polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242. By “recombinant kinase polypeptide” is meant a polypeptide produced by recombinant DNA techniques such that it is distinct from a naturally occurring polypeptide either in its location (e.g., present in a different cell or tissue than found in nature), purity or structure. Generally, such a recombinant polypeptide will be present in a cell in an amount different from that normally observed in nature.

In a fifth aspect, the invention features an antibody (e.g., a monoclonal or polyclonal antibody) having specific binding affinity to a kinase polypeptide or a kinase polypeptide domain or fragment where the polypeptide is selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ I) NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242. In preferred embodiments, the antibody binds specifically to domains of kinase polypeptides, that are defined supra.

By “specific binding affinity” is meant that the antibody binds to the target kinase polypeptide with greater affinity than it binds to other polypeptides under specified conditions. Antibodies or antibody fragments are polypeptides that contain regions that can bind other polypeptides. The term “specific binding affinity” describes an antibody that binds to a kinase polypeptide with greater affinity than it binds to other polypeptides under specified conditions.

The term “polyclonal” refers to antibodies that are heterogenous populations of antibody molecules derived from the sera of animals immunized with an antigen or an antigenic functional derivative thereof For the production of polyclonal antibodies, various host animals may be immunized by injection with the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species.

“Monoclonal antibodies” are substantially homogenous populations of antibodies to a particular antigen. They may be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. Monoclonal antibodies may be obtained by methods known to those skilled in the art (Kohler et al., Nature 256:495-497, 1975, and U.S. Pat. No. 4,376,110, both of which are hereby incorporated by reference herein in their entirety including any figures, tables, or drawings).

The term “antibody fragment” refers to a portion of an antibody, often the hyper variable region and portions of the surrounding heavy and light chains, that displays specific binding affinity for a particular molecule. A hyper variable region is a portion of an antibody that physically binds to the polypeptide target.

Antibodies or antibody fragments having specific binding affinity to a kinase polypeptide or domains of a kinase polypeptide of the invention may be used in methods for detecting the presence and/or amount of kinase polypeptide in a sample by probing the sample with the antibody under conditions suitable for kinase-antibody immunocomplex formation and detecting the presence and/or amount of the antibody conjugated to the kinase polypeptide. Diagnostic kits for performing such methods may be constructed to include antibodies or antibody fragments specific for the kinase as well as a conjugate of a binding partner of the antibodies or the antibodies themselves.

An antibody or antibody fragment with specific binding affinity to a kinase polypeptide of the invention can be isolated, enriched, or purified from a prokaryotic or eukaryotic organism. Routine methods known to those skilled in the art enable production of antibodies or antibody fragments, in both prokaryotic and eukaryotic organisms. Purification, enrichment, and isolation of antibodies, which are polypeptide molecules, are described above.

Antibodies having specific binding affinity to a kinase polypeptide of the invention may be used in methods for detecting the presence and/or amount of kinase polypeptide in a sample by contacting the sample with the antibody under conditions such that an immunocomplex forms and detecting the presence and/or amount of the antibody conjugated to the kinase polypeptide. Diagnostic kits for performing such methods may be constructed to include a first container containing the antibody and a second container having a conjugate of a binding partner of the antibody and a label, such as, for example, a radioisotope. The diagnostic kit may also include notification of an FDA approved use and instructions therefor.

In a sixth aspect, the invention features a hybridoma which produces an antibody having specific binding affinity to a kinase polypeptide or a kinase polypeptide domain, where the polypeptide is selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242; and where the domains are defined as above. By “hybridoma” is meant an immortalized cell line that is capable of secreting an antibody, for example an antibody to a kinase of the invention. In preferred embodiments, the antibody to the kinase comprises a sequence of amino acids that is able to specifically bind a kinase polypeptide of the invention.

In a seventh aspect, the invention features a kinase polypeptide binding agent able to bind to a kinase polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242. The binding agent is preferably a purified antibody that recognizes an epitope present on a kinase polypeptide of the invention. Other binding agents include molecules that bind to kinase polypeptides and analogous molecules that bind to a kinase polypeptide. Such binding agents may be identified by using assays that measure kinase binding partner activity, such as those that measure PDGFR activity.

The invention also features a method for screening for human cells containing a kinase polypeptide of the invention or an equivalent sequence. The method involves identifying the novel polypeptide in human cells using techniques that are routine and standard in the art, such as those described herein for identifying the kinases of the invention (e.g., cloning, Southern or Northern blot analysis, in situ hybridization, PCR amplification, etc.).

In an eighth aspect, the invention features methods for identifying a substance that modulates kinase activity comprising the steps of: (a) contacting a kinase polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 with a test substance; (b) measuring the activity of said polypeptide; and (c) determining whether said substance modulates the activity of said polypeptide.

The term “modulates” refers to the ability of a compound to alter the function of a kinase of the invention. A modulator preferably activates or inhibits the activity of a kinase of the invention.

The term “activates” refers to increasing the cellular activity of the kinase. The term inhibit refers to decreasing the cellular activity of the kinase. Kinase activity is preferably the interaction with a natural binding partner.

The term “modulates” also refers to altering the function of kinases of the invention by increasing or decreasing the probability that a complex forms between the kinase and a natural binding partner. A modulator preferably increases the probability that such a complex forms between the kinase and the natural binding partner, more preferably increases or decreases the probability that a complex forms between the kinase and the natural binding partner depending on the concentration of the compound exposed to the kinase, and most preferably decreases the probability that a complex forms between the kinase and the natural binding partner.

The term “complex” refers to an assembly of at least two molecules bound to one another. Signal transduction complexes often contain at least two protein molecules bound to one another. For instance, a protein tyrosine receptor protein kinase, GRB2, SOS, RAF, and RAS assemble to form a signal transduction complex in response to a mitogenic ligand.

The term “natural binding partner” refers to polypeptides, lipids, small molecules, or nucleic acids that bind to kinases in cells. A change in the interaction between a kinase and a natural binding partner can manifest itself as an increased or decreased probability that the interaction forms, or an increased or decreased concentration of kinase/natural binding partner complex.

The term “contacting” as used herein refers to mixing a solution comprising the test compound with a liquid medium bathing the cells of the methods. The solution comprising the compound may also comprise another component, such as dimethyl sulfoxide (DMSO), which facilitates the uptake of the test compound or compounds into the cells of the methods. The solution comprising the test compound may be added to the medium bathing the cells by utilizing a delivery apparatus, such as a pipet-based device or syringe-based device.

In a ninth aspect, the invention features methods for identifying a substance that modulates kinase activity in a cell comprising the steps of: (a) expressing a kinase polypeptide in a cell, wherein said polypeptide is selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242; (b) adding a test substance to said cell; and (c) monitoring a change in cell phenotype or the interaction between said polypeptide and a natural binding partner.

The term “expressing” as used herein refers to the production of kinases of the invention from a nucleic acid vector containing kinase genes within a cell. The nucleic acid vector is transfected into cells using well known techniques in the art as described herein.

In a tenth aspect, the invention provides methods for treating a disease or abnormal condition by administering to a patient in need of such treatment a substance that modulates the activity of a polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242. Preferably, the disease is selected from the group consisting of immune-related diseases and disorders, cardiovascular disease, neurodegenerative disorders, and cancer. Also included are metabolic disorders, such as diabetes mellitus, and reproductive disorders, such as infertility.

Preferably, the disease or disorder is selected from the group consisting of rheumatoid arthritis, artherosclerosis, autoimmune disorders, and organ transplantation. Preferably the disease or disorder is selected from the group consisting of immune-related diseases and disorders, myocardial infarction, cardiomyopathies, stroke, renal failure, and oxidative stress-related neurodegenerative disorders. Most preferably, the immune-related diseases and disorders are selected from the group consisting of rheumatoid arthritis, chronic inflammatory bowel disease, chronic inflammatory pelvic disease, multiple sclerosis, asthma, osteoarthritis, psoriasis, atherosclerosis, rhinitis, autoimmunity, and organ transplantation.

Substances useful for treatment of disorders or diseases preferably show positive results in one or more in vitro assays for an activity corresponding to treatment of the disease or disorder in question Substances that modulate the activity of the polypeptides preferably include, but are not limited to, antisense oligonucleotides and inhibitors of protein kinases.

The term “preventing” refers to decreasing the probability that an organism contracts or develops an abnormal condition.

The term “treating” refers to having a therapeutic effect and at least partially alleviating or abrogating an abnormal condition in the organism.

The term “therapeutic effect” refers to the inhibition or activation factors causing or contributing to the abnormal condition. A therapeutic effect relieves to some extent one or more of the symptoms of the abnormal condition. In reference to the treatment of abnormal conditions, a therapeutic effect can refer to one or more of the following: (a) an increase in the proliferation, growth, and/or differentiation of cells; (b) inhibition (i.e., slowing or stopping) of cell death; (c) inhibition of degeneration; (d) relieving to some extent one or more of the symptoms associated with the abnormal condition; and (e) enhancing the function of the affected population of cells. Compounds demonstrating efficacy against abnormal conditions can be identified as described herein.

The term “abnormal condition” refers to a function in the cells or tissues of an organism that deviates from their normal functions in that organism. An abnormal condition can relate to cell proliferation, cell differentiation or cell survival. An abnormal condition may also include irregularities in cell cycle progression, i.e., irregularities in normal cell cycle progression through mitosis and meiosis.

Abnormal cell proliferative conditions include cancers such as fibrotic and mesangial disorders, abnormal angiogenesis and vasculogenesis, wound healing, psoriasis, diabetes mellitus, and inflammation.

Abnormal differentiation conditions include, but are not limited to neurodegenerative disorders, slow wound healing rates, and slow tissue grafting healing rates.

Abnormal cell survival conditions relate to conditions in which programmed cell death (apoptosis) pathways are activated or abrogated. A number of protein kinases are associated with the apoptosis pathways. Aberrations in the function of any one of the protein kinases could lead to cell immortality or premature cell death.

The tern “aberration”, in conjunction with the function of a kinase in a signal transduction process, refers to a kinase that is over- or under-expressed in an organism, mutated such that its catalytic activity is lower or higher than wild-type protein kinase activity, mutated such that it can no longer interact with a natural binding partner, is no longer modified by another protein kinase or protein phosphatase, or no longer interacts with a natural binding partner.

The term “administering” relates to a method of incorporating a compound into cells or tissues of an organism. The abnormal condition can be prevented or treated when the cells or tissues of the organism exist within the organism or outside of the organism. Cells existing outside the organism can be maintained or grown in cell culture dishes. For cells harbored within the organism, many techniques exist in the art to administer compounds, including (but not limited to) oral parenteral, dermal, injection, and aerosol applications. For cells outside of the organism, multiple techniques exist in the art to administer the compounds, including (but not limited to) cell microinjection techniques, transformation techniques, and carrier techniques.

The abnormal condition can also be prevented or treated by administering a compound to a group of cells having an aberration in a signal transduction pathway to an organism. The effect of administering a compound on organism function can then-be monitored. The organism is preferably a mouse, rat, rabbit, guinea pig, or goat, more preferably a monkey or ape, and most preferably a human.

In an eleventh aspect, the invention features methods for detection the expression of a polypeptide in a sample as a diagnostic tool for diseases or disorders, wherein the method comprises the steps of: (a) contacting the sample with a nucleic acid probe which hybridizes under hybridization assay conditions to a nucleic acid target region of a kinase polypeptide selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, said probe comprising the nucleic acid sequence encoding the polypeptide, fragments thereof, and the complements of the sequences and fragments; and (b) detecting the presence or amount of the probe:target region hybrid as an indication of the disease.

In preferred embodiments of the invention, the disease or disorder is selected from the group consisting of rheumatoid arthritis, artherosclerosis, autoimmune disorders, organ transplantation, myocardial infarction, cardiomyopathies, stroke, renal failure, oxidative stress-related neurodegenerative disorders, metabolic disorder including diabetes, reproductive disorders including infertility, and cancer.

The kinase “target region” is a nucleotide base sequence selected from the group consisting of those set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:l 1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:l09, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121, or the corresponding full-length sequences, a functional derivative thereof, or a fragment thereof to which the nucleic acid probe will specifically hybridize. Specific hybridization indicates that in the presence of other nucleic acids the probe only hybridizes detectably with the kinase of the invention's target region. Putative target regions can be identified by methods well known in the art consisting of alignment and comparison of the most closely related sequences in the database.

In preferred embodiments the nucleic acid probe hybridizes to a kinase target region encoding at least 6, 12, 75, 90, 105, 120, 150, 200, 250, 300 or 350 contiguous amino acids of the sequence set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or the corresponding full-length amino acid sequence, or a functional derivative thereof. Hybridization conditions should be such that hybridization occurs only with the kinase genes in the presence of other nucleic acid molecules. Under stringent hybridization conditions only highly complementary nucleic acid sequences hybridize. Preferably, such conditions prevent hybridization of nucleic acids having more than 1 or 2 mismatches out of 20 contiguous nucleotides. Such conditions are defined supra.

Hybridization conditions should be such that hybridization occurs only with the genes in the presence of other nucleic acid molecules. Under stringent hybridization conditions only highly complementary nucleic acid sequences hybridize. Preferably, such conditions prevent hybridization of nucleic acids having 1 or 2 mismatches out of 20 contiguous nucleotides. Such conditions are defined supra.

The diseases for which detection of kinase genes in a sample could be diagnostic include diseases in which kinase nucleic acid (DNA and/or RNA) is amplified in comparison to normal cells. By “amplification” is meant increased numbers of kinase DNA or RNA in a cell compared with normal cells. In normal cells, kinases are typically found as single copy genes. In selected diseases, the chromosomal location of the kinase genes may be amplified, resulting in multiple copies of the gene, or amplification. Gene amplification can lead to amplification of kinase RNA, or kinase RNA can be amplified in the absence of kinase DNA amplification.

“Amplification” as it refers to RNA can be the detectable presence of kinase RNA in cells, since in some normal cells there is no basal expression of kinase RNA. In other normal cells, a basal level of expression of kinase exists, therefore in these cases amplification is the detection of at least 1-2-fold, and preferably more, kinase RNA, compared to the basal level.

The diseases that could be diagnosed by detection of kinase nucleic acid in a sample preferably include cancers. The test samples suitable for nucleic acid probing methods of the present invention include, for example, cells or nucleic acid extracts of cells, or biological fluids. The samples used in the above-described methods will vary based on the assay format, the detection method and the nature of the tissues, cells or extracts to be assayed. Methods for preparing nucleic acid extracts of cells are well known in the art and can be readily adapted in order to obtain a sample that is compatible with the method utilized.

Another aspect of the invention involves a method of agonizing (stimulating) or antagonizing a target of the invention and a natural binding partner associated activity in a mammal comprising administering to said mammal an agonist or antagonist to one of the above disclosed polypeptides in an amount sufficient to effect said agonism or antagonism. A method of treating diseases in a mammal with an agonist or antagonist of the protein of the present invention activity comprising administering the agonist or antagonist to a mammal in an amount sufficient to agonize or antagonize associated functions is also encompassed in the present application.

In an effort to discover novel treatments for diseases, biomedical researchers and chemists have designed, synthesized, and tested molecules that inhibit the function of protein polypeptides. Some small organic molecules form a class of compounds that modulate the function of protein polypeptides. Examples of molecules that have been reported to inhibit the function of protein kinases include, but are not limited to, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642, published Nov. 26, 1992 by Maguire et al.), vinylene-azaindole derivatives (PCT WO 94/14808, published Jul. 7, 1994 by Ballinari et al.), 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992), styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP application No. 0,566,266 A1), seleoindoles and selenides (PCT WO 94/03427, published Feb. 17, 1994 by Denny et al.), tricyclic polyhydroxylic compounds (PCT WO 92/21660, published Dec. 10, 1992 by Dow), and benzylphosphonic acid compounds (PCT WO 91/15495, published Oct. 17, 1991 by Dow et al, all of which are incorporated by reference herein, including any drawings.

Compounds that can traverse cell membranes and are resistant to acid hydrolysis are potentially advantageous as therapeutics as they can become highly bioavailable after being administered orally to patients. However, many of these protein inhibitors only weakly inhibit function. In addition, many inhibit a variety of protein kinases and will therefore cause multiple side-effects as therapeutics for diseases.

Some indolinone compounds, however, form classes of acid resistant and membrane permeable organic molecules. WO 96/22976 (published Aug. 1, 1996 by Ballinari et al.) describes hydrosoluble indolinone compounds that harbor tetralin, naphthalene, quinoline, and indole substituents fused to the oxindole ring. These bicyclic substituents are in turn substituted with polar groups including hydroxylated alkyl, phosphate, and ether substituents. U.S. patent application Ser. No. 08/702,232, filed Aug. 23, 1996, entitled “Indolinone Combinatorial Libraries and Related Products and Methods for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 221/187) and Ser. No. 08/485,323, filed Jun. 7,1995, entitled “Benzylidene-Z-Indoline Compounds for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 223/298) and International Patent Publication WO 96/22976, published Aug. 1, 1996 by Ballinari et al., all of which are incorporated herein by reference in their entirety, including any drawings, describe indolinone chemical libraries of indolinone compounds harboring other bicyclic moieties as well as monocyclic moieties fused to the oxindole ring. Applications Ser. No. 08/702,232, filed Aug. 23, 1996, entitled “Indolinone Combinatorial Libraries and Related Products and Methods for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 221/187), Ser. No. 08/485,323, filed Jun. 7, 1995, entitled “Benzylidene-Z-Indoline Compounds for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 223/298), and WO 96/22976, published Aug. 1, 1996 by Ballinari et al. teach methods of indolinone synthesis, methods of testing the biological activity of indolinone compounds in cells, and inhibition patterns of indolinone derivatives, both of which are incorporated by reference herein, including any drawings.

Other examples of substances capable of modulating kinase activity include, but are not limited to, tyrphostins, quinazolines, quinoxolines, and quinolines. The quinazolines, tyrphostins, quinolines, and quinoxolines referred to above include well known compounds such as those described in the literature. For example, representative publications describing quinazolines include Barker et al., EPO Publication No. 0 520 722 Al; Jones et al., U.S. Pat. No. 4,447,608; Kabbe et al., U.S. Pat. No. 4,757,072; Kaul and Vougioukas, U.S. Pat. No. 5,316,553; Kreighbaum and Comer, U.S. Pat. No. 4,343,940; Pegg and Wardleworth, EPO Publication No. 0 562 734 Al; Barker et al., Proc. of Am. Assoc. for Cancer Research 32:327 (1991); Bertino, J. R., Cancer Research 3:293-304 (1979); Bertino, J. R, Cancer Research 9(2 part 1):293-304 (1979); Curtin et al., Br. J. Cancer 53:361-368 (1986); Fernandes et al., Cancer Research 43:1117-1123 (1983); Ferris et al. J. Org. Chem. 44(2):173-178; Fry et al., Science 265:1093-1095 (1994); Jackman et al., Cancer Research 51:5579-5586 (1981); Jones et al. J. Med. Chem. 29(6):1114-1118; Lee and Skibo, Biochemistry 26(23):7355-7362 (1987); Lemus et al., J. Org. Chem. 54:3511-3518 (1989); Ley and Seng, Synthesis 1975:415-522 (1975); Maxwell et al., Magnetic Resonance in Medicine 17:189-196 (1991); Mini et al., Cancer Research 45:325-330 (1985); Phillips and Castle, J. Heterocyclic Chem. 17(19):1489-1596 (1980); Reece et al., Cancer Research 47(11):2996-2999 (1977); Sculier et al., Cancer Immunol. and Immunother. 23:A65 (1986); Sikora et al., Cancer Letters 23:289-295 (1984); and Sikora et al., Analytical Biochem. 172:344-355 (1988), all of which are incorporated herein by reference in their entirety, including any drawings.

Quinoxaline is described in Kaul and Vougioukas, U.S. Pat. No. 5,316,553, incorporated herein by reference in its entirety, including any drawings.

Quinolines are described in Dolle et al., J. Med. Chem. 37:2627-2629 (1994); MaGuire, J. Med. Chem. 37:2129-2131 (1994); Burke et al., J. Med. Chem. 36:425-432 (1993); and Burke et al. BioOrganic Med. Chem. Letters 2:1771-1774 (1992), all of which are incorporated by reference in their entirety, including any drawings.

Tyrphostins are described in Allen et al., Clin. Exp. Immunol. 91:141-156 (1993); Anafi et al., Blood 82:12:3524-3529 (1993); Baker et al., J. Cell Sci. 102:543-555 (1992); Bilderet al., Amer. Physiol. Soc. pp. 6363-6143:C721-C730 (1991); Brunton et al., Proceedings of Amer. Assoc. Cancer Rsch. 33:558 (1992); Bryckaert et al., Experimental Cell Research 199:255-261 (1992); Dong et al., J. Leukocyte Biology 53:53-60 (1993); Dong et al., J. Immunol. 151(5):2717-2724 (1993); Gazit et al., J. Med. Chem. 32:2344-2352 (1989); Gazit et al., “J. Med. Chem. 36:3556-3564 (1993); Kaur et al., Anti-Cancer Drugs 5:213-222 (1994); Kaur et al., King et al., Biochem. J. 275:413418 (1991); Kuo et al., Cancer Letters 74:197-202 (1993); Levitzki, A., The FASEB J. 6:3275-3282 (1992); Lyall et al., J. Biol. Chem. 264:14503-14509 (1989); Peterson et al., The Prostate 22:335-345 (1993); Pillemer et al., Int. J. Cancer 50:80-85 (1992); Posner et al., Molecular Pharmacology 45:673-683 (1993); Rendu et al., Biol. Pharmacology 44(5):881-888 (1992); Sauro and Thomas, Life Sciences 53:371-376 (1993); Sauro and Thomas, J. Pharm. and Experimental Therapeutics 267(3):119-1125 (1993); Wolbring et al., J. Biol. Chem. 269(36):22470-22472 (1994); and Yoneda et al., Cancer Research 51:4430-4435 (1991); all of which are incorporated herein by reference in their entirety, including any drawings.

Other compounds that could be used as modulators include oxindolinones such as those described in U.S. patent application Ser. No. 08/702,232 filed Aug. 23, 1996, incorporated herein by reference in its entirety, including any drawings.

Methods of Treating a Disease (Enablement—i.e., Dosing)

Methods of determining the dosages of compounds to be administered to a patient and modes of administering compounds to an organism are disclosed in U.S. application Ser. No. 08/702,282, filed Aug. 23, 1996 and International patent publication number WO 96/22976, published Aug. 1, 1996, both of which are incorporated herein by reference in their entirety, including any drawings, figures or tables. Those skilled in the art will appreciate that such descriptions are applicable to the present invention and can be easily adapted to it.

The proper dosage depends on various factors such as the type of disease being treated, the particular composition being used and the size and physiological condition of the patient. Therapeutically effective doses for the compounds described herein can be estimated initially from cell culture and animal models. For example, a dose can be formulated in animal models to achieve a circulating concentration range that initially takes into account the IC₅₀as determined in cell culture assays. The animal model data can be used to more accurately determine useful doses in humans.

Plasma half-life and biodistribution of the drug and metabolites in the plasma, tumors and major organs can also be determined to facilitate the selection of drugs most appropriate to inhibit a disorder. Such measurements can be carried out. For example, HPLC analysis can be performed on the plasma of animals treated with the drug and the location of radiolabeled compounds can be deter-mined using detection methods such as X-ray, CAT scan and MRI. Compounds that show potent inhibitory activity in the screening assays, but have poor pharmacokinetic characteristics, can be optimized by altering the chemical structure and retesting. In this regard, compounds displaying good pharmacokinetic characteristics can be used as a model.

Toxicity studies can also be carried out by measuring the blood cell composition. For example, toxicity studies can be carried out in a suitable animal model as follows: 1) the compound is administered to mice (an untreated control mouse should also be used); 2) blood samples are periodically obtained via the tail vein from one mouse in each treatment group; and 3) the samples are analyzed for red and white blood cell counts, blood cell composition and the percent of lymphocytes versus polymorphonuclear cells. A comparison of results for each dosing regime with the controls indicates if toxicity is present.

At the termination of each toxicity study, further studies can be carried out by sacrificing the animals (preferably, in accordance with the American Veterinary Medical Association guidelines Report of the American Veterinary Medical Assoc. Panel on Euthanasia, Journal of American Veterinary Medical Assoc., 202:229-249, 1993). Representative animals from each treatment group can then be examined by gross necropsy for immediate evidence of metastasis, unusual illness or toxicity. Gross abnormalities in tissue are noted and tissues are examined histologically. Compounds causing a reduction in body weight or blood components are less preferred, as are compounds having an adverse effect on major organs. In general, the greater the adverse effect the less preferred the compound.

For the treatment of cancers the expected daily dose of a hydrophobic pharmaceutical agent is between 1 to 500 mg/day, preferably 1 to 250 mg/day, and most preferably 1 to 50 mg/day. Drugs can be delivered less frequently provided plasma levels of the active moiety are sufficient to maintain therapeutic effectiveness.

Plasma levels should reflect the potency of the drug. Generally, the more potent the compound the lower the plasma levels necessary to achieve efficacy.

In a final aspect, the invention features a method for detection of a kinase polypeptide in a sample as a diagnostic tool for a disease or disorder, wherein the method comprises: (a) comparing a nucleic acid target region encoding the kinase polypeptide in a sample, where the kinase polypeptide is selected from the group consisting of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or one or more fragments thereof, with a control nucleic acid target region encoding the kinase polypeptide, or one or more fragments thereof; and (b) detecting differences in sequence or amount between the target region and the control target region, as an indication of the disease or disorder. Preferably, the disease or disorder is selected from the group consisting of immune-related diseases and disorders, organ transplantation, myocardial infarction, cardiovascular disease, stroke, renal failure, oxidative stress-related neurodegenerative disorders, and cancer. Immune-related diseases and disorders include, but are not limited to, those discussed previously.

The term “comparing” as used herein refers to identifying discrepancies between the nucleic acid target region isolated from a sample, and the control nucleic acid target region. The discrepancies can be in the nucleotide sequences, e.g. insertions, deletions, or point mutations, or in the amount of a given nucleotide sequence. Methods to determine these discrepancies in sequences are well-known to one of ordinary skill in the art. The “control” nucleic acid target region refers to the sequence or amount of the sequence found in normal cells, e.g. cells that are not diseased as discussed previously.

The term also includes anti-sense molecules drawn thereto.

The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. For example, in some instances the nucleotide sequence of particular kinase polypeptides may not be part of a preferred embodiment.

The summary of the invention described above is not limiting and other features and advantages of the invention will be apparent from the following detailed description of the invention, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A to 1BB shows the amino acid sequences of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242.

FIGS. 2A to 2MMMM shows the nucleic acid sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in part to kinase polypeptides, nucleic acids encoding such polypeptides, cells containing such nucleic acids, antibodies to such polypeptides, assays utilizing such polypeptides, and methods relating to all of the foregoing. The present invention is based upon the isolation and characterization of new kinase polypeptides. The polypeptides and nucleic acids may be produced using well-known and standard synthesis techniques when given the sequences presented herein.

I. The Nucleic Acids of the Invention

Included within the scope of this invention are the functional equivalents of the herein-described isolated nucleic acid molecules. The degeneracy of the genetic code permits substitution of certain codons by other codons that specify the same amino acid and hence would give rise to the same protein. The nucleic acid sequence can vary substantially since, with the exception of methionine and tryptophan, the known amino acids can be coded for by more than one codon. Thus, portions or all of the kinase genes of the invention could be synthesized to give a nucleic acid sequence significantly different from one selected from the group consisting of those set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121. The encoded amino acid sequence thereof would, however, be preserved.

In addition, the nucleic acid sequence may comprise a nucleotide sequence which results from the addition, deletion or substitution of at least one nucleotide to the 5′-end and/or the 3′-end of the nucleic acid sequence shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ D NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:1 19, SEQ ID NO:120, and SEQ ID NO:121, or a derivative thereof. Any nucleotide or polynucleotide may be used in this regard, provided that its addition, deletion or substitution does not alter the amino acid sequence of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, that is encoded by the nucleotide sequence. For example, the present invention is intended to include any nucleic acid sequence resulting from the addition of ATG as an initiation codon at the 5′-end of the inventive nucleic acid sequence or its derivative, or from the addition of TTA, TAG or TGA as a termination codon at the 3′-end of the inventive nucleotide sequence or its derivative. Moreover, the nucleic acid molecule of the present invention may, as necessary, have restriction endonuclease recognition sites added to its 5′-end and/or 3′-end.

Such functional alterations of a given nucleic acid sequence afford an opportunity to promote secretion and/or processing of heterologous proteins encoded by foreign nucleic acid sequences fused thereto, for example. All variations of the nucleotide sequence of the kinase genes of the invention and fragments thereof permitted by the genetic code are, therefore, included in this invention.

Further, it is possible to delete codons or to substitute one or more codons with codons other than degenerate codons to produce a structurally modified polypeptide, but one which has substantially the same utility or activity as the polypeptide produced by the unmodified nucleic acid molecule. As recognized in the art, the two polypeptides are functionally equivalent, as are the two nucleic acid molecules that give rise to their production, even though the differences between the nucleic acid molecules are not related to the degeneracy of the genetic code. This is discussed further in the “Functional Derivatives” section, herein.

Finally, many of the nucleic acid molecules of the invention are provided as a partial sequence only (FIG. 2A through 2QQ). However, it is standard for one of ordinary skill in the art to obtain a full-length sequence when provided with a partial sequence. Similarly, when provided with a partial or full-length sequence it is standard for one of ordinary skill in the art to obtain nucleic acid sequence coding for homologous proteins. Therefore, these nucleic acid molecules are also part of the invention.

The characteristics of the protein kinase nucleic acid sequences of the invention are provided in Table 1. The protein kinases fall into 10 known groups: AGC, CAMK, CKI, CMGC, dsPK, EIFK, LIMK, MLK, STE and TK. In addition, there are a significant number of protein kinases that do not belong to any of the known groups, and therefore presumably define new protein kinase groups.

Additional characteristics may be found, inter alia, in the tables, namely Table 1, Table 2, Table 3 and Table 4, shown below.

II. Nucleic Acid Probes. Methods. and Kits for Detection of Protein Kinases

A nucleic acid probe of the present invention may be used to probe an appropriate chromosomal or cDNA library by usual hybridization methods to obtain other nucleic acid molecules of the present invention. A chromosomal DNA or cDNA library may be prepared from appropriate cells according to recognized methods in the art (cf. “Molecular Cloning: A Laboratory Manual”, second edition, Cold Spring Harbor Laboratory, Sambrook, Fritsch, & Maniatis, eds., 1989).

In the alternative, chemical synthesis can be carried out in order to obtain nucleic acid probes having nucleotide sequences that correspond to N-terminal, kinase or C-terminal portions, for example, of the amino acid sequence of the polypeptide of interest. The synthesized nucleic acid probes may be used as primers in a polymerase chain reaction (PCR) carried out in accordance with recognized PCR techniques, essentially according to PCR Protocols, “A Guide to Methods and Applications”, Academic Press, Michael, et al., eds., 1990, utilizing the appropriate chromosomal or cDNA library to obtain the fragment of the present invention.

One skilled in the art can readily design such probes based on the sequence disclosed herein using methods of computer alignment and sequence analysis known in the art (“Molecular Cloning: A Laboratory Manual”, 1989, supra). The hybridization probes of the present invention can be labeled by standard labeling techniques such as with a radiolabel, enzyme label, fluorescent label, biotin-avidin label, chemiluminescence, and the like. After hybridization, the probes may be visualized using known methods.

The nucleic acid probes of the present invention include RNA, as well as DNA probes, such probes being generated using techniques known in the art. The nucleic acid probe may be immobilized on a solid support. Examples of such solid supports include, but are not limited to, plastics such as polycarbonate, complex carbohydrates such as agarose and sepharose, and acrylic resins, such as polyacrylamide and latex beads. Techniques for coupling nucleic acid probes to such solid supports are well known in the art.

The test samples suitable for nucleic acid probing methods of the present invention include, for example, cells or nucleic acid extracts of cells, or biological fluids. The samples used in the above-described methods will vary based on the assay format, the detection method and the nature of the tissues, cells or extracts to be assayed. Methods for preparing nucleic acid extracts of cells are well known in the art and can be readily adapted in order to obtain a sample that is compatible with the method utilized.

One method of detecting the presence of nucleic acids of the invention in a sample comprises (a) contacting said sample with the above-described nucleic acid probe under conditions such that hybridization occurs, and (b) detecting the presence of said probe bound to said nucleic acid molecule. One skilled in the art would select the nucleic acid probe according to techniques known in the art as described above. Samples to be tested include but should not be limited to RNA samples of human tissue.

A kit for detecting the presence of nucleic acids of the invention in a sample comprises at least one container means having disposed therein the above-described nucleic acid probe. The kit may further comprise other containers comprising one or more of the following: wash reagents and reagents capable of detecting the presence of bound nucleic acid probe. Examples of detection reagents include, but are not limited to radiolabelled probes, enzymatic labeled probes (horseradish peroxidase, alkaline phosphatase), and affinity labeled probes (biotin, avidin, or steptavidin).

In detail, a compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allow the efficient transfer of reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the probe or primers used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, and the like), and containers which contain the reagents used to detect the hybridized probe, bound antibody, amplified product, or the like. One skilled in the art will readily recognize that the nucleic acid probes described in the present invention can readily be incorporated into one of the established kit formats that are well known in the art.

III. DNA Constructs Comprising a Protein Kinase Nucleic Acid Molecule and Cells Containing These Constructs.

The present invention also relates to a recombinant DNA molecule comprising, 5′ to 3′, a promoter effective to initiate transcription in a host cell and the above-described nucleic acid molecules. In addition, the present invention relates to a recombinant DNA molecule comprising a vector and an above-described nucleic acid molecule. The present invention also relates to a nucleic acid molecule comprising a transcriptional region functional in a cell, a sequence complementary to an RNA sequence encoding an amino acid sequence corresponding to the above-described polypeptide, and a transcriptional termination region functional in said cell. The above-described molecules may be isolated and/or purified DNA molecules.

The present invention also relates to a cell or organism that contains an above-described nucleic acid molecule and thereby is capable of expressing a polypeptide. The polypeptide may be purified from cells that have been altered to express the polypeptide. A cell is said to be “altered to express a desired polypeptide” when the cell, through genetic manipulation, is made to produce a protein which it normally does not produce or which the cell normally produces at lower levels. One skilled in the art can readily adapt procedures for introducing and expressing either genomic, cDNA, or synthetic sequences into either eukaryotic or prokaryotic cells.

A nucleic acid molecule, such as DNA, is said to be “capable of expressing” a polypeptide if it contains nucleotide sequences which contain transcriptional and translational regulatory information and such sequences are “operably linked” to nucleotide sequences which encode the polypeptide. An operable linkage is a linkage in which the regulatory DNA sequences and the DNA sequence sought to be expressed are connected in such a way as to permit gene sequence expression. The precise nature of the regulatory regions needed for gene sequence expression may vary from organism to organism, but shall in general include a promoter region which, in prokaryotes, contains both the promoter (which directs the initiation of RNA transcription) as well as the DNA sequences which, when transcribed into RNA, will signal synthesis initiation. Such regions will normally include those 5′-non-coding sequences involved with initiation of transcription and translation, such as the TATA box, capping sequence, CAAT sequence, and the like.

If desired, the non-coding region 3′ to the sequence encoding a kinase of the invention may be obtained by the above-described methods. This region may be retained for its transcriptional termination regulatory sequences, such as termination and polyadenylation. Thus, by retaining the 3′-region naturally contiguous to the DNA sequence encoding a kinase of the invention, the transcriptional termination signals may be provided. Where the transcriptional termination signals are not satisfactorily functional in the expression host cell, then a 3′ region functional in the host cell may be substituted.

Two DNA sequences (such as a promoter region sequence and a sequence encoding a kinase of the invention) are said to be operably linked if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter region sequence to direct the transcription of a gene sequence encoding a kinase of the invention, or (3) interfere with the ability of the gene sequence of a kinase of the invention to be transcribed by the promoter region sequence. Thus, a promoter region would be operably linked to a DNA sequence if the promoter were capable of effecting transcription of that DNA sequence. Thus, to express a gene encoding a kinase of the invention, transcriptional and translational signals recognized by an appropriate host are necessary.

The present invention encompasses the expression of a gene encoding a kinase of the invention (or a functional derivative thereof) in either prokaryotic or eukaryotic cells. Prokaryotic hosts are, generally, very efficient and convenient for the production of recombinant proteins and are, therefore, one type of preferred expression system for kinases of the invention. Prokaryotes most frequently are represented by various strains of E. coli. However, other microbial strains may also be used, including other bacterial strains.

In prokaryotic systems, plasmid vectors that contain replication sites and control sequences derived from a species compatible with the host may be used. Examples of suitable plasmid vectors may include pBR322, pUC118, pUC 119 and the like; suitable phage or bacteriophage vectors may include γgt10, γgt11 and the like; and suitable virus vectors may include pMAM-neo, pKRC and the like. Preferably, the selected vector of the present invention has the capacity to replicate in the selected host cell.

Recognized prokaryotic hosts include bacteria such as E. coli, Bacillus, Streptomyces, Pseudomonas, Salmonella, Serratia, and the like. However, under such conditions, the polypeptide will not be glycosylated. The prokaryotic host must be compatible with the replicon and control sequences in the expression plasmid.

To express a kinase of the invention (or a functional derivative thereof) in a prokaryotic cell, it is necessary to operably link the sequence encoding the kinase of the invention to a functional prokaryotic promoter. Such promoters may be either constitutive or, more preferably, regulatable (ie., inducible or derepressible). Examples of constitutive promoters include the int promoter of bacteriophage λ, the bla promoter of the β-lactamase gene sequence of pBR322, and the cat promoter of the chloramphenicol acetyl transferase gene sequence of pPR325, and the like. Examples of inducible prokaryotic promoters include the major right and left promoters of bacteriophage λ (P_Land P_R), the trp, recA, λacZ, λacI, and gal promoters of E. coli, the λ-amylase (Ulmanen et al., J. Bacteriol. 162:176-182, 1985) and the ç-28-specific promoters of B. subtilis (Gilman et al., Gene Sequence 32:11-20, 1984), the promoters of the bacteriophages of Bacillus (Gryczan, In: The Molecular Biology of the Bacilli, Academic Press, Inc., NY, 1982), and Streptomyces promoters (Ward et al., Mol. Gen. Genet. 203:468-478, 1986). Prokaryotic promoters are reviewed by Glick (Ind. Microbiot. 1:277-282, 1987), Cenatiempo (Biochimie 68:505-516, 1986), and Gottesman (Ann. Rev. Genet. 18:415-442, 1984).

Proper expression in a prokaryotic cell also requires the presence of a ribosome-binding site upstream of the gene sequence-encoding sequence. Such ribosome-binding sites are disclosed, for example, by Gold et al. (Ann. Rev. Microbiol. 35:365-404, 1981). The selection of control sequences, expression vectors, transformation methods, and the like, are dependent on the type of host cell used to express the gene. As used herein, “cell”, “cell line”, and “cell culture” may be used interchangeably and all such designations include progeny. Thus, the words “transformants” or “transformed cells” include the primary subject cell and cultures derived therefrom, without regard to the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. However, as defined, mutant progeny have the same functionality as that of the originally transformed cell.

Host cells which may be used in the expression systems of the present invention are not strictly limited, provided that they are suitable for use in the expression of the kinase polypeptide of interest. Suitable hosts may often include eukaryotic cells. Preferred eukaryotic hosts include, for example, yeast, fungi, insect cells, mammalian cells either in vivo, or in tissue culture. Mammalian cells which may be useful as hosts include HeLa cells, cells of fibroblast origin such as VERO or CHO-K1, or cells of lymphoid origin and their derivatives. Preferred mammalian host cells include SP2/0 and J558L, as well as neuroblastoma cell lines such as IMR 332, which may provide better capacities for correct post-translational processing.

In addition, plant cells are also available as hosts, and control sequences compatible with plant cells are available, such as the cauliflower mosaic virus 35S and 19S, and nopaline synthase promoter and polyadenylation signal sequences. Another preferred host is an insect cell, for example the Drosophila larvae. Using insect cells as hosts, the Drosophila alcohol dehydrogenase promoter can be used (Rubin, Science 240:1453-1459, 1988). Alternatively, baculovirus vectors can be engineered to express large amounts of kinases of the invention in insect cells (Jasny, Science 238:1653, 1987; Miller et al., In: Genetic Engineering, Vol. 8, Plenum, Setlow et al., eds., pp. 277-297, 1986).

Any of a series of yeast expression systems can be utilized which incorporate promoter and termination elements from the actively expressed sequences coding for glycolytic enzymes that are produced in large quantities when yeast are grown in mediums rich in glucose. Known glycolytic gene sequences can also provide very efficient transcriptional control signals. Yeast provides substantial advantages in that it can also carry out post-translational modifications. A number of recombinant DNA strategies exist utilizing strong promoter sequences and high copy number plasmids which can be utilized for production of the desired proteins in yeast. Yeast recognizes leader sequences on cloned mammalian genes and secretes peptides bearing leader sequences (i.e., pre-peptides). Several possible vector systems are available for the expression of kinases of the invention in a mammalian host.

A wide variety of transcriptional and translational regulatory sequences may be employed, depending upon the nature of the host. The transcriptional and translational regulatory signals may be derived from viral sources, such as adenovirus, bovine papilloma virus, cytomegalovirus, simian virus, or the like, where the regulatory signals are associated with a particular gene sequence which has a high level of expression. Alternatively, promoters from mammalian expression products, such as actin, collagen, myosin, and the like, may be employed. Transcriptional initiation regulatory signals may be selected which allow for repression or activation, so that expression of the gene sequences can be modulated. Of interest are regulatory signals which are temperature-sensitive so that by varying the temperature, expression can be repressed or initiated, or are subject to chemical (such as metabolite) regulation.

Expression of kinases of the invention in eukaryotic hosts requires the use of eukaryotic regulatory regions. Such regions will, in general, include a promoter region sufficient to direct the initiation of RNA synthesis. Preferred eukaryotic promoters include, for example, the promoter of the mouse metallothionein I gene sequence (Hamer et al., J. Mol. Appl. Gen. 1:273-288, 1982); the TK promoter of Herpes virus (McKnight, Cell 31:355-365, 1982); the SV40 early promoter (Benoist et al., Nature (London) 290:304-31, 1981); and the yeast gal4 gene sequence promoter (Johnston et al., Proc. Natl. Acad. Sci. (USA) 79:6971-6975, 1982; Silver et al., Proc. Natl. Acad. Sci. (USA) 81:5951-5955, 1984).

Translation of eukaryotic mRNA is initiated at the codon that encodes the first methionine. For this reason, it is preferable to ensure that the linkage between a eukaryotic promoter and a DNA sequence which encodes a kinase of the invention (or a functional derivative thereof) does not contain any intervening codons which are capable of encoding a methionine (i.e., AUG). The presence of such codons results either in the formation of a fusion protein (if the AUG codon is in the same reading frame as the kinase of the invention coding sequence) or a frame-shift mutation (if the AUG codon is not in the same reading frame as the kinase of the invention coding sequence).

A nucleic acid molecule encoding a kinase of the invention and an operably linked promoter may be introduced into a recipient prokaryotic or eukaryotic cell either as a nonreplicating DNA or RNA molecule, which may either be a linear molecule or, more preferably, a closed covalent circular molecule. Since such molecules are incapable of autonomous replication, the expression of the gene may occur through the transient expression of the introduced sequence. Alternatively, permanent expression may occur through the integration of the introduced DNA sequence into the host chromosome.

A vector may be employed which is capable of integrating the desired gene sequences into the host cell chromosome. Cells which have stably integrated the introduced DNA into their chromosomes can be selected by also introducing one or more markers which allow for selection of host cells which contain the expression vector. The marker may provide for prototrophy to an auxotrophic host, biocide resistance, e.g., antibiotics, or heavy metals, such as copper, or the like. The selectable marker gene sequence can either be directly linked to the DNA gene sequences to be expressed, or introduced into the same cell by co-transfection. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include splice signals, as well as transcription promoters, enhancers, and termination signals. cDNA expression vectors incorporating such elements include those described by Okayama (Mol. Cell. Biol. 3:280-, 1983).

The introduced nucleic acid molecule can be incorporated into a plasmid or viral vector capable of autonomous replication in the recipient host. Any of a wide variety of vectors may be employed for this purpose. Factors of importance in selecting a particular plasmid or viral vector include: the ease with which recipient cells that contain the vector may be recognized and selected from those recipient cells which do not contain the vector, the number of copies of the vector which are desired in a particular host; and whether it is desirable to be able to “shuttle” the vector between host cells of different species.

Preferred prokaryotic vectors include plasmids such as those capable of replication in E. coli (such as, for example, pBR322, ColEl, pSC101, pACYC 184, πVX; “Molecular Cloning: A Laboratory Manual”, 1989, supra). Bacillus plasmids include pC194, pC221, pT127, and the like (Gryczan, In: The Molecular Biology of the Bacilli, Academic Press, NY, pp. 307-329, 1982). Suitable Streptomyces plasmids include p1J101 (Kendall et al., J. Bacteriol. 169:41774183, 1987), and streptomyces bacteriophages such as φC31 (Chater et al., In: Sixth International Symposium on Actinomycetales Biology, Akademiai Kaido, Budapest, Hungary, pp. 45-54, 1986). Pseudomonas plasmids are reviewed by John et al. (Rev. Infect. Dis. 8:693-704, 1986), and Izaki (Jpn. J. Bacteriol. 33:729-742, 1978).

Preferred eukaryotic plasmids include, for example, BPV, vaccinia, SV40, 2-micron circle, and the like, or their derivatives. Such plasmids are well known in the art (Botstein et al., Miarni Wntr. Symp. 19:265-274, 1982; Broach, In: “The Molecular Biology of the Yeast Saccharomyces: Life Cycle and Inheritance”, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., p. 445-470, 1981; Broach, Cell 28:203-204, 1982; Bollon et al., J. Clin. Hematol. Oncol. 10:39-48, 1980; Maniatis, In: Cell Biology: A Comprehensive Treatise, Vol. 3, Gene Sequence Expression, Academic Press, N.Y., pp. 563-608, 1980).

Once the vector or nucleic acid molecule containing the construct(s) has been prepared for expression, the DNA construct(s) may be introduced into an appropriate host cell by any of a variety of suitable means, i.e., transformation, transfection, conjugation, protoplast fusion, electroporation, particle gun technology, calcium phosphate-precipitation, direct microinjection, and the like. After the introduction of the vector, recipient cells are grown in a selective medium, which selects for the growth of vector-containing cells. Expression of the cloned gene(s) results in the production of a kinase of the invention, or fragments thereof. This can take place in the transformed cells as such, or following the induction of these cells to differentiate (for example, by administration of bromodeoxyuracil to neuroblastoma cells or the like). A variety of incubation conditions can be used to form the peptide of the present invention. The most preferred conditions are those which mimic physiological conditions.

IV. The Proteins of the Invention

A variety of methodologies known in the art can be utilized to obtain the polypeptides of the present invention. The polypeptides may be purified from tissues or cells that naturally produce the polypeptides. Alternatively, the above-described isolated nucleic acid fragments could be used to express the kinases of the invention in any organism. The samples of the present invention include cells, protein extracts or membrane extracts of cells, or biological fluids. The samples will vary based on the assay format, the detection method, and the nature of the tissues, cells or extracts used as the sample.

Any eukaryotic organism can be used as a source for the polypeptides of the invention, as long as the source organism naturally contains such polypeptides. As used herein, “source organism” refers to the original organism from which the amino acid sequence of the subunit is derived, regardless of the organism the subunit is expressed in and ultimately isolated from.

One skilled in the art can readily follow known methods for isolating proteins in order to obtain the polypeptides free of natural contaminants. These include, but are not limited to: size-exclusion chromatography, HPLC, ion-exchange chromatography, and immuno-affinity chromatography.

Further, the polypeptides of the invention include the full-length polypeptides that can be identified from the full-length or partial sequences encoded by SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242 (FIG. 1). In addition, the polypeptides of the invention include the domains of these polypeptides, including, but not limited to, the N-terminal, kinase/catalytic, and C-terminal domains.

The characteristics of the protein kinase nucleic acid sequences of the invention are provided in Table 1. The protein kinases fall into 10 known groups: AGC, CAMK, CKI, CMGC, dsPK, EIFK, LIMK, MLK, STE and TY, In addition, there are a significant number of protein kinases that do not belong to any of the known groups, and therefore presumably define new protein kinase groups.

Additional characteristics are shown in, inter alia, the tables, namely Table 1, Table 2, Table 3 and Table 4, provided below.

V. Antibodies. Hybridomas, Methods of Use and Kits for Detection of Protein Kinases

The present invention relates to an antibody having binding affinity to a kinase of the invention. The polypeptide may have an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165. SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, and SEQ ID NO:242, or a functional derivative thereof, or at least 9 contiguous amino acids thereof (preferably, at least 20, 30, 35, or 40 or more contiguous amino acids thereof). Alternatively, the antibody may bind to a part of the polypeptide not provided in the sequences above, but that is present in the full-length sequence of the polypeptide and that is easily obtained using methods standard in the art. Further, the antibody may bind specifically to particular domains of one or more of the kinases of the invention, including, but not limited to, the N-terminal, kinase/catalytic, or C-terminal domains.

The present invention also relates to an antibody having specific binding affinity to a kinase or kinase domain of the invention. Such an antibody may be isolated by comparing its binding affinity to a kinase of the invention with its binding affinity to other polypeptides. Those that bind selectively to a kinase of the invention would be chosen for use in methods requiring a distinction between a kinase of the invention and other polypeptides. Such methods could include, but should not be limited to, the analysis of altered kinase expression in tissue containing other polypeptides.

The kinases of the present invention can be used in a variety of procedures and methods, such as for the generation of antibodies, for use in identifying pharmaceutical compositions, and for studying DNA/protein interaction.

The kinases of the present invention can be used to produce antibodies or hybridomas. One skilled in the art will recognize that if an antibody is desired, such a peptide could be generated as described herein and used as an immunogen. The antibodies of the present invention include monoclonal and polyclonal antibodies, as well fragments of these antibodies, and humanized forms. Humanized forms of the antibodies of the present invention may be generated using one of the procedures known in the art such as chimerization or CDR grafting.

The present invention also relates to a hybridoma that produces the above-described monoclonal antibody, or binding fragment thereof A hybridoma is an immortalized cell line that is capable of secreting a specific monoclonal antibody.

In general, techniques for preparing monoclonal antibodies and hybridomas are well known in the art (Campbell, “Monoclonal Antibody Technology: Laboratory Techniques in Biochemistry and Molecular Biology,” Elsevier Science Publishers, Amsterdam, The Netherlands, 1984; St. Groth et al., J. Immunol. Methods 35:1-21, 1980). Any animal (mouse, rabbit, and the like) which is known to produce antibodies can be immunized with the selected polypeptide. Methods for immunization are well known in the art. Such methods include subcutaneous or intraperitoneal injection of the polypeptide. One skilled in the art will recognize that the amount of polypeptide used for immunization will vary based on the animal that is immunized, the antigenicity of the polypeptide and the site of injection.

The polypeptide may be modified or administered in an adjuvant in order to increase the peptide antigenicity. Methods of increasing the antigenicity of a polypeptide are well known in the art. Such procedures include coupling the antigen with a heterologous protein (such as globulin or β-galactosidase) or through the inclusion of an adjuvant during immunization.

For monoclonal antibodies, spleen cells from the immunized animals are removed, fused with myeloma cells, such as SP2/0-Ag14 myeloma cells, and allowed to become monoclonal antibody producing hybridoma cells. Any one of a number of methods well known in the art can be used to identify the hybridoma cell that produces an antibody with the desired characteristics. These include screening the hybridomas with an ELISA assay, western blot analysis, or radioimmunoassay (Lutz et al., Exp. Cell Res. 175:109-124, 1988). Hybridomas secreting the desired antibodies are cloned and the class and subclass are determined using procedures known in the art (Campbell, “Monoclonal Antibody Technology: Laboratory Techniques in Biochemistry and Molecular Biology”, supra, 1984).

For polyclonal antibodies, antibody-containing antisera is isolated from the immunized animal and is screened for the presence of antibodies with the desired specificity using one of the above-described procedures. The above-described antibodies may be detectably labeled. Antibodies can be detectably labeled through the use of radioisotopes, affinity labels (such as biotin, avidin, and the like), enzymatic labels (such as horse radish peroxidase, alkaline phosphatase, and the like) fluorescent labels (such as FITC or rhodamine, and the like), paramagnetic atoms, and the like. Procedures for accomplishing such labeling are well-known in the art, for example, see Stemberger et al., J. Histochem. Cytochem. 18:315, 1970; Bayer et al., Meth. Enzym. 62:308-, 1979; Engval et al., Immunol. 109:129-, 1972; Goding, J. Immunol. Meth. 13:215-, 1976. The labeled antibodies of the present invention can be used for in vitro, in vivo, and in situ assays to identify cells or tissues that express a specific peptide.

The above-described antibodies may also be immobilized on a solid support. Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and sepharose, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir et al., “Handbook of Experimental Immunology” 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10, 1986; Jacoby et al., Meth. Enzym. 34, Academic Press, N.Y., 1974). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as in immunochromotography.

Furthermore, one skilled in the art can readily adapt currently available procedures, as well as the techniques, methods and kits disclosed herein with regard to antibodies, to generate peptides capable of binding to a specific peptide sequence in order to generate rationally designed antipeptide peptides (Hurby et al., “Application of Synthetic Peptides: Antisense Peptides”, In Synthetic Peptides, A User's Guide, W. H. Freeman, NY, pp. 289-307, 1992; Kaspczak et al., Biochemistry 28:9230-9238, 1989).

Anti-peptide peptides can be generated by replacing the basic amino acid residues found in the peptide sequences of the kinases of the invention with acidic residues, while maintaining hydrophobic and uncharged polar groups. For example, lysine, arginine, and/or histidine residues are replaced with aspartic acid or glutarnic acid and glutamic acid residues are replaced by lysine, arginine or histidine.

The present invention also encompasses a method of detecting a kinase polypeptide in a sample, comprising: (a) contacting the sample with an above-described antibody, under conditions such that immunocomplexes form, and (b) detecting the presence of said antibody bound to the polypeptide. In detail, the methods comprise incubating a test sample with one or more of the antibodies of the present invention and assaying whether the antibody binds to the test sample. Altered levels of a kinase of the invention in a sample as compared to normal levels may indicate disease.

Conditions for incubating an antibody with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the antibody used in the assay. One skilled in the art will recognize that any one of the commonly available immunological assay formats (such as radioimmunoassays, enzyme-linked immunosorbent assays, diffusion based Ouchterlony, or rocket immunofluorescent assays) can readily be adapted to employ the antibodies of the present invention. Examples of such assays can be found in Chard (“An Introduction to Radioimmunoassay and Related Techniques” Elsevier Science Publishers, Amsterdam, The Netherlands, 1986), Bullock et al. (“Techniques in Immunocytochemistry,” Academic Press, Orlando, Fla. Vol. 1, 1982; Vol. 2, 1983; Vol. 3, 1985), Tijssen (“Practice and Theory of Enzyme Immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology,” Elsevier Science Publishers, Amsterdam, The Netherlands, 1985).

The immunological assay test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as blood, serum, plasma, or urine. The test samples used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is testable with the system utilized.

A kit contains all the necessary reagents to carry out the previously described methods of detection. The kit may comprise: (i) a first container means containing an above-described antibody, and (ii) second container means containing a conjugate comprising a binding partner of the antibody and a label. In another preferred embodiment, the kit further comprises one or more other containers comprising one or more of the following: wash reagents and reagents capable of detecting the presence of bound antibodies.

Examples of detection reagents include, but are not limited to, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the chromophoric, enzymatic, or antibody binding reagents that are capable of reacting with the labeled antibody. The compartmentalized kit may be as described above for nucleic acid probe kits. One skilled in the art will readily recognize that the antibodies described in the present invention can readily be incorporated into one of the established kit formats that are well known in the art.

VI. Isolation of Compounds That Interact With Protein Kinases

The present invention also relates to a method of detecting a compound capable of binding to a protein kinase of the invention, comprising incubating the compound with a kinase of the invention and detecting the presence of the compound bound to the kinase. The compound may be present within a complex mixture, for example, serum, body fluid, or cell extracts.

The present invention also relates to a method of detecting an agonist or antagonist of kinase activity or kinase binding partner activity comprising incubating cells that produce a kinase of the invention in the presence of a compound and detecting changes in the level of kinase activity or kinase binding partner activity. The compounds thus identified would produce a change in activity indicative of the presence of the compound. The compound may be present within a complex mixture, for example, serum, body fluid, or cell extracts. Once the compound is identified it can be isolated using techniques well known in the art.

The present invention also encompasses a method of agonizing (stimulating) or antagonizing kinase associated activity in a mammal comprising administering to said mammal an agonist or antagonist to a kinase of the invention in an amount sufficient to effect said agonism or antagonism. A method of treating diseases in a mammal with an agonist or antagonist of kinase activity comprising administering the agonist or antagonist to a mammal in an amount sufficient to agonize or antagonize kinase associated functions is also encompassed in the present application.

In an effort to discover novel treatments for diseases, biomedical researchers and chemists have designed, synthesized, and tested molecules that inhibit the function of protein kinases. Some small organic molecules form a class of compounds that modulate the function of protein kinases. Examples of molecules that have been reported to inhibit the function of protein kinases include, but are not limited to, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92120642, published Nov. 26, 1992 by Maguire et al.), vinylene-azaindole derivatives (PCT WO 94/14808, published Jul. 7, 1994 by Ballinari et al.), 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992), styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1), seleoindoles and selenides (PCT WO 94/03427, published Feb. 17, 1994 by Denny et al.), tricyclic polyhydroxylic compounds (PCT WO 92/21660, published Dec. 10, 1992 by Dow), and benzylphosphonic acid compounds (PCT WO 91/15495, published Oct. 17, 1991 by Dow et al).

Compounds that can traverse cell membranes and are resistant to acid hydrolysis are potentially advantageous as therapeutics as they can become highly bioavailable after being administered orally to patients. However, many of these protein kinase inhibitors only weakly inhibit the function of protein kinases. In addition, many inhibit a variety of protein kinases and will cause multiple side-effects as therapeutics for diseases.

Some indolinone compounds, however, form classes of acid resistant and membrane permeable organic molecules. WO 96/22976 (published Aug. 1, 1996 by Ballinari et al.) describes hydrosoluble indolinone compounds that harbor tetralin, naphthalene, quinoline, and indole substituents fused to the oxindole ring. These bicyclic substituents are in turn substituted with polar moieties including hydroxylated alkyl, phosphate, and ether moieties. U.S. patent application Ser. No. 08/702,232, filed Aug. 23, 1996, entitled “Indolinone Combinatorial Libraries and Related Products and Methods for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 221/187) and Ser. No. 08/485,323, filed Jun. 7, 1995, entitled “Benzylidene-Z-Indoline Compounds for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 223/298) and International Patent Publication WO 96/22976, published Aug. 1, 1996 by Ballinari et al., all of which are incorporated herein by reference in their entirety, including any drawings, describe indolinone chemical libraries of indolinone compounds harboring other bicyclic moieties as well as monocyclic moieties fused to the oxindole ring. Applications Ser. No. 08/702,232, filed Aug. 23, 1996, entitled “Indolinone Combinatorial Libraries and Related Products and Methods for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 221/187), Ser. No. 08/485,323, filed Jun. 7, 1995, entitled “Benzylidene-Z-Indoline Compounds for the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 223/298), and WO 96/22976, published Aug. 1, 1996 by Ballinari et al teach methods of indolinone synthesis, methods of testing the biological activity of indolinone compounds in cells, and inhibition patterns of indolinone derivatives.

Other examples of substances capable of modulating kinase activity include, but are not limited to, tyrphostins, quinazolines, quinoxolines, and quinolines. The quinazolines, tyrphostins, quinolines, and quinoxolines referred to above include well known compounds such as those described in the literature. For example, representative publications describing quinazolines include Barker et al., EPO Publication No. 0 520 722 A1; Jones et al., U.S. Pat. No.4,447,608; Kabbe et al., U.S. Pat. No. 4,757,072; Kaul and Vougioukas, U.S. Pat. No. 5, 316,553; Kreighbaum and Comer, U.S. Pat. No. 4,343,940; Pegg and Wardleworth, EPO Publication No. 0 562 734 A1; Barker et al., Proc. of Am. Assoc. for Cancer Research 32:327 (1991); Bertino, J. R, Cancer Research 3:293-304 (1979); Bertino, J. R., Cancer Research 9(2 part 1):293-304 (1979); Curtin te al., Br. J. Cancer 53:361-368 (1986); Fernandes et al., Cancer Research 43:1117-1123 (1983); Ferris et al. J. Org. Chem. 44(2):173-178; Fry et al., Science 265:1093-1095 (1994); Jackman et al., Cancer Research 51:5579-5586 (1981); Jones et al. J. Med. Chem. 29(6):1114-1118; Lee and Skibo, Biochemistry 26(23):7355-7362 (1987); Lemus et al., J. Org. Chem. 54:3511-3518 (1989); Ley and Seng, Synthesis 1975:415-522 (1975); Maxwell et al., Magnetic Resonance in Medicine 17:189-196 (1991); Mini et al., Cancer Research 45:325-330 (1985); Phillips and Castle, J. Heterocyclic Chem. 17(19):1489-1596 (1980); Reece et al., Cancer Research 47(11):2996-2999 (1977); Sculier et al., Cancer Immunol. and Immunother. 23:A65 (1986); Sikora et al., Cancer Letters 23:289-295 (1984); Sikora et al., Analytical Biochem. 172:344-355 (1988); all of which are incorporated herein by reference in their entirety, including any drawings.

Quinoxaline is described in Kaul and Vougioukas, U.S. Pat. No. 5,316,553, incorporated herein by reference in its entirety, including any drawings.

Tyrphostins are described in Allen et al., Clin. Exp. Immunol. 91:141-156 (1993); Anafi et al., Blood 82:12:3524-3529 (1993); Baker et al., J. Cell Sci. 102:543-555 (1992); Bilder et al., Amer. Physiol. Soc. pp. 6363-6143:C721-C730 (1991); Brunton et al., Proceedings of Amer. Assoc. Cancer Rsch. 33:558 (1992); Bryckaert et al., Experimental Cell Research 199:255-261 (1992); Dong et al., J. Leukocyte Biology 53:53-60 (1993); Dong et al, J. Immunol. 151(5):2717-2724 (1993); Gazit et al., J. Med. Chem. 32:2344-2352 (1989); Gazit et al., “J. Med. Chem. 36:3556-3564 (1993); Kaur et al., Anti-Cancer Drugs 5:213-222 (1994); Kaur et al., King et al., Biochem. J. 275:413-418 (1991); Kuo et al., Cancer Letters 74:197-202 (1993); Levitzki, A., The FASEB J. 6:3275-3282 (1992); Lyall et al., J. Biol. Chem. 264:14503-14509 (1989); Peterson et al., The Prostate 22:335-345 (1993); Pillemer et al., Int. J. Cancer 50:80-85 (1992); Posner et al., Molecular Pharmacology 45:673-683 (1993); Rendu et al., Biol. Pharmacology 44(5):881-888 (1992); Sauro and Thomas, Life Sciences 53:371-376 (1993); Sauro and Thomas, J. Pharm. and Experimental Therapeutics 267(3):119-1125 (1993); Wolbring et al., J. Biol. Chem. 269(36):22470-22472 (1994); and Yoneda et al., Cancer Research 51:4430-4435 (1991); all of which are incorporated herein by reference in their entirety, including any drawings.

VII. Biological Significance, Applications and Clinical Relevance of Novel Protein Kinases

For each protein kinase in this application, we provide a classification of the protein class and family to which it belongs, a summary of non-cataltyic protein motifs, a profile of its expression in several hundred tissue and cell sources, and a chromosomal location. This information can be used to suggest potential function, regulation or therapeutic utility for each of the proteins.

The kinase classification and protein domains often reflect pathways, cellular roles, or mechanisms of up- or down-stream regulation. Also disease-relevant genes often occur in families of related genes. For example if one member of a kinase family functions as an oncogene, a tumor suppressor, or has been found to be disrupted in an immune, neurologic, cardiovascular, or metabolic disorder, frequently other family members may play a related role.

The expression analysis organizes kinases into groups that are transcriptionally upregulated in tumors and those that are more restricted to specific tumor types such as melanoma or prostate. This analysis also identifies genes that are regulated in a cell cycle dependent manner, and are therefore likely to be involved in maintaining cell cycle checkpoints, entry, progression, or exit from mitosis, oversee DNA repair, or are involved in cell proliferation and genome stability. Expression data also can identify genes expressed in endothelial sources or other tissues that suggest a role in angiogenesis, thereby implicating them as targets for control of diseases that have an angiogenic component, such as cancer, endometriosis, retinopathy and macular degeneration, and various ischemic or vascular pathologies. A proteins' role in cell survival can also be suggested based on restricted expression in cells subjected to external stress such as oxidative damage, hypoxia, drugs such as cisplatinum, or irradiation. Metastases-associated genes can be implicated when expression is restricted to invading regions of a tumor, or is only seen in local or distant metastases compared to the primary tumor, or when a gene is upregulated during cell culture models of invasion, migration, or motility.

Chromosomal location can identify candidate targets for a tumor amplicon or a tumor-suppressor locus. Summaries of prevelant tumor amplicons are available in the literature, and can identify tumor types to experimentally be confirmed to contain amplified copies of a kinase gene which localizes to an adjacent region.

Based on these criteria several kinases immediately stand out as being of potential therapeutic relevance. The protein kinases can be divided into the following disease-relevant categories (nucleotide Seq ID #s in parentheses):

Tumor associated: Mok (SEQ ID NO:NO:57), EPK2, AA316804 (SEQ ID NO:11), AA435956 (SEQ ID NO:NO:48), AA278842 (SEQ ID NO:88), AA599286 (SEQ ID NO:89), AA826850 (SEQ ID NO:3), HRI (SEQ ID NO:73), MLK4 AA232253 (SEQ ID NO:82), AA883975 SGK 235 (SEQ ID NO:95), AA311714 (SEQ ID NO:101), MPSK1 (SEQ ID NO:110), R19609 (Seq ID111), AA383293 (SEQ ID NO:26).

Prostate-specific: AA234451 (SEQ ID NO:47), TSK4 (SEQ ID NO:93), RIP4 (SEQ ID NO:84), KIAA0965 (SEQ ID NO:8).

Oncogenic or proliferation associated: KIAA0781 (SEQ ID NO:38), AA789239 (SEQ ID NO:52), CCRK (SEQ ID NO:54), CLK4 (SEQ ID NO:55), H85389 (SEQ ID NO:97).

Neuronal restricted: CAMKKB (SEQ ID NO:66)

Hematopoietic expressed: PTK9L (SEQ ID NO:22), DRAK2 (SEQ ID NO:29), AI025291 (SEQ ID NO:94)

Angiogenic or endothelial expressed: DRAK1 (SEQ ID NO:31), MAK-V (SEQ ID NO:40), TRAD (SEQ ID NO:44), MOK (SEQ ID NO:57), AA08847 (SEQ ID NO:78), HGP_—66444466 (SEQ ID NO:79), RSK4 (SEQ ID NO:16).

Cell cycle regulated: AA454060 (SEQ ID NO:45), KIAA0999 (Mitotic—SEQ ID NO:32), AA579641 (Mitotic—SEQ ID NO:60), AA305176 (Mitotic—SEQ ID NO:6), AA018361 (S1 phase—SEQ ID NO:100).

VIII. Transgenic Animals.

A variety of methods are available for the production of transgenic animals associated with this invention. DNA can be injected into the pronucleus of a fertilized egg before fusion of the male and female pronuclei, or injected into the nucleus of an embryonic cell (e.g., the nucleus of a two-cell embryo) following the initiation of cell division (Brinster et al., Proc. Nat. Acad. Sci. USA 82: 4438-4442, 1985) Embryos can be infected with viruses, especially retroviruses, modified to carry inorganic-ion receptor nucleotide sequences of the invention.

Pluripotent stem cells derived from the inner cell mass of the embryo and stabilized in culture can be manipulated in culture to incorporate nucleotide sequences of the invention. A transgenic animal can be produced from such cells through implantation into a blastocyst that is implanted into a foster mother and allowed to come to term. Animals suitable for tansgenic experiments can be obtained from standard commercial sources such as Charles River (Wilmington, Mass.), Taconic (Germantown, N.Y.), Harlan Sprague Dawley (Indianapolis, Ind.), etc.

The procedures for manipulation of the rodent embryo and for microinjection of DNA into the pronucleus of the zygote are well known to those of ordinary skill in the art (Hogan et al., supra). Microinjection procedures for fish, amphibian eggs and birds are detailed in Houdebine and Chourrout (Experientia 47: 897-905, 1991). Other procedures for introduction of DNA into tissues of animals are described in U.S. Pat. No. 4,945,050 (Sanford el al., Jul. 30, 1990).

By way of example only, to prepare a transgenic mouse, female mice are induced to superovulate. Females are placed with males, and the mated females are sacrificed by CO₂asphyxiation or cervical dislocation and embryos are recovered from excised oviducts. Surrounding cumulus cells are removed. Pronuclear embryos are then washed and stored until the time of injection. Randomly cycling adult female mice are paired with vasectomized males. Recipient females are mated at the same time as donor females. Embryos then are transferred surgically. The procedure for generating transgenic rats is similar to that of mice (Hammer et al., Cell 63:1099-1112, 1990).

Methods for the culturing of embryonic stem (ES) cells and the subsequent production of transgenic animals by the introduction of DNA into ES cells using methods such as electroporation, calcium phosphate/DNA precipitation and direct injection also are well known to those of ordinary skill in the art (Teratocarcinomas and Embryonic Stem Cells, A Practical Approach, E.J. Robertson, ed., JRL Press, 1987).

In cases involving random gene integration, a clone containing the sequence(s) of the invention is co-transfected with a gene encoding resistance. Alternatively, the gene encoding neomycin resistance is physically linked to the sequence(s) of the invention. Transfection and isolation of desired clones are carried out by any one of several methods well known to those of ordinary skill in the art (E. J. Robertson, supra).

DNA molecules introduced into ES cells can also be integrated into the chromosome through the process of homologous recombination (Capecchi, Science 244: 1288-1292, 1989). Methods for positive selection of the recombination event (i.e., neo resistance) and dual positive-negative selection (i.e., neo resistance and gancyclovir resistance) and the subsequent identification of the desired clones by PCR have been described by Capecchi, supra and Joyner et al. (Nature 338: 153-156, 1989), the teachings of which are incorporated herein in their entirety including any drawings. The final phase of the procedure is to inject targeted ES cells into blastocysts and to transfer the blastocysts into pseudopregnant females. The resulting chimeric animals are bred and the offspring are analyzed by Southern blotting to identify individuals that carry the transgene. Procedures for the production of non-rodent mammals and other animals have been discussed by others (Houdebine and Chourrout, supra; Pursel et al., Science 244:1281 -1288, 1989; and Simms et al., Bio/Technology 6:179-183, 1988).

Thus, the invention provides transgenic, nonhuman mammals containing a transgene encoding a kinase of the invention or a gene effecting the expression of the kinase. Such transgenic nonhuman mammals are particularly useful as an in vivo test system for studying the effects of introduction of a kinase, or regulating the expression of a kinase (ie., through the introduction of additional genes, antisense nucleic acids, or ribozymes).

A “Transgenic animal” is an animal having cells that contain DNA which has been artificially inserted into a cell, which DNA becomes part of the genome of the animal which develops from that cell. Preferred transgenic animals are primates, mice, rats, cows, pigs, horses, goats, sheep, dogs and cats. The transgenic DNA may encode human STE20-related kinases. Native expression in an animal may be reduced by providing an amount of anti-sense RNA or DNA effective to reduce expression of the receptor.

IX. Gene Therapy

Protein kinases of the invention, or their genetic sequences will also be useful in gene therapy (reviewed in Miller, Nature 357:455-460, 1992). Miller states that advances have resulted in practical approaches to human gene therapy that have demonstrated positive initial results. The basic science of gene therapy is described in Mulligan (Science 260:926-931, 1993).

In one preferred embodiment, an expression vector containing protein kinase coding sequence is inserted into cells, the cells are grown in vitro, and then are infused in large numbers into patients. In another preferred embodiment, a DNA segment containing a promoter of choice (for example a strong promoter) is transferred into cells containing an endogenous gene encoding kinases of the invention in such a manner that the promoter segment enhances expression of the endogenous kinase gene (for example, the promoter segment is transferred to the cell such that it becomes directly linked to the endogenous kinase gene).

The gene therapy may involve the use of an adenovirus containing kinase cDNA targeted to a tumor, systemic kinase increase by implantation of engineered cells, injection with kinase-encoding virus, or injection of naked kinase DNA into appropriate tissues.

Target cell populations may be modified by introducing altered forms of one or more components of the protein complexes in order to modulate the activity of such complexes. For example, by reducing or inhibiting a complex component activity within target cells, an abnormal signal transduction event(s) leading to a condition may be decreased, inhibited, or reversed. Deletion or missense mutants of a component, that retain the ability to interact with other components of the protein complexes but cannot function in signal transduction may be used to inhibit an abnormal, deleterious signal transduction event.

Expression vectors derived from viruses such as retroviruses, vaccinia virus, adenovirus, adeno-associated virus, herpes viruses, several RNA viruses, or bovine papilloma virus, may be used for delivery of nucleotide sequences (e.g., cDNA) encoding recombinant kinase of the invention protein into the targeted cell population (e.g. tumor cells). Methods which are well known to those skilled in the art can be used to construct recombinant viral vectors containing coding sequences (Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, N.Y., 1989; Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and Wiley Interscience, N.Y., 1989). Alternatively, recombinant nucleic acid molecules encoding protein sequences can be used as naked DNA or in a reconstituted system e.g., liposomes or other lipid systems for delivery to target cells (e.g., Feigner et al., Nature 337:387-8, 1989). Several other methods for the direct transfer of plasmid DNA into cells exist for use in human gene therapy and involve targeting the DNA to receptors on cells by complexing the plasmid DNA to proteins (Miller, supra).

In its simplest form, gene transfer can be performed by simply injecting minute amounts of DNA into the nucleus of a cell, through a process of microinjection (Capecchi, Cell 22:479-88, 1980). Once recombinant genes are introduced into a cell, they can be recognized by the cell's normal mechanisms for transcription and translation, and a gene product will be expressed. Other methods have also been attempted for introducing DNA into larger numbers of cells. These methods include: transfection, wherein DNA is precipitated with CaPO₄and taken into cells by pinocytosis (Chen et al., Mol. Cell Biol. 7:2745-52, 1987); electroporation, wherein cells are exposed to large voltage pulses to introduce holes into the membrane (Chu et al., Nucleic Acids Res. 15:1311-26, 1987); lipofection/liposome fusion, wherein DNA is packaged into lipophilic vesicles which fuse with a target cell (Felgner et al., Proc. Natl. Acad. Sci. USA. 84:7413-7417, 1987); and particle bombardment using DNA bound to small projectiles (Yang et al., Proc. Natl. Acad. Sci. 87:9568-9572, 1990). Another method for introducing DNA into cells is to couple the DNA to chemically modified proteins.

It has also been shown that adenovirus proteins are capable of destabilizing endosomes and enhancing the uptake of DNA into cells. The admixture of adenovirus to solutions containing DNA complexes, or the binding of DNA to polylysine covalently attached to adenovirus using protein crosslinking agents substantially improves the uptake and expression of the recombinant gene (Curiel et al., Am. J. Respir. Cell. Mol. Biol., 6:247-52, 1992).

As used herein “gene transfer” means the process of introducing a foreign nucleic acid molecule into a cell. Gene transfer is commonly performed to enable the expression of a particular product encoded by the gene. The product may include a protein, polypeptide, anti-sense DNA or RNA, or enzymatically active RNA. Gene transfer can be performed in cultured cells or by direct administration into animals. Generally gene transfer involves the process of nucleic acid contact with a target cell by non-specific or receptor mediated interactions, uptake of nucleic acid into the cell through the membrane or by endocytosis, and release of nucleic acid into the cytoplasm from the plasma membrane or endosome. Expression may require, in addition, movement of the nucleic acid into the nucleus of the cell and binding to appropriate nuclear factors for transcription.

As used herein “gene therapy” is a form of gene transfer and is included within the definition of gene transfer as used herein and specifically refers to gene transfer to express a therapeutic product from a cell in vivo or in vitro. Gene transfer can be performed ex vivo on cells which are then transplanted into a patient, or can be performed by direct administration of the nucleic acid or nucleic acid-protein complex into the patient.

In another preferred embodiment, a vector having nucleic acid sequences encoding a protein Iinase polypeptide of the invention is provided in which the nucleic acid sequence is expressed only in specific tissue. Methods of achieving tissue-specific gene expression are set forth in International Publication No. WO 93/09236, filed Nov. 3, 1992 and published May 13, 1993.

In all of the preceding vectors set forth above, a further aspect of the invention is that the nucleic acid sequence contained in the vector may include additions, deletions or modifications to some or all of the sequence of the nucleic acid, as defined above.

In another preferred embodiment, a method of gene replacement is set forth. “Gene replacement” as used herein means supplying a nucleic acid sequence which is capable of being expressed in vivo in an animal and thereby providing or augmenting the function of an endogenous gene that is missing or defective in the animal.

X. Administration of Substances

Methods of determining the dosages of compounds to be administered to a patient and modes of administering compounds to an organism are disclosed in U.S. application Ser. No. 08/702,282, filed Aug. 23, 1996 and International patent publication number WO 96/22976, published Aug. 1, 1996, both of which are incorporated herein by reference in their entirety, including any drawings, figures, or tables. Those skilled in the art will appreciate that such descriptions are applicable to the present invention and can be easily adapted to it.

The proper dosage depends on various factors such as the type of disease being treated, the particular composition being used, and the size and physiological condition of the patient. Therapeutically effective doses for the compounds described herein can be estimated initially from cell culture and animal models. For example, a dose can be formulated in animal models to achieve a circulating concentration range that initially takes into account the IC₅₀as determined in cell culture assays. The animal model data can be used to more accurately determine useful doses in humans.

Plasma half-life and biodistribution of the drug and metabolites in the plasma, tumors, and major organs can be also be determined to facilitate the selection of drugs most appropriate to inhibit a disorder. Such measurements can be carried out. For example, HPLC analysis can be performed on the plasma of animals treated with the drug and the location of radiolabeled compounds can be determined using detection methods such as X-ray, CAT scan, and MRI. Compounds that show potent inhibitory activity in the screening assays, but have poor pharmacokinetic characteristics, can be optimized by altering the chemical structure and retesting. In this regard, compounds displaying good pharmacokinetic characteristics can be used as a model.

Toxicity studies can also be carried out by measuring the blood cell composition. For example, toxicity studies can be carried out in a suitable animal model as follows: 1) the compound is administered to mice (an untreated control mouse should also be used); 2) blood samples are periodically obtained via the tail vein from one mouse in each treatment group; and 3) the samples are analyzed for red and white blood cell counts, blood cell composition, and the percent of lymphocytes versus polyrnorphonuclear cells. A comparison of results for each dosing regime with the controls indicates if toxicity is present.

At the termination of each toxicity study, further studies can be carried out by sacrificing the animals (preferably, in accordance with the American Veterinary Medical Association guidelines Report of the American Veterinary Medical Assoc. Panel on Euthanasia, Journal of American Veterinary Medical Assoc., 202:229-249, 1993). Representative animals from each treatment group can then be examined by gross necropsy for immediate evidence of metastasis, unusual illness, or toxicity. Gross abnormalities in tissue are noted, and tissues are examined histologically. Compounds causing a reduction in body weight or blood components are less preferred, as are compounds having an adverse effect on major organs. In general, the greater the adverse effect the less preferred the compound.

Plasma levels should reflect the potency of the drug. Generally, the more potent the compound the lower the plasma levels necessary to achieve efficacy.

EXAMPLES

The examples below are not limiting and are merely representative of various aspects and features of the present invention. The examples below demonstrate the isolation and characterization of the protein kinases of the invention.

Example 1
Isolation of cDNA Clones Encoding Novel Mammalian Protein Kinases Materials and Methods Identification from cDNA Databases and Isolation of Clones Encoding Novel Protein Kinases

Novel kinases were identified from the public EST databases using a Hidden Markov model, abbreviated HMM (Krogh, A., Brown, M., Mian, I. S., Sjolander, K., and Haussler, D. 1994. Hidden Markov models in computational biology: Applications to protein modeling. J. Mol Biol., 235:1501-1531). The model was built with 70 mammalian and yeast kinase catalytic domain sequences. These sequences were chosen from a comprehensive collection of kinases such that no two sequences had more than 50% sequence identity. ESTs were tnanslated in six open reading frames and were searched against the model. ESTs that had a score of at least 10 against the HMM were then masked for repetitive sequences and vectors and were clustered using MSA. The resulting contigs were searched against known kinases to identify EST clones that encode novel kinases.

Approximately 40% of the ESTs encoding potentially novel kinases did not correspond to the correct EST upon sequence analysis. Most of these discrepancies were resolved by ordering additional clones, however, 14 remained unavailable. These 14 ESTs were amplified from a variety of single-stranded cDNA sources with primers derived from the corresponding EST entry as shown on Table 5. The PCR product was subcloned into a bluescript vector, digested to confirm the presence of a correct size insert and sequenced. Full sequencing of EST and PCR was carried out using a cycle sequencing Big-dye kit with AmpliTaq DNA Polymerase, FS (ABI, Foster City, Calif.). Sequencing reaction products were run on an ABI Prism 377 DNA Sequencer.

TABLE 5Primers used to clone PCR products corresponding to novelkinasesID#ID#Parent5′ primer3′ primerspnaaaSequenceSequence*Sequence*H331532R22-5-11GAGATCGRNTTYAARGATGTCACNCCNAGNSWCCANRTTYGAAYRTTM812005R57_10_2_—GCTGCTGGACAGTGACTGAAAGCAAAGCCTTCACACm TESK2_mTGTATTTCTTH67187SR69_17_2_hCTCTCACCTCAGGAACTGCTTGCGGATCTTCTCAGGH46166SGK309_hGACATCCTGCCGGCCAACGGCCCTGGAGCTGCATCACTACGCTAM672285R72_16_2_hTGCGCGACACCATTGACCTCAGGGCTTACATACAGACAGGH451655R72_8_2_hAAAGGAGAACTACATTTCTTCATCATCTCTAATACATTGAAAATTGGTTGGH41161Z36720CAAATTAAGATCATTGAGGAAACAAAGTCCTTGGCCCTTTGGGTCH115234AL031652-GTGGACATCTGGTCCCTGTAGGTCCTTCACTCTTGGPak6CGAG
*degenerate oligonucleatide residue designation:

N = A,C,G ot T

R = A or G

Y = C or T

S = C or G

W = A or T

Full-length Sequence Extension of Protein Kinases Using cDNA and Genomic Databases

Extension of partial cDNA sequences to encompass the full-length open-reading frame was carried out by iterative blastn searching of the cDNA databases listed in Table 6. All blastn searches were conducted using a blosum62 matrix, a penalty for a nucleotide mismatch of −3 and reward for a nucleotide match of 1. The gapped blast algortihm is described in: (Altschul, Stephen F., Thomas L. Madden, Alejandro A. Schaffer, Jinghui Zhang, Zheng Zhang, Webb Miller, and David J. Lipman (1997), “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs”, Nucleic Acids Res. 25:3389-3402).

TABLE 6Databases used for cDNA-based sequence extensionsDatabaseDatabase DateLifeGold templatesFebruary 2000LifeGold compseqsFebruary 2000LifeGold compseqsMarch 2000LifeGold compseqsApril 2000LifeGold flFebruary 2000LifeGold flftApril 2000NCBI human EstsMay 2000NCBI murine EstsMay 2000NCBI nonredundantMay 2000

Extension of partial cDNA sequences to encompass the full-length open-reading frame was also carried out by iterative searches of genomic databases. Three methods were used. The first method made use of the Smith-Waterman algorithm to carry out protein-protein searches of the closest homologue or orthologue to the partial kinase. The target databases consisted of Genescan and open-reading frame (ORF) predictions of all human genomic sequence derived from the human genome project (HGP) as well as from Celera. The complete set of genomic databases searched is shown in Table 7 below. Genomic sequences encoding potential extensions were further assessed by blastp analysis against the NCBI nonredundant to confirm the novelty of the hit. The extending genomic sequences were incorporated into the cDNA sequence after removal of potential introns using the Seqman program from DNAStar. The default parameters used for Smith-Waterman searches were as shown next. Matrix: blosum 62; gap-opening penalty:12; gap extension penalty:2. Genescan predictions were made using the Genescan program as detailed in (Chris Burge and Sam Karlin “Prediction of Complete Gene Structures in Human Genomic DNA”, JMB (1997) 268(1):78-94). ORF predictions from genomic DNA were made using a standard 6-frame translation.

The second method for genomic sequence-based extensions made use of tBlastn searches of the homologue or orthologue to the partial kinase against the cDNA databases listed in Table 7. The recognition of significant hits in these databases made possible to identify bridging partial cDNA clones. The iterative application of the two methods made possible the assemblage of the virtual full-length sequence for a large number of the kinases presented in this application. All tblastn searches were conducted using a blosum62 matrix, a penalty for a nucleotide mismatch of −3 and reward for a nucleotide match of 1.

The last method for defining cDNA extensions from genomic sequence used iterative searches of genomic databases through the Genescan program to predict exon splicing and the Genewise program (http://www.sanger.ac.uk/SoftwarefWise2/) to predict potential ORFs based on homology to the closest orthologue/homologue. Table 7. Databases used for genomic-based sequence extensions

TABLE 7Databases used for genomic-based sequence extensionsDatabaseNumber of entriesDatabase DateCelera v. 1-55,306,158Jan 19/00Celera v. 6-104,209,980Mar 24/00Celera v. 11-147,222,425Apr 24/00Celera v. 15243,044May 14/00HGP all Genescan25,885Apr 04/00HGP; Phase 04,944May 04/00HGP; Phase 128,478May 05/00HGP; Phase 21,508May 04/00HGP; Phase 39,971May 05/00

Virtual Extensions

Human AA826850 (SEQ ID NO: 3, SEQ ID NO:124)

Blastn analysis of the partial AA826850 sequence revealed an extension to encompass the complete ORF in the Incyte EST 238299.1. A frame-shift correction at position 595 of this EST (marked by X in NA sequence) generated an uninterrupted ORF.

Human AA960957 (SEQ ID NO: 4, SEQ ID NO:125)

Since the initial filing of this application, the partial AA960957 sequence appeared in the public database as the full-length gene for a protein kinase encoded by a gene that maps adjacent to the evc (AJ250839) (ellis-van creveld syndrome and weyers acrodental dysostosis) gene from 4p 16.1.

Human 5R79-46-1_h (SEQ ID NO:5, SEQ ID NO:126)

Blastn analysis of the partial 5R79-46-1 sequence revealed an extension to encompass the complete ORF in the Incyte EST 463894.6. Since the initial filing of this application, the full-length virtual 5R79-46-1 appeared in the public database as the full-length gene for the TANK-binding kinase (TBK1) (Pomerantz, J. L. and Baltimore, D. (1999) EMBO J. 18 (23), 6694-6704). TBK1 participates in NF-kB activation through the formation of a signaling complex with TRAF2 and TANK.

Human AA305176 (SEQ ID NO: 6, SEQ ID NO:127)

Blastn analysis of the partial AA305176 sequence revealed an extension to encompass the complete ORF in the Incyte EST 220937.1.

Human AA256100 (SEQ ID NO: 8, SEQ ID NO:129)

Blastn analysis of the partial AA256100 sequence revealed an extension to encompass the complete ORF through the assembly of three partial clones: Incyte EST 480815.6, KIAA0965 (BAA76809) and AA256100.

Human AA210825 (SEQ ID NO: 9, SEQ ID NO: 130)

Blastn analysis of the partial AA210825 sequence revealed an extension to encompass the nearly complete ORF through the assembly of three partial clones: Incyte EST 014721.7, and the NCBI EST's AW01158 and AA210825. An insertion of two “N's” at positions 1915 and 1916 generated an uninterrupted ORF. Blastx analysis indicated the possibility of a start Met in the range of 400-450 nucleotides (i.e. compared to the closest homolog, human PKCmu (CAA53384.1). However, no Met was found in this region; rather ORF ends in an in-frame stop preceeded by the sequence “RGLLAPGDPPCPPPNPAPATPPSSRLPTELFSNFCDS”. It is possible that part of the sequence covered by nucleotide positions 1-400 derived from AW01158 comes from an intron, explaining the absence of a start Met.

Human AA127299 (SEQ ID NO:10, SEQ ID NO:131)

No entries in the database extended this sequence. The 1684 bp insert of this EST contains a 1369 bp intron at the 3′ end. Blastx and SW analysis of the 315 bp coding region revealed homology to the extracatalytic C2 domain of PKC. This EST, may or may not encode a kinase.

Human AA316804 (SEQ ID NO:11, SEQ ID NO:132)

Since the initial filing of this application, the partial AA316804 sequence appeared in the public database as the full-length gene for the PKC family protein kinase EPK2 or PKCnu (AB015982).

Human H19102 (SEQ ID NO:14, SEQ ID NO:135)

Genewise and Genescan analyses of the partial H19102 sequence revealed an extension from the HGP phase 3 contig 3810672 to encompass the complete catalytic domain of this EST. Blastn analysis against the non-redundant database revealed that this gene is found in the cosmid AC005726 from chromosome 17.H19102 may encode a dual catalytic kinase given the homology to S6 kinase. Analysis of genomic sequence upstream of the 5′ end of H19102 revealed a non-kinase gene oriented in the same polarity as H19102 suggestive of the start Met for H19102 being close to the 5′ end of the H19102 sequence. From this analysis it is deduced that the second catalytic domain of H19102, if present, is most likely located within the 47334-185,215 bp region of the genomic sequence of AC005726.

Human AA476563 (SEQ ID NO:15, SEQ ID NO:136) Since the initial filing of this application, the partial AA476563 sequence appeared in the public database as the full-length gene for the protein kinase RPS6KC1 (NM_—012424)(Zhang, H. et al Genomics (1999) 61, 314-318), which is an S6 kinase mapping to 12q12-q13.1.

Human AA626690 (SEQ ID NO:16, SEQ ID NO:137)

Since the initial filing of this application, the partial AA626690 sequence appeared in the public database as the full-length gene for the protein kinase RPS6KA6 (AF184965) (Yntema H. G et al (1999) Genomics 62, 332-343), an S6 kinase commonly deleted in patients with complex X-linked (Xq21.1) mental retardation.

Human AI215680 (SEQ ID NO: 17, SEQ ID NO:138)

Since the initial filing of this application, the partial AI215680 sequence appeared in the public database as the full-length gene encoding a hypothetical protein (AAD30182) from the locus AC006530.4 from chromosome 14.

Human AA887783 (SEQ ID NO:21, SEQ ID NO:142)

Blastn analysis of the partial AA887783 sequence revealed an extension to encompass the nearly complete ORF through the assembly of three partial clones: Incyte 415390R6 and the NCBI EST's AA887783 and N94726. Since the initial filing of this application, the nearly full-length virtual AA887783 sequence appeared in the public database as the fill-length gene encoding SGK3 (AF169035), a serum- and glucocorticoid-induced protein kinase (Kobayashi, T. et al (1999) Biochemical J. 344, 189-197.

Human R47805 (SEQ ID NO:22, SEQ ID NO:143)

A cDNA clone encoding the full-length ORF of R47805 was isolated using R47805 as a screening probe. A full-length form for R47805 has also appeared in the public database as

PTK9L (NM_—007284), an A6-related protein kinase.

Human H60215 (SEQ ID NO:23, SEQ ID NO:144)

Blastn analysis of the partial H60215 sequence revealed an extension to encompass the complete ORF in the public EST AI275726. This was confirmed through the full insert sequencing of this EST (2,310 bp) which corresponds to the sequence under SEQ ID NO:144.

A different stop codon was predicted for AI275726 compared to H60215 due to a single nucleotide insertion at position 1586 in AI1275726. Evidence for the extra nucleotide comes from EST AI191922.

SGK324_n—h orthologue of W30246_m (SEQ ID NO:24, SEQ ID NO:145)

Blastn, blastx and Smith-Waterman analyses of genomic databases revealed an extension to encompass the complete ORF corresponding to the human orthologue of murine W30246. Exons predicted from the following sequences were used for contig construction: Celera 17000189645083, 17000057549105 and 11000501939981; Incytel42404.1, HGP_—7249119, Incyte 7196489H1, Celera 11000501939981, 17000028165594; Incyte 7249119_—3, Celera 17000035772368, 11000502081575 and 17000140274329. The latter Celera sequence provides the N-terminus.

Human AA383293 (SEQ ID NO:26, SEQ ID NO:147)

Blastn, blastx and Smith-Waterman analyses of genomic databases revealed an extension to encompass the complete ORF corresponding for AA383293. Exons predicted from the following sequences were used for contig construction: (numbers in parenthesis refer to the aa sequence of the closest homolog (RU2S, NP_—057440) used for the Smith-Waterman query): N-term from Incyte 6010175_—2 (14-97), Incyte 6981981 (134-184) 7596749 (186-232) Celera 17000020789545 (243-301) CAB75619.1 (310-341)-(56-145 DCX homology) 6010175_—2, Celera 17000030058129 (241-262 DCX homology).

Human AA021445 (SEQ ID NO:32, SEQ ID NO:152)

Blastn analysis revealed an extension to encompass the nearly complete ORF corresponding for AA021445. Contig reconstruction was as follows: nucleotides 1-802 from KIAA0999 (AB023216); nucleotides 803-4321 from full-insert sequence of AA021445. A pairwise alignment between the AA021445 and KIAA0999 revealed three inserts in the extracatalytic C-terminus of 48, 48 and 161 aminoacids. In addition, both AA021445 and KIAA0999 have 15 copies of a CAG repeat. Trinucleotide repeats are often found in genes that linked to neurodegenerative diseases.

Human 2R22-55-1 (SEQ ID NO:33, SEQ ID NO:153)

Blastn analysis revealed an extension in the Incyte EST clone 321074.1 to encompass the complete ORF corresponding to 2R22-55-1.

Human orthologue of AA544838_m (SEQ ID NO:36, SEQ ID NO:156)

tBlastn analysis identified the partial human KIAA0135 (U79240) clone as the human orthologue of murine AA544838. Blastn revealed an extension KIAA0135_h (U79240) to encompass the complete ORF. The full ORF was reconstructed from Incyte406786.5, KFZp430051 and KIAA0135 (U79240).

Human orthologue of AI785735_m (SEQ ID NO:38, SEQ ID NO:158)

tBlastn analysis identified the partial human KIAA0781 (AB018324) clone as the human orthologue of murine AI785735. Blastn revealed an extension KIAA0135_h (U79240) to encompass the complete ORF. The full ORF was reconstructed from Incyte 986123.37 KIAA0781 (AB018324).

Human AA207220 (SEQ ID NO:39, SEQ ID NO:159)

Blastn analysis revealed an extension to encompass the nearly complete ORF corresponding for AA021445. The full ORF was reconstructed from Incyte 402740.1 and AA207220. Frame corrections: deletion of 441 and 595 over Inc402740.1 seq based on blastx to keep frame open; two n insertions 940, 941 over AA207220 to keep frame open.

Human AA426580 (SEQ ID NO:40, SEQ ID NO:160)

Since the initial filing of this application, the partial AA426580 sequence appeared in the public database as the full-length gene encoding MAK-V (AJ271722) from chromosome 21q22.1.

Human 5R79-54-1 (SEQ ID NO: 41, SEQ ID NO:161)

Genewise and Genescan analyses of the partial 5R79-54-1 sequence revealed an extension from genomic sequence to encode the full ORF for SR79-54-1.

Human orthologue of AA542015_m (SEQ ID NO: 42, SEQ ID NO:162)

tblastn analysis identified KIAA1297 (AB037718). Blastn extended the KIAA1297 sequence to provide the C-terminus through the Incyte 224074.1 EST. The partial ORF consists of a dual catalytic domain flanked by 6 Ig domains and 2 fibronectin repeats. Based on homology-to the bt drosophila protein (AAF59316.1), the human form of AA542015 is expected to be missing 16 Ig domains.

Human R19772 (SEQ ID NO:44, SEQ ID NO:164)

The full-length ORF for R19772 was isolated by screening a cDNA library using a probe derived from RI 9772. Since the initial filing of this application, the R19772 sequence appeared in the public database as the full-length gene encoding Trio (Duet) (AB011422). CDNA library screening revealed multiple isoforms for this gene which are summarized in the Table below.

TABLE 8Isoforms for R19772KestrlKestrlAAIsoformNameAcc #typeSourceDescription*TradR19772BSkeletalDeletion of K at 124(Duet)muscleDeletion of Q at 616Substitution of E for G at762CSkeletalDeletion of K at 124muscleDeletion of Q at 616Substitution of E for G at762Deletion of 32 aa (160-191)DLung tumorDeletion of Q at 616Deletion of 32 aa (160-191)ELung tumorDeletion of Q at 616Deletion of 32 aa (160-191)
*reference amino acid position are with respect to sequence of Trad (AB011422)

Human AA435956 (SEQ ID NO:48, SEQ ID NO:168)

Blastn analysis revealed an extension to encompass the nearly complete catalytic region of AA435956. 5′ end sequence extension was provided by genomic locus AC007242.3_h (range 44880-43801). Based on blastx analysis, the extended sequence encodes is full-length at the C-terminus.

Human AA397553 (SEQ ID NO: 51, SEQ ID NO:171)

Since the initial filing of this application, the partial AA397553 sequence appeared in the public database as the full-length gene encoding CRK7 (AF227198), a novel CDC2-related protein kinase that colocalizes with interchromatin granule clusters.

Human AA789239 (SEQ ID NO: 52, SEQ ID NO:172)

Since the initial filing of this application, the partial AA789239 sequence appeared in the public database as the full-length gene encoding NKIAMRE (AF130372), a novel kinase deleted in human leukemia

Human AA631990 (SEQ ID NO:55, SEQ ID NO:175)

Blastn analysis revealed an extension to encompass the full-length ORF for AA631990. The full ORF was reconstructed from 253847.5 and AA631990 and AA207220. Frame corrections: delete 1 C at 1380, delete 2N's at 2033/2034.

Human AA557536 (SEQ ID NO:56, SEQ HD NO:176)

Blastn analysis revealed an extension to encompass full-length ORF for AA557536. The full ORF was reconstructed from AA557536, celera 11000504061899 and the Incyte 097089.1 EST. An 85 bp intron was removed from AA557536.

Human N34132 (SEQ D) NO: 63, SEQ ID NO:183)

Full sequencing of EST N34132 (1.3 kb) confirmed that this cDNA encodes a novel NEK-subfamily kinase. Blast analysis against the EST database showed that four EST sequences (AA283140, AA283140, AA282911 and N53011) extended the sequence of N34132 at the 3′ end to form a 2.31 kb contig. Blast analysis of the new contig against the nonredunat public database showed that the N34132 extended contig overlapped (100% identity) over 228 bp at its 3′ end with human KIAA0344 (AB002342), a 5,787 bp cDNA encoding a 1246 aa polypeptide. The 5′790 bp of the KIAA0344 cDNA (encoding the 58 N-terminal protein sequence) were found to be divergent with respect to the extended 2.32 kb N34132 contig. Evidence that the extended N34132 contig (2.31 kb) and KIAA0344 (AB002342) belong to the same gene is the following. First, blast analysis of the nucleotide sequences for N34132 and KIAA0344 against the NRN database confirmed that these cDNA's are transcribed from the same genomic locus defined by two overlapping BACs (AC004765 and AC004803) from chromosome 12p 13.3. Second, full sequence determination of a PCR fragment amplified from single-stranded cDNA confirmed the junction between the extended N34132 contig and KIAA0344_h (AB002342). The 462 PCR product was amplified with primers CTCCTCAACAGACAGTGCAG (5′ primer) and GACATTCTACTACTCGGTCTC (3′ primer) designed from the N34132 extended contig and KIAA0344 sequences, respectively. The region of N34132 containing the start Met was isolated by PCR from a testis cDNA library (Clontech).

Human 5R69-17-2 (SEQ ID NO:67, SEQ ID NO:187)

The full-length ORF for 5R69-17-2 was isolated by screening a cDNA library using a probe derived from 5R69-17-2.

Human H85811 (SEQ ID NO:68, SEQ ID NO:188)

Tblastn, Smith-Waterman and blastn analyses using cDNA databases revealed an extension to encompass full-length ORF for H85811. The full ORF was reconstructed from Incyte ESTs 202971.8, 034583.3 and 034583.1 and public ESTs H85811 and AI570599.

Human R43524 (SEQ ID NO:73, SEQ ID NO:192)

Blastn analysis revealed an extension to encompass the complete catalytic region and the C-terminus of R43524. Since the initial Sling of this application, the partial R43524 sequence appeared in the public database as the full-length gene encoding the heme-regulated initiation factor 2-alpha kinase (HRI) (AF1 81071).

Human AA088547 (SEQ ID NO:78, SEQ ID NO:197)

Genewise and Genescan analyses of genornic databases revealed an extension to encompass the complete ORF for AA088547.

Human orthologue of AA139478_m (SEQ ID NO:80, SEQ ID NO:199) Tblastn identified the Incyte 211475.1 as the potential full-length human orthologue of murine AA139478

Human AA232253 (SEQ ID NO:82, SEQ ID NO:201)

The full-length ORF for AA232253 was isolated by screening a cDNA library using a probe derived from AA232253. Since the initial filing of this application, the AA232253 sequence appeared in the public database as the full-length gene encoding SLK (ABO11422). SLK is a stress-regulated mixed lineage kinase-like protein that activation of Rac and induction of apoptosis. cDNA library screening revealed multiple isoforms for this gene which are summarized in the Table below.

TABLE 9Isoforms for AA232253KestrlKestrl AAIsoformNameAcc #typeDescription*MLK4AA232253MLK4Substitution of C for W at 346MLK4BDifferent Cterm (332-800); seq inMLK4B is as shown in*
*C-terminus specific to MLK4B

LPLAARMSEESYFESKTEESNSAEMSCQITATSNGEGHGMNPSLQAMMLMGFGDI

FSMNKAGAVMHSGMQINMQAKQNSS

KTTSKRRGKKVNMALGFSDFDLSEGDDDDDDDGEEEDNDMDNSE

Human H97685 (SEQ ID NO:84, SEQ ID NO:203)

Blastn analysis revealed an extension to encompass the full-length ORF for H97685. The full ORF was reconstructed from Incyte 474824.1 and the public ESTs H97685 and M62021.

Human AI052250 (SEQ ID NO:87, SEQ ID NO:206)

Blastn analysis revealed an extension to encompass the full-length ORF for AI052250. The fall ORF was reconstructed from Incyte 396868.1, the public partial cDNA FLJ10074 (minus intron) and the public ESTs and the public ESTs AI052250 and H97685, AI499220 and M62021.

Human AA278842 (SEQ ID NO:88, SEQ ID NO:206)

A nearly full-length cDNA (FL4F12) for AA278842 was isolated by screening a cDNA library using a probe derived from AA278842. A full-length virtual ORF was generated using FL4AF12 and AA278842.

Human AA599286 (SEQ ID NO:89, SEQ ID NO:208)

Since the initial filing of this application, the partial AA599286 sequence appeared in the public database as a full-length ORF (AK000342).

Human AA425725 (SEQ ID NO:90, SEQ ID NO:209)

Since the initial filing of this application, the partial AA425725 sequence appeared in the public database as MSSK1, a serine kinase gene located from human chromosome Xq28.

Human SGK022 orthologue of AA060026_m (SEQ ID NO:91, SEQ ID NO:210)

Tblastn, Smith-Waterman and blastn analyses of cDNA and genomic databases databases revealed a potential human orthologue for murine AA060026. The full-length ORF for SGK022 was reconstructed from genomic locus AC022307.

Human AA399669 (SEQ ID NO:93, SEQ ID NO:212)

Blastn analysis revealed an extension to encompass the full-length ORF for AA399669. The full ORF was reconstructed as follows: sequence 1-1007 from AL136295.2; sequence1008-2319 from AA399669 and Incyte 428177.1.

Human AA883975 (SEQ ID NO:95, SEQ ID NO:214)

Genescan and Genewise analyses of the genomic databases revealed an extension for AA883975 to encompass the full-length ORF

Human AA905446 (SEQ ID NO:96, SEQ ID NO:215)

Tblastn, Smith-Waterman and blastn analyses of cDNA and genomic databases databases revealed an extension for AA905446 to encompass the full-length ORF. For the Smith-Waterman analysis murine STK22 ( NP_—033462) was used as the closest orthologue. Contig formation: range 162133-163687 from HGP_h 6921333_—9; removed intron (146-893) predicted from blastx analysis.

Human H29974 (SEQ ID NO: 97 SEQ ID NO:216)

Blastn analysis revealed an extension to encompass a complete catalytic ORF for AA399669. The nearly full-length ORF was reconstructed using Incyte 213829.1 and H29974.

Human AA215311 (SEQ ID NO:99, SEQ ID NO:218)

Blastn analysis revealed an extension to encompass the full-length ORF for AA21531. The full ORF was reconstructed from Incyte 067584.1, 022456.1, AA215311 and the reverse complement of CPG_—043208.

Human AA018361 (SEQ ID NO:100, SEQ ID NO:219)

The full-length ORF for AA018361 was isolated by screening a cDNA library using a probe derived from AA018361. This yielded clone Sug4-30. Clone Sug4-30, like multiple, independent cDNA clones contained a 181 bp intron. The existence of intron-less RNA's was confirmed by a PCR reaction that generated a product that upon sequence analysis skipped the intron region. The full-length virtual ORF for AA018361 was generated through a contig between AL117482 (seq 1-367) and the sequence for clone Sug4-30.

Human orthologue of AA396601_m (SEQ ID NO:106, SEQ ID NO:225)

tBlastn and Smith-Waterman analyses of genomic sequence revealed an extension to encompass the full catalytic region for the human orthologue of AA396601. The ORF was reconstructed from Incyte 018653.9 (7261449H1, 6891740J1) and genomic sequence CPG_—040010.

Human orthologue of AA671275_m (SEQ ID NO:108, SEQ ID NO:227)

Since the initial filing of this application, a potential human orthologue for murine AA671275 appeared in the public database as the full-length ORF for vaccinia related kinase 3 (BAA90769).

Human H05721 (SEQ ID NO:111, SEQ ID NO:230)

Genescan and Genewise analyses of genomic sequence revealed an extension to encompass the full-length ORF for H05721.

Human AI086865 (SEQ ID NO:112, SEQ ID NO:231)

Genescan and Genewise analyses of genomic sequence revealed an extension to encompass the full-length ORF for AI086865. The full-length ORF was reconstructed from Celera 17000102901516, Incyte 243269.1 and public AL1377531.

Human AA836348 (SEQ ID NO:113, SEQ ID NO:232)

Genescan and Genewise analyses of genomic sequence revealed an extension to encompass the full-length ORF for AA836348.

Human R86668 (SEQ ID NO:14, SEQ ID NO:233)

The full-length ORF for R86668 was isolated by screening a cDNA library using a probe derived from R86668. Since the initial filing of this application, the R8668 sequence appeared in the public database as the full-length gene mitogen-activated protein kinase kinase kinase 6 (MAP3K6)(NM_—00467).

Human 2R41-9-4 (SEQ ID NO:16, SEQ ID NO:235)

The full-length virtual ORF for 2R41-9-4 was generated using genomic sequence to provide the Nterminus for the partial ORF predicted from clone 2R41-9-4

TABLE 10Sequences deleted from the provisional patent dueto duplication with other genes in the patentProv. SEQ ID NO: (na)Prov. SEQ ID NO: (aa)1601962132142152161221261191231481844207232052061430153135564263517244657791789279938094157193

Results

Table 1 documents the results from the analysis of the nucleic acid sequence data. From left to right the data presented is as follows. “Gene name” refers to the EST or PCR fragment that defined the novel kinase. “Species” refers to the organism the sequence was derived from. “ID#” refers to the nucleic acid and amino acid sequence ID number designation from this patent. “Kinase family” and “Kinase group” refers to the protein kinase classification defined by sequence homology and based on previously established phylogenetic analysis [Hardie, G. and Hanks S. The Protein Kinase Book, Academic Press (1995) and Hunter T. and Plowman, G. Trends in Biochemical Sciences (1977) 22:18-22 and Plowman G. D. et al. (1999) Proc. Natl. Acad. Sci. 96:13603-13610)]. “ORF Start”, “ORF End”, “ORF Length” refer to the open reading frame range and length as calculated by standard nucleic acid translation programs such as MapDraw (DNAStar). “DNA Repeats” refers to regions of low complexity sequence or repetitive elements such as Alu, LINE, SINE, and LTR sequences. The chromosomal location (CHR localization) for 37 of the 110 novel protein kinases is shown on Table 1 (NA, not available). The methods for determining chromosomal position are outlined below, in Example 2.

Table 2 documents the results from the analysis of the amino acid sequence data. From left to right the data presented is as follows. “Gene name” refers to the EST or PCR fragment that defined the novel kinase. “Species” refers to the organism the sequence was derived from. “ID#” refers to the nucleic acid and amino acid sequence ID number designation from this patent. “Kinase family” and “Kinase group” refers to the protein kinase classification defined by sequence homology and based on previously established phylogenetic analysis [Hardie, G. and Hanks S. The Protein Kinase Book, Academic Press (1995) and Hunter T. and Plowman, G. Trends in Biochemical Sciences (1977) 22:18-22 and Plowman G. D. et al. (1999) Proc. Natl. Acad. Sci. 96:13603-13610)]. “nraa Score”, “ID match aa”, “Identity”, “Similar”, “nraa Match Acc#”, Description” refer to the data obtained using a Smith-Waterman search of the amino acid sequence against the non-redundant protein database (Matrix: Pam100; gap open/extension penalties 14/1). “Kinase Domain Start”, “Kinase Domain End”, “Profile Start” and “Profile End” refer to data obtained using a Hidden-Markov Model to define catalytic range boundaries. The profile has a length of 261 amino acids, corresponding to the complete protein kinase catalytic domain Proteins in which the profile recognizes a full length catalytic domain have a “Profile Start” of 1 and a “Profile End” of 261. The boundaries of the catalytic domain within the overall protein are noted in the “Kinase Domain Start” and “Kinase Domain End” columns.

The following abbreviations were used for kinases:

ASK Apoptosis signal-regulating kinase
K Ca2+/calmodulin-dependent protein kinase
RK Cell cycle-related kinase
CDK Cyclin-dependent kinase
CK Casein kinase
DAPK Death-associated protein kinase
DM myotonic dystrophy kinase
Dyrk dual-specificity-tyrosine phosphorylating-regulated kinase
GAK Cyclin G-associated kinase
GRK G-protein coupled receptor
GuC Guanylate cyclase
HEPK Homeodomain-interacting protein
IRAK Interleukin-1 receptor-associated kin
MAPK Mitogen activated protein kinase
MAST Micotubule-associated STK
MLCK Myosin-light chain kinase
MLK Mixed lineage kinase
NIMA NimA-related protein kinase
PKA cAMP-dependent protein kinase
RSK Ribosomal protein S6 kinase
RTK Receptor tyrosine kinase
SGK Serum and glucocorticoid-regulated kinase
STK serine threonine kinase
ULK UNC-51-like kinase

The following abbreviations were used for species

H Human
M Murine
R Rat
FV Fowlpox virus
MT M. thermoautotrophicum
CE Caenorhabditis elegans
DM Drosophila melanogaster
OS Oryza sativa
SP Schizosaccharomyces pombe
TP Tetrahymena pyriformis
PI Petunia inflata
NC Neurospora crassa
MSV Medicago sativa
MSV Moloney murine sarcoma virus
SA Squalus acanthias
CS Cucumis sativus
GM Glycine max
LL Lilium longiflorum
TV Trichomonas vaginalis
MP Mycoplasma pneumoniae
DD Dictyostelium discoideum
SC Saccharomyces cerevisiae
MT Methanobacterium thermoautotrophicum

Domain and Motif Identification

A Hidden Markov model (HMM) (Krogh, A., Brown, M., Mian, I. S., Sjolander, K, and Haussler, D. (1994). Hidden Markov models in computational biology: Applications to protein modeling. J. Mol. Biol., 235:1501-1531) was used to identify, both catalytic and extracatalytic domains. Table 4 shows extra-catalytic domains that were identified using the HMM program. Other domains such as coiled-coil and pest motifs were identified as described next.

Potential coiled-coil domains were identified using the COILS program (www.ch.embnet.org/software/COILS_form.html). The matrix used was MTIDK with windows of 14, 21, 28 amino acids. Only regions scoring 0.5 or higher were considered to have potential coiled-coil domain region.

Protein sequences containing potential pest motifs were identified using the program PESTfind (www.at.embnet.org/embnet/tools/bio/PESTfind/). PEST regions in proteins are by definition sequences that tend to be rich in proline, glutamic or aspartic acid, argininine and histidine; they have been associated with increased protein turnover rates (Rogers S. et al. (1986) Science 234, 364-368. The algorithm defines PEST sequences as hydrophilic stretches of amino acids greater than or equal to 12 residues in length. Such regions contain at least one P, one E or D and one S or T. They are flanked by lysine (K), arginine (R) or histidine (H) residues, but positively charged residues are disallowed within the PEST sequence. PESTfind produces a score ranging form about −50 to +50. By definition, a score above zero denotes a possible PEST region; a value greater than +5 defines a high probability that there is a PEST domain.

Identification of Potential Coiled-Coil Domains and PEST Domains in N34132

Potential coiled-coil domains were identified in N34132 (SEQ ID NO:183) using the COILS program. Only regions scoring 0.5 or higher were considered to have potential coiled-coil domain region. The amino acid positions within N34231 scoring for potential coil-coil regions are shown below.

TABLE 11coiled-coil domains predicted for N34132Coiled-coil RegionAmino acid rangeLength (aa)1124-147242437-451153495-5263241,723-1,74927

Potential PEST domains were identified in N34132 using PESTfind, a value greater than +5 defines a high probability that there is a PEST domain. The amino acid positions within N34132 scoring for potential PEST regions are shown below.

TABLE 12Potential Pest domains identified in N34132PEST RegionScoreAmino acid rangeAmino Acid Length1+4.9154-95422+11.4537-570343+31.081293-1304124+10.151543-1565235+6.171698-173235

Example 2
Chromosomal Localization of Novel Mammalian Protein Kinases Materials and Methods

Several sources were used to find information about the chromosomal localization of each of the genes described in this patent. First, the accession number for the nucleic acid sequence was used to query the Unigene database. The site containing the Unigene search engine is: http://www.ncbi.nlm.nih.gov/UniGene/Hs.Home.html. Information on map position within the Unigene database is imported from several sources, including the Online Mendelian Inheritance in Man (OMIM, http://www.ncbi.nlm.nih.gov/Omnim/searchomim.html), The Genome Database (http://gdb.infobiogen.fr/gdb/simpleSearch.html), and the Whitehead Institute human physical map (http://carbon.wi.mit.edu:8000/cgi-bin/contig/sts_info?database=release). For example, searching Unigene with W56561, an EST for a MAK-like kinase, the following information is retrieved: Chr.14, D14S65-qTEL. The location of this gene on an “ideogram” of the cytogenetic map of chromosome 14 is also provided, showing that W56561 maps to the bottom of chromosome 14, between 14q31 and 14qTel. If Unigene has not mapped the EST, then the nucleic acid for the gene of interest is used as a query against databases, such as dbsts and htgs (described at http://www.ncbi.nhn.nih.gov/BLAST/blast_databases.html) containing sequences that have been mapped already. The nucleic acid sequence is searched using BLAST-2 at NCBI (http://www.ncbi.nlm.nih.gov/cgi-bin/BLAST/nph-newblast) and is used to query either dbsts or htgs. In addition to the Whitehead and GDB sites mentioned above, Stanford University maintains a useful site for chromosomal mapping from STS data (http://www-shgc.stanford.edu/RH/rhserverformnew.html). Matches in htgs are often resolved immediately because the genomic region hit is annotated in the htgs entry. If an text missing or illegible when filed match is found (defined roughly as 99% identity over a region of about 100 pairs or longer, excluding any repetitive sequence), then the mapped position of the entry in the database is assigned to the original kinase query. Once a cytogenetic region has been identified by one of these approaches, disease association is established by searching OMIM (see above for URL) with the cytogenetic location. OMIM maintains a searchable catalog of cytogenetic map locations organized by disease. A thorough search of available literature for the cytogenetic region is alo made using Medline (http://www.ncbi.nlm.nih.gov/PubMed/medline.html). References for association of the mapped sites with chromosomal abnormalities found in human cancer can be found in: Knuutila, et al., Am J Pathol, 1998, 152:1107-1123.

Results

The chromosomal location for 37 of the 110 novel protein kinases is shown on Table 1. Three of the novel protein kinases were mapped to regions associated with cancer amplicons, as shown on this table. The regions were also cross-checked with the Mendelian Inheritance in Man database, which tracks genetic information for many human diseases, including cancer. References for association of the mapped sites with chromosomal abnormalities found in human cancer can be found in: Knuutila, et al., Am J Pathol, 1998, 152:1107-1123. Association of these mapped regions with other diseases is documented in the Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/htbin-post/Omim).

Example 3
Generation of Specific Immunoreagents

Materials and Methods

Peptide sequences to extra-catalytic regions of novel kinases are chosen which are not homologous to other known kinases based on a Smith Waterman homology search against the non-redundant protein database and predicted to be antigenic based on the DNAStar Protean program. These peptides are conjugated to KLH using Glutaraldehyde.

Rabbits are immunized with the KLH-peptide conjugates by four injections three weeks apart. The rabbits are bled ten and fourteen days following the third injection and bled out ten days after the fourth. The serum is checked against the peptide by ELISA.

TABLE 13Peptides to be used as immununogens for raisingantibodiesCloneSEQ IDAminoNameNO (aa)Peptide SequenceLocationAA8256850124KSRDNSRDSSQSEND339-353TEKLKRSQDLPREPLP372-386RGWRPYDIHS223-2325R79-46-1126FEGPRRNKEVMYK224-236KDDYNETVHKKTE451-463GTHPKDRNVEKLQ541-553EVSKYQEYTNELQET643-657AA256100129IDDTSNFDDFPESDI405-419TEPDYKSKDWVFL427-439EEKKLRRSQHARKET61-75AA210825130SNKDTLRKRHYWRLD507-521RHTTRKSSTTLRE488-500FQNNTTNRYYKEIPL528-542GKHRKTGRDVAVK668-680FPTKQESQLRNE687-698AA316804132ESHVHQEPSKRIPS239-252HTKRKSSTMVKEGW409-422PSDLDVERDEEAVK375-388SPGQGKDHKDLSTSI543-557R47805143EPVGRWDQDYDRAVL44-58KPKGPGGKRGHKRLI325-339PTDVAQLPSRVPRDA219-233AA234451167DPFDWEKTGNDGSLT293-307HPRPQEKDVWEE374-385RENTDEVFPDEQLSD340-354RSEITQPDRDIPLVR427-441AA460132180LKSYSTSSKKARPVL222-236KKLDEVRLRGRKRSM237-251ETEKTAQGLSNLAKT131-145N34132183SGRRRRPTKSKGSKS1848-1862PGTAPSKPPLTKAPV1474-1488VDSDTQPKAPGIDD1365-1378AHSLDKTSHSSTTGL1253-12675R69-17-2187GTTREKTDRVKST178-190HSEAPELHGKIRSSN138-152DETVTPPQFSIV87-98QYDVKSEIYS204-213AA278842206TVDPEKSVRDQAFKA515-529DSSTADRWDDEDWGS637-651SVSEDPTQLEEVEKD539-553AA836348232NAPTKRPRSSTVTEA323-337LDSEEDYYTPQKVDV514-528GDKASYRQPKHVEKL409-423

Example 4
Expression analysis of Novel Mammalian Protein Kinases

Gene Expression Analysis

Tissue Arrays

“cDNA libraries” derived from a variety of sources were immobilized onto nylon membranes and probed with 32P-labeled cDNA fragments derived from the gene(s) of interest.

Total RNA or mRNA was used as template in a reverse transcription reaction to generate single-stranded cDNAs (ss cDNA) that were tagged with specific sequences at each end. An oligo dT primer containing a specific sequence (CDS: AAGCAGTGGTAACAACGCAGAGTACT30VN (V=A,G,C N=A,G,C,T)) anneals at the polyA track at the 3′ end of the mRNA and the reverse transcriptase (MMLV RnaseH-) transcribes the antisense strand until it reaches the end of the RNA strand when it adds additional C residues. If a primer (SMII: AAGCAGTGGTAACAACGCAGAGTACGCGGG or ML2G: AAGTGGCAACAGAGATAACGCGTACGCGGG) ending with 3 Gs is added, it anneals to the added Cs and the MMLV recognizes the rest of the primer sequence as template and continues transcription. As a result, the synthesized cDNAs contain specific sequence tags at both the 5′ and the 3′ end. When the 5′ and the 3′ ends are tagged with the same sequence (CDS and SMII) it is referred to as “symmetric.” When the 5′ end is tagged with a different sequence than the 3′ end (CDS and ML2G) is referred to as “asymmetric” A double-stranded “cDNA library” is then generated by PCR amplification using the 3′PCR and ML2 primers (3′ PCR: AAGCAGTGGTAACAACGCAGAGT and ML2:AAGTGGCAACAGAGATAACGCGT) that anneal to the added sequence tags.

The amplified “cDNA libraries” were manually arrayed onto nylon membranes with a 384 pin replicator. The DNA was denatured by alkali treatment, neutralized and cross-inked by WV light. The arrays were pre-hybridized with Express Hyb (Clontech) and hybridized with 32P labeled probes generated by random hexamer priming of cDNA fragments corresponding to the genes of interest. After washing, the blots were exposed to phosphorimaging cassettes and the intensity of the signal was quantified. The amount of the DNA on the arrays was also quantified by treating non-denatured or denatured arrays with Syber Green I or Syber Green II respectively (1:100,000 in 50 mM Tris, pH8.0) for 2 minutes. After washing with 50 mM Tris, pH8.0, the fluorescent emission was detected with a phosphorimager (Molecular Dynamics) and quantified. The amount of the arrayed DNA was used to normalize the hybridization signal and the corrected values are tabulated in Table 3.

Results

The results of the microarray expression analysis of the protein kinases presented in this application is shown in Table 3. Data presentation from left to right is as follows: “Tissue”: tissue type of the cDNA; “Tumor sym”, indicates that the tissue is derived from a tumor, “sym” refers to the fact that the 5′ and 3′ primers used to make the sample are the same; “Normal Sym”, indicates normal tissue was used to make the sample, with symmetric primers as described above; “Tumor lo”, indicates that primary tumor tissue was used to make the cDNA; “Tumor cells”, indicates that these cDNA samples were made from cultured tumor cells; “Normal”, indicates that these samples are derived from normal tissue or cell lines; “Endos”, indicates that these samples are derived from endothelium-related tissue sources; “p53” refers to the status, mutant or wild-type, of the p53 gene in the source samples. Normalized expression values are presented for each gene referred to by its SEQ ID# on the subsequent columns. Genes represented in expression Table 3 are: SEQ ID NO:3 (AA826850), SEQ ID NO:5 (TBK1), SEQ ID NO:6 (AA305176), SEQ ID NO:8 (AA256100), SEQ ID NO:9 (CAB43292), SEQ ID NO:11 (EPK2), SEQ ID NO:12 (PKNbeta), SEQ ID NO:14 (H19102), SEQ ID NO:16 (RSK4), SEQ ID NO:17 (AAD30182), SEQ ID NO:20 (SGK2), SEQ ID NO:22 (PTK9L), SEQ ID NO:26 (AA383293), SEQ ID NO:29 (DRAK2), SEQ ID NO:31 (DRAK1), SEQ ID NO:032 (AA015726), SEQ ID NO:40 (MAK-V), SEQ ID NO:044 (TRAD), SEQ ID NO:044 (TRAD), SEQ ID NO:45 (AA454060), SEQ ID NO:47 (AA234451), SEQ ID NO:48 (AA436054), SEQ ID NO:49 (AA626859), SEQ ID NO:51 (KIAA0904), SEQ ID NO:52 (AA789239), SEQ ID NO:54 (CCRK), SEQ ID NO:55 (CLK4), SEQ ID NO:56 (AA557536), SEQ ID NO:57 (W56561), SEQ ID NO:60 (AA579641), SEQ ID NO:63 (NEK7), SEQ ID NO:66 (CAMKKB), SEQ ID NO:68 (HIPK2), SEQ ID NO:72 (R19609), SEQ ID NO:73 (HRI), SEQ ID NO:78 (AA088547), SEQ ID NO:79 (AA449542), SEQ ID NO:082a (MLK4), SEQ ID NO:82 (MLK4b), SEQ ID NO:84 (RIP4), SEQ ID NO:88 (AA278842), SEQ ID NO:89 (AA195964), SEQ ID NO:90 (MSSK1), SEQ ID NO:93 (TSK4), SEQ ID NO:94 (AI025291), SEQ ID NO:95 (AA948538), SEQ ID NO:96 (AA905446), SEQ ID NO:97 (H85389), SEQ ID NO:100 (AA018361), SEQ ID NO:101 (AA311714), SEQ ID NO:110 (AA452647), SEQ ID NO:111 (AA310219), SEQ ID NO:1 12 (AI086865), SEQ ID NO:114 (MEKK6), and SEQ ID NO:116 (SuRTK106).

Example 5
Kinase Assays for Erk, JNK1 and D38 MAP Kinases

293T cells were transiently transfected with HA-p38 or co-transfected with Flag-tagged wt MIX4A, kinase-dead MIX4A, wild-type MLK4B or kinase-dead MLK4B using Lipofectarmine 2000 (Lifetech). Cells were lysed 36 hr post-transfection. Cell lysates normalized to contain equivalent amounts of HA-p38 were immunoprecipitated with anti-HA antibody (Mab HA-11, Babco). Immunoprecipitates were split in two portions, one portion was Western-blotted with anti-HA antibody and the other with a text missing or illegible when filed o-specific p38 antibody (Promega) to detect activated levels of p38. Activation of Jnk1 was measured similarly. (This example applies to AA232253 (SEQ ID NO:82, SEQ ID NO:201).)

Results:

In transient assays wild-type MLK4A and MLK4B (but not kinase-inactive MLK4A(K45M) or MLK4B(K45M)) activate Erk, JNK1 and p38 MAP kinases.

Example 6
RAC1 Guanine-Exchange Factor Assay

293T cells were transiently transfected with HA-Rac1 or co-transfected with Flag-tagged Duet C, Duet E, Dbl and HA-Tiam-1. Cells were lysed 36 hour post-transfection. Cell lysates normalized to contain equivalent amounts of Rac1 were affinity precipitated with immobilized GST-PBD (p21-binding domain of Pak3). Bound proteins were Western blotted and probed with anti-HA antibody to detect levels of activated Rac1. ((This example applies to R199772 (Trad/Duet)(SEQ ID NO:44, SEQ ID NO:164).)

Results:

Duet C and Duet E both act as guanine nucleotide exchange factors on Rac1.

CONCLUSION

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The molecular complexes and the methods, procedures, treatments, molecules, specific compounds described herein are presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.

All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

In particular, although some formulations described herein have been identified by the excipients added to the formulations, the invention is meant to also cover the final formulation formed by the combination of these excipients. Specifically, the invention includes formulations in which one to all of the added excipients undergo a reaction during formulation and are no longer present in the final formulation, or are present in modified forms.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully describe

Other embodiments are within the following claims.

TABLE 1Gene Name5PProv_Seq_ID_NAProv_Seq_ID_AASeq_ID_ text missing or illegible when filed

_naSeq_ID_ text missing or illegible when filed

_aaFamilyGroupX69117_h_BARK2_hHxx1122AGCGRKAA144574_m BARK2_mM1172123AGCGRKAA826550_hH1401763124AGCMo3C11.1_caAA950957_hH11274125AGCMo3C11.1_ca5R79-45-1_h, TBK1_hH2072065126AGCMo3C11.1_caAA305176_hH4, 218, 206127AGCNDRAA116841_mM4, 218, 207128AGCNDRAA256100_hH3198129AGCNDRAA210825_hH5219130AGCPKCAA127299_hH20320410131AGCPKCAA316604_h, EPK2H62211132AGCPKCN42050_h PKNbetaH text missing or illegible when filed

2412133AGCPKCAI021023_m PKNbeta_mMx text missing or illegible when filed

13134AGCPKCH19102_hH122814135AGCS6KAA476563_h RPS6KC1H92515136AGCS6KAA626690_h RSK4H102616137AGCS6KAA215680_hH22722617138AGCS6KSGK_hHxx18139AGCSGKAA107515_mMxx19140AGCSGKAA109506_mM132920141AGCSGKAA557783_h SGK3, SGKLH103221142AGCSGKR47805_h PTK9LH13116722143AtypicalA6H60215_hH335423144CAMKAMPKSGK324_hHxx24145CAMKCAMKW30246_m SGK324_mM365725146CAMKCAMKAA383293_hH385926147CAMKCAMKAA197883_mM345528148CAMKCAMKAA172300_h DRAK2H375829149CAMKDAPKW44150_m DRAK2_mMxx30150CAMKDAPKH01248_h, DRAK1_hH406131151CAMKDAPKAA021445_hH456632152CAMKEMK2R22-5-11_hH436433153CAMKEMKR31237_1_h, AAC33487Hxx34154CAMKEMKW90839_mM497035155CAMKEMK406785, 5_hHx text missing or illegible when filed

36156CAMKEMKAA544838_m 406786_mM486937157CAMKEMKAA785735_hHx text missing or illegible when filed

38158CAMKEMKAA207220_hH466739159CAMKEMKAA426580_h, MAK_V_hH476640160CAMKEMKZ36720_hH507141161CAMKMLCKSGK068_hHx text missing or illegible when filed

42162CAMKTrioAA542015_m SGK088_mM398043163CAMKTrioR19772_hH527344164CAMKTrio5R72_8_2_hH537445165CAMKUniqueSGK309_hH15919546166CKICKIAA234451_hH757547167CKICKIAA435956_hH829548168CMGCCDKAA625859_hH849849169CMGCCDKAA061797_mMx text missing or illegible when filed

50170CMGCCDKAA397553_h CRK7H619551171CMGCCDKAA769239_hH859952172CMGCCDKAA124976_mMxx53173CMGCCDKAA575635_m CCRK_mMxx54174CMGCCDKAA631990_h CLK4H10510755175CMGCCLKAA557536_hH6910356176CMGCRCKN28806_h, MOKH9010457177CMGCRCKAB023153_h, ICKH text missing or illegible when filed

x58178CMGCRCKAA839940_mM text missing or illegible when filed

x59179CMGCRCKAA460132_hH16520160180Microbial PKYGR262_ text missing or illegible when filed

cSGK034_hH text missing or illegible when filed

x61181OtherC26C2_ceAA103218_m SGK034_mM14718362182OtherC26C2_ceNEK7_h, N34132_hH12212563183OtherC26C2_ceBCON3_hHxx64184OtherC26C2_ceAA711629_mM14818465185OtherC26C2_ceAA099102_h_CaMKKBH13216866186OtherCAMKK5R69_17_2_hH15819467187OtherCTR1H85811_hH13417068188OtherDYRKAA02193_h DYRK3Hxx69189OtherDYRKAA589241_m DYRK3_mM13316970190OtherDYRK5R72_16_2_h, R19927_hH10011271191OtherEIFKR43524_h, HR1_h, R19609H11111473192OtherEIFK17000057519457_hHxx74193OtherEndopAA013524_mM13517175194OtherEndop17000139801197_h, IRAKMHxx76195OtherIRAKAA840598_m IRAKM_mM13717377196OtherIRAKAA088547_hH13817478197OtherIREHGP_5644468Hxx79198OtherKYK2_ddAA449542_mM13917580199OtherKYK2_dd5R57_10_2_m TESK2_mM11511681200OtherLIMKAA232253_hH11711882201OtherMLKAI375137_hH20921083202OtherMLKH97865_hH14317984203OtherRIPW20810_mM14418085204OtherRIPAA744236_hH21121286205OtherSCY1_scAI052250_hH22522687206OtherSCY1_scAA276842_hH16420088207OtherSCY1_scAA599288_hH14518189208OtherSLO87AA425725_hH14818290209OtherSRPKSGK022_1_hHxx91210OtherSTK22AAA050025_m SGK022_mM14918592211OtherSTK22AAA399669_hH15018693212OtherSTK22AAA758539_hH15118794213OtherSTK22AAA853975_hH15318995214OtherTSKAA905445_hH22222496215OtherTSKH29974_hH5810297216OtherUNCAA498104_m H29974_mMxx98217OtherUNCAA215311_hH15519199218OtherUNCAA018361_hH154190100219OtherUNCAA311714_hH156192101220OtherUNCSGK384_hHxx102221OtherUniqueAA210451_m SGK384_mM106108103222OtherUniqueSGK071_2_hHxx104223OtherUniqueAA115352_m SGK071_mM161197105224OtherUniqueO18653.9_hH162198106225OtherUniqueAA396601_mMxx107226OtherUniqueAA671275_h VRK3H153199108227OtherVRKS71575_m VRK3_mMxx109228OtherVRKAA452647_h MPSK1H138172110229OtherYPL238_scH05721_hH100202111230OtherYC09_ceAI086865_hH86100112231STENEKAA638348_hH120124113232STENEKR86668_h, MKK8H121125114233STESTE11PAK6_h 5R95-20-11H219220115234STESTE20-02SuRTK108_h 2R41-9-4_hH128, 127129, 130116235TKRTK-20AA096024_mM128, 127130117236TKRTK-20SGK2alpha_hHxx118237AGCSGKH06950_h_CCRKH67101120238CMGCCDKNM_007170_h TESK2Hxx121239OtherLIMKGene NameLength_NALength_AAORF_StartORF_endORF_LengthDNA RepeatsCHR localizationX69117_h_BARK2_h2067658120642064x22q11AA144574_m BARK2_m1365378211351134xNAAA826550_h1785419812641257285-304NAAA950957_h32244145513061242x4p16.15R79-45-1_h, TBK1_h30137299322792167xNAAA305176_h1421329531039 text missing or illegible when filed

67x10p11.2AA116841_m562883260264xNAAA256100_h49834545614771392x12q11AA210825_h326397811730502934x19q13-q13.3AA127299_h3151051315315xNAAA316604_h, EPK22673890126702670x2p21N42050_h PKNbeta26708891266726672221-2280NAAI021023_m PKNbeta_m9292052615815xNAH19102_h1155384111521152599-635CHR17AA476563_h RPS6KC11410459114071407x12q12-q13.1AA626690_h RSK42238745122352235xxq21.1AA215680_h1650549115471547757-78614q24.3SGK_h1296431112931293856-8835q21-q22AA107515_m243243075136412901804-1830NAAA109506_m13462442733732xNAAA557783_h SGK3, SGKL22504453613731338xNAR47805_h PTK9L1050349110471047x3p14.3H60215_h231044042017381320x1p31.1-1p32.3SGK324_h3240692720622076208-227NAW30246_m SGK324_m12482971891591xNAAA383293_h2424685120582058439-458NAAA197883_m2421805124182418xNAAA172300_h DRAK2162637326213801119x2q31-2q24.3W44150_m DRAK2_m267137217112851116xNAH01248_h, DRAK1_h1245414112421242 91-1107p11-q11AA021445_h4321131114640783933x11q22.1-11q22.32R22-5-11_h23114368712178130681-2251, 1256-12NAR31237_1_h, AAC334872190729121572157xNAW90839_m1594520115801560xNA406785, 5_h413913307740853990x2q34-q37AA544838_m 406786_m13502303692 text missing or illegible when filed

1002-1022NAAA785735_h518392615529322776xNAAA207220_h229162910319591587xNAAA426580_h, MAK_V_h2145714121422142x21q11Z36720_h2625874126222622xNASGK068_h77102285158588858xNAAA542015_m SGK088_m12511271381381xNAR19772_h38541287130613861x3q13.3-q215R72_8_2_h258851440519471542x11p15.1-11p15.2SGK309_h18205069716201524843-852NAAA234451_h245247840516391434xNAAA435956_h10772661796795xNAAA625859_h9112472742741 54-119NAAA061797_m26152962689885xNAAA397553_h CRK7447314901447044701210-1238NAAA769239_h1 text missing or illegible when filed

534618071802x5q23-q23.3AA124976_m1 text missing or illegible when filed

337110111011xNAAA575635_m CCRK_m13802111633633163-191NAAA631990_h CLK424884993415301497xNAAA557536_h18315453016641635516-538NAN28806_h, MOK1260419112571257x14q32AB023153_h, ICK1599632118961896xNAAA839940_m1776413112391239xNAAA460132_h1428253199957759x20q12 AmpliconSGK034_h3304462113661386xNAAA103218_m SGK034_m23282512544843xNANEK7_h, N34132_h73281952425897 text missing or illegible when filed

x12p13.33BCON3_h216453811317171608246-267NAAA711629_m1568378111341134xNAAA099102_h_CaMKKB176758811764176465-8412q23-q145R69_17_2_h338724116502572723499-521NAH85811_h39931171163369535131326-1348CHR7AA02193_h DYRK3214155325319111859xNAAA589241_m DYRK3_m7411683500504xNA5R72_16_2_h, R19927_h516318492049584947xNAR43524_h, HR1_h, R196091693530118901890x7p22-p22.317000057519457_h30552532199777592263-2365NAAA013524_m9282181648648xNA17000139801197_h, IRAKM1791595117881758xNAAA840598_m IRAKM_m2243392111751175xNAAA088547_h2759922127562766xNAHGP_564446818573221791144906xNAAA449542_m12512802641840602-621NA5R57_10_2_m TESK2_140412124123xNAmAA232253_h2403800124002400xNAAI375137_h25088351250525052219-2238NAH97865_h238483416120621002x1q31W20810_m10732893859567xNAAA744236_h2067685120842064x1q23AI052250_h173950517416351515xNAAA276842_h2658508105252824241764-178311q12-q13 AmpliconAA599288_h1949549119491949xNAAA425725_h1602533115991599xXq28SGK022_1_h1038268154987804xNAAA050025_m SGK022_m1004268147950804xNAAA399669_h15372923721244808x14p11-q11AA758539_h132235810111741074xNAAA853975_h8222731819819xNAAA905445_h10652163651012645xNAH29974_h163833321000999xNAAA498104_m H29974_m1490412112381238701-729NAAA215311_h201134119912211023xNAAA018361_h276948111315551443x15q23AA311714_h187556513818331595xNASGK384_h117391117117xNAAA210451_m SGK384_m2721349222126810472251-2288NASGK071_2_h211570412112211257-76, 318-337NAAA115352_m SGK071_m1729540315221820xNAO18653.9_h2461540116201620240-259NAAA396601_m1886385310971095xNAAA671275_h VRK31425474114221422x19q13S71575_m VRK3_m10092343704702937-957NAAA452647_h MPSK19153061915915x3cen-3q21H05721_h26385819515371743x1p32.3-31 AmpliconAI086865_h2463598721002094xNAAA638348_h2511838125082508xNAR86668_h, MKK830361011130333033x1p32.3-p31. text missing or illegible when filed

PAK6_h 5R95-20-112180719121572157x20p12SuRTK108_h 2R41-9-4_h2480495114851485x12p12.3AA096024_m179315315495491352-1362NASGK2alpha_h18123878811851101xNAH06950_h_CCRK1359452113581358x9q21.1-q21.3NM_007170_h TESK2301655539620601585xNA

TABLE 2

Patent
Patent

ID

nraa

Seq
Seq

nraa
Length
match
%
%
Match

SP
ID# na
ID# aa
Family
Group
Pscore
aa
aa
Identity
Similar
ACC#

H
1
122
AGC
GRK
2.7e−314
688
687
100
100
CAB45857.1

M
2
123
AGC
GRK
1.30E−190
378
371
98
99
NP_037029.1

H
3
124
AGC
o3C11.1_ce
5.80E−106
419
262
71
86
CAB76471.1

H
4
125
AGC
o3C11.1_ce
1.40E−137
414
414
100
100
CAB76471.1

H
5
126
AGC
o3C11.1_ce
0
729
729
100
100
|NP_037386.1

H
6
127
AGC
NDR
1.20E−09
329
73
46
66
BAA76817.1

M
7
128
AGC
NDR
1.30E−19
88
42
49
71
AAF55594.1

H
8
129
AGC
NDR
6.10E−181
464
463
100
100
BAA76809.1

H
9
130
AGC
PKC
8.60E−160
978
615
67
80
NP_002733.1

H
10
131
AGC
PKC
1.10E−10
105
42
42
57
P05127

H
11
132
AGC
PKC
0
890
590
100
100
NP_005804.1

H
12
133
AGC
PKC
9.4e−319
589
589
100
100
NP_037487.1

M
13
134
AGC
PKC
1.20E−106
205
204
100
100
JC7083

H
14
135
AGC
S6K
3.60E−12
384
94
38
55
AAC62495.1

H
15
136
AGC
S6K
2.90E−257
469
469
100
100
NP_036556.1

H
16
137
AGC
S6K
7.00E−176
745
745
100
100
NP_055311.1

H
17
138
AGC
S6K
9.60E−222
549
649
100
100
AAD30182.1

H
18
139
AGC
SGK
9.20E−103
431
430
100
100
AAD41091.1

M
19
140
AGC
SGK
2.90E−157
430
426
99
99
NP_035491.1

M
20
141
AGC
SGK
2.00E−76
244
244
100
100
AAF12757.2

H
21
142
AGC
SGK
4.10E−211
446
375
88
88
AAF27051.1

H
22
143
Atypical
A6
5.60E−216
349
349
100
100
NP_009215.1

H
23
144
CAMK
AMPK
1.40E−19
440
68
39
61
CAA04119.1

H
24
145
CAMK
CAMK
1.50E−165
699
466
65
77
O15075

M
25
146
CAMK
CAMK
1.60E−62
297
199
67
83
AAF26675.1

H
26
147
CAMK
CAMK
2.60E−48
708
181
44
60
O15075

M
28
148
CAMK
CAMK
2.60E−31
806
147
55
73
AAF26675.1

H
29
149
CAMK
DAPK
3.10E−121
372
372
100
100
NP_004217.1

M
30
150
CAMK
DAPK
7.90E−93
372
340
91
95
NP_004217.1

H
31
151
CAMK
DAPK
1.20E−113
414
414
100
100
NP_004751.1

H
32
152
CAMK
EMK
5.90E−165
1311
1053
80
80
BAA76843.1

H
33
153
CAMK
EMK
1.20E−45
436
153
51
70
T22427

H
33
153
CAMK
EMK
1.40E−32
436
122
46
65
AAC15093.1

H
34
154
CAMK
EMK
1.30E−184
729
729
100
100
AAC15093.1

M
35
155
CAMK
EMK
3.50E−126
462
462
100
100
AAC33487.1

H
36
156
CAMK
EMK
0
1330
1235
100
100
BAA09484.1

M
37
157
CAMK
EMK
5.10E−59
230
183
79
85
BAA09484.1

H
38
158
CAMK
EMK
3.00E−111
926
636
100
100
BAA34501.1

H
39
159
CAMK
EMK
7.30E−80
629
367
57
69
NP_055655.1

H
40
160
CAMK
EMK
1.40E−244
714
714
100
100
NP_055401.1

H
41
161
CAMK
MLCK
8.20E−76
874
211
63
80
AAA73168.1

H
42
162
CAMK
Trio
0
2286
2227
100
100
BAA92535.1

M
43
163
CAMK
Trio
7.60E−37
127
67
99
99
BAA92535.1

H
44
164
CAMK
Trio
0
1287
1264
100
100
NP_008995.1

H
45
165
CAMK
Unique
5.00E−20
514
114
41
63
P25323

H
46
166
CKI
CKI
3.30E−89
508
181
53
65
AAF59340.1

H
47
167
CKI
CKI
8.60E−98
478
188
57
68
AAF59340.1

H
48
168
CMGC
CDK
9.60E−39
266
138
62
79
NP_036527.1

H
49
169
CMGC
CDK
7.10E−48
247
146
59
75
NP_004187.1

M
50
170
CMGC
CDK
2.90E−64
296
193
65
78
NP_004187.1

H
51
171
CMGC
CDK
1.10E−264
1490
1490
100
100
AAF36401.1

H
52
172
CMGC
CDK
9.20E−101
534
377
82
82
AAF36509.1

M
53
173
CMGC
CDK
1.40E−128
337
225
92
96
AAF34871.1

M
54
174
CMGC
CDK
3.00E−68
211
159
79
84
NP_036261.1

H
55
175
CMGC
CLK
1.50E−242
499
436
91
93
NP_031740.1

H
56
176
CMGC
RCK
9.10E−89
544
343
57
64
AAD12719.1

H
57
177
CMGC
RCK
2.30E−189
419
419
100
100
NP_055041.1

H
58
178
CMGC
RCK
1.50E−180
632
632
100
100
AAF37278.1

M
59
179
CMGC
RCK
1.60E−79
413
198
60
77
P20689

H
60
180
Microbial PK
YGR262_sc
2.50E−45
253
102
46
67
AAF50799.1

H
61
181
Other
C26C2_ce
2.30E−158
509
258
100
100
CAB70864.1

M
62
182
Other
C26C2_ce
1.80E−152
281
243
94
98
CAB70864.1

H
63
183
Other
C26C2_ce
8.70E−300
1952
1193
99
99
NP_055638.1

H
64
184
Other
C26C2_ce
1.10E−254
535
535
100
100
NP_037524.1

M
65
185
Other
C26C2_ce
2.50E−208
378
372
98
100
NP_037624.1

H
66
186
Other
CAMKK
3.80E−148
588
588
100
100
AAD31507.1

H
67
187
Other
CTR1
9.90E−24
287
87
33
52
JQ1743

H
68
188
Other
DYRK
0
1171
1137
97
99
AAD52566.1

H
69
189
Other
DYRK
2.10E−280
553
553
100
100
NP_003573.1

M
70
190
Other
DYRK
2.30E−95
168
149
90
96
NP_003573.1

H
71
191
Other
EIFK
0
1649
1493
90
98
NP_038747.1

H
73
192
Other
EIFK
1.50E−220
630
630
100
100
NP_055228.1

H
74
193
Other
Endop
2.50E−45
253
102
46
67
AAF50799.1

M
75
194
Other
Endop
3.70E−45
216
100
45
64
AAF50799.1

H
76
195
Other
IRAK
0
596
596
100
100
NP_009130.1

M
77
196
Other
IRAK
1.20E−170
392
293
75
85
NP_009130.1

H
78
197
Other
IRE
1.5e−323
922
746
82
69
NP_036146.1

H
79
198
Other
KYK2_dd
8.70E−40
225
102
45
62
AAF48758.1

M
80
199
Other
KYK2_dd
5.90E−32
280
109
32
50
AAF48758.1

M
81
200
Other
LIMK
2.60E−17
41
37
92
95
NP_009101.1

H
82
201
Other
MLK
2.50E−282
800
799
100
100
AAF63490.1

H
83
202
Other
MLK
8.60E−251
835
835
100
100
AAD29832.1

H
84
203
Other
RIP
2.20E−158
634
365
100
100
BAA32317.1

M
85
204
Other
RIP
5.30E−158
289
288
100
100
AAF03133.1

H
86
205
Other
SCY1_sc
0
688
688
100
100
CAB55300.1

H
87
206
Other
SCY1_sc
1.70E−209
505
354
98
98
BAA92598.1

H
88
207
Other
SCY1_sc
2.20E−157
808
396
45
61
AAF56933.1

H
89
208
Other
SLOB?
7.40E−196
649
649
100
100
BAA91097.1

H
90
209
Other
SRPK
5.80E−252
533
533
100
100
NP_0.55185.1

H
91
210
Other
STK22A
3.80E−53
268
122
46
70
NP_033461.1

M
92
211
Other
STK22
2.70E−52
268
127
48
68
NP_033462.1

H
93
212
Other
STK22A
4.60E−16
292
112
45
64
NP_033461.1

H
94
213
Other
STK22A
5.10E−123
358
322
90
96
NP_033462.1

H
95
214
Other
TSK
2.10E−33
273
122
46
62
NP_033461.1

H
96
215
Other
TSK
2.50E−32
216
93
41
58
NP_033462.1

H
97
216
Other
UNC
0.000062
333
57
36
56
AAD32767.1

M
98
217
Other
UNC
0.002492
412
53
37
52
BAA77341.1

H
99
218
Other
UNC
0.001096
341
50
36
56
BAA77341.1

H
100
219
Other
UNC
1.90E−68
480
247
100
100
T17265

H
101
220
Other
UNC
1.60E−208
585
468
96
96
BAA91270.1

H
102
221
Other
Unique
6.70E−10
39
27
69
90
AAD00575.1

M
103
222
Other
Unique
0.000022
349
38
30
50
CAA18116.1

H
104
223
Other
Unique
0.000126
704
54
30
45
BAA86576.1

M
105
224
Other
Unique
0.007365
540
25
42
61
AAF47916.1

H
106
225
Other
Unique
0.31334
540
52
30
42
P10162

M
107
226
Other
Unique
0.022948
365
25
34
57
NP_006276.1

H
108
227
Other
VRK
3.10E−263
474
474
100
100
BAA90769.1

M
109
228
Other
VRK
1.20E−111
234
191
82
90
BAA90769.1

H
110
229
Other
YPL236_sc
7.40E−144
305
304
100
100
AAC28337.1

H
111
230
Other
YQ09_ce
6.10E−49
561
135
43
63
AAF46188.1

H
112
231
STE
NEK
3.30E−30
698
122
48
67
P51954

H
113
232
STE
NEK
2.70E−119
836
357
86
86
AAD31939.1

H
114
233
STE
STE11
1.10E−291
1011
1011
100
100
NP_004663.1

H
115
234
STE
STE20-02
7.70E−177
719
719
100
100
BAA94194.1

H
116
235
TK
RTK-20
4.90E−24
495
77
36
56
AAA98465.1

M
117
236
TK
RTK-20
5.30E−18
183
53
39
57
NP_032036.1

H
118
237
AGC
SGK
6.30E−112
367
367
100
100
AAF12757.2

H
120
238
CMGC
CDK
2.80E−137
452
452
100
100
NP_036251.1

H
121
239
Other
LIMK
6.50E−233
555
555
100
100
NP_009101.1

Kinase
Kinase

Domain(s)
Domain (s)
Profile
Profile

SP
Description
start
end
start
end

H
BARK2 [Homo sapiens]
191
453
1
261

M
Adrenergic receptor kinase, beta 2 (G-protein-linked receptor kk text missing or illegible when filed

3
143
121
261

H
Serine/threonine protein kinase [Homo sapiens]
26
286
1
261

H
Serine/threonine protein kinase [Homo sapiens]
23
283
1
261

H
TANK-binding kinase 1 [Homo sapiens]
9
304
1
261

H
KIAA0973 protein [Homo sapiens]
35
310
1
261

M
CG7719 gene product [Drosophila melanogaster]
24
44
242
261

H
KIAA0965 protein [Homo sapiens]
90
383
1
261

H
Protein kinase C, mu [Homo sapiens]
651
907
1
261

H
Protein kinase C, BETA-II TYPE (PKC-BETA-2) [Homo sapiens]
19
24
256
261

H
Protein kinase C, nu [Homo sapiens]
576
832
1
261

H
PKNbeta [Homo sapiens]
559
816
1
261

M
Protein kinase N beta [Homo sapiens]
1
134
126
261

H
Ribosomal protein S6 kinase 3 [Homo sapiens]
81
333
1
261

H
Ribosomal protein S6 kinase, 52 kD, polypeptide 1 [Homo sapiens]
225
459
1
261

H
Ribosomal protein S6 kinase, 90 kD, polypeptide 6 [Homo sapiens]
73 & 428
330 & 883
1
261

H
Unknown [Homo sapiens]
153
539
1
261

H
SGK [Homo sapiens]
98
355
1
261

M
Serum/glucocorticoid regulated kinase [Mus musculus]
98
354
1
261

M
Protain kinase [Homo sapiens]
1
169
24
261

H
SGK-like protein SGKL [Homo sapiens]
182
369
1
261

H
Protein tyrosine kinase 9-like (A6-related protein) [Homo sapiens]
10
17
253
261

H
Phosphoprotein [Homo sapiens]
40
333
1
261

H
DCAMKL1 (DOUBLECORTIN-LIKE AND CAM KINASE-LIKE 1)
368
625
1
261

M
CPG 16 [Mus musculus]
59
297
1
261

H
DCAMKL1 (DOUBLECORTIN-LIKE AND CAM KINASE-LIKE 1)
415
673
1
261

M
CPG 16 [Mus musculus]
514
771
1
261

H
Death-associated protein kinase-related 2
33
293
1
261

M
Death-associated protein kinase-related 2
32
293
1
261

H
Death-associated protein kinase-related 1
61
321
1
261

H
KIAA0999 protein [Homo sapiens]
8
259
1
261

H
Hypothetical protein F49C.4 - [Caenorhabditis elegans]
74
325
1
261

H
Cdc25C associated protein kinace C_TAK1 [Homo sapiens]

H
Cdc25C associated protein kinace C_TAK1 [Homo sapiens]
56
307
1
261

M
R31237_1, partial CDS [Homo sapiens]
59
340
1
261

H
KIAA0135 gene is related to plm-1 oncogene. [Homo sapiens]
999
1258
1
261

M
KIAA0135 gene, related to plm-1 oncogene. [Homo sapiens]
1
158
23
261

H
KIAA0781 protein [Homo sapiens]
20
271
1
261

H
KIAA0537 gene product [Homo sapiens]
53
304
1
261

H
Hormonally upregulated neu tumor-associated kinase [Homo sa text missing or illegible when filed

61
320
1
261

H
Skeletal muscle myosin light chain kinase [Galus gallus]
570
625
1
261

H
KIAA1297 [Homo sapiens]
620 & 1086
873 & 1356
1
261

M
KIAA1297 [Homo sapiens]
3
78
186
261

H
STK with Dbl- and pleckstrin homology domains [Homo sapiens]
985
1239
1
261

H
MLCK [Dictyostelium discoideum]
116
381
1
261

H
CG11533 gene product [Drosophila melanogaster]
34
313
1
261

H
CG11533 gene product [Drosophila melanogaster]
21
471
1
261

H
PFTAIRE protein kinase 1 [Homo sapiens]
1
218
23
261

H
Cyclin-dependent kinase-like 1 (CDC2-related kinase) [Homo sa text missing or illegible when filed

1
191
23
261

M
Cyclin-dependent kinase-like 1 (CDC2-related kinase) [Homo sa text missing or illegible when filed

1
240
24
261

H
CDC2-related protein kinase 7 [Homo sapiens]
21
1020
1
261

H
NKIAMRE [Homo sapiens]
4
385
1
261

M
NKIATRE alpha [Rattus norvegicus]
1
28
235
261

M
Call cycle related kinase [Homo sapiens]
1
153
134
261

H
Cyclin-dependent kinase-like 1 (CDC2-related kinase) [Homo sa text missing or illegible when filed

177
493
1
261

H
Extracellular signal-regulated kinase 7; ERK7 [Rattus norvegicus
13
305
1
261

H
Renal tumor antigen [Homo sapiens]
4
285
1
261

H
Intestinal cell kinase [Homo sapiens]
4
284
1
261

M
MLCK [Rattus norvegicus]
109
364
1
261

H
CG10673 gene product [Drosophila melanogaster]
101
187
65
147

H
Hypothetical protein [Homo sapiens]
2
267
1
261

M
Hypothetical protein [Homo sapiens]
59
86
235
261

H
KIAA0344 gene product [Homo sapiens]
221
479
1
261

H
Nuclear receptor binding protein [Homo sapiens]
73
327
1
261

M
Nuclear receptor binding protein [Homo sapiens]
1
170
85
261

H
Ca2+/calmodulin-dependent protein kinase beta [Homo s text missing or illegible when filed

165
448
1
261

H
Hypothetical 33.6K protein - rabbit fibroma virus
24
285
1
261

H
Nuclear body associated kinase 1a [Mus musculus]
199
527
1
261

H
Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 3
174
487
1
261

M
Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 3
76
103
235
261

H
GCN2 eIF2alpha kinase [Mus musculus]
280 & 590
639 & 1001
1
261

H
Homo-regulated initiation factor 2-alpha kinase [Homo sapiens]
167
583
1
261

H
CG10673 gene product [Drosophila melanogaster]
101
187
65
147

M
(AE003567) CG10673 gene product [Drosophila melanogaster]
116
150
116
147

H
Interleukin-1 receptor-associated kinase M [Homo sapiens]
165
443
1
261

M
Interleukin-1 receptor-associated kinase M [Homo sapiens]
1
239
19
261

H
Ira1, inositol-requiring 1 gene [Mus musculus]
516
777
1
261

H
CG8173 gene product [Drosophila melanogaster]
32
318
1
261

M
CG8173 gene product [Drosophila melanogaster]
12
266
1
261

M
testis-specific kinase 2 [Homo sapiens]
12
39
101
128

H
Mixed lineage kinase [Homo sapiens]
16
259
1
261

H
Putative protein-tyrosine kinase [Homo sapiens]
463
723
1
261

H
KIAA0472 protein [Homo sapiens]
357
620
1
261

M
Receptor interacting protein 3 [Mus musculus]
7
27
161
202

H
Hypothetical protein [Homo sapiens]
57
63
50
78

H
KIAA1360 protein [Homo sapiens]
32
327
1
261

H
CG1973 gene product [Drosophila melanogaster]
65
131
47
116

H
Unnamed protein product [Homo sapiens]
230
305
81
143

H
Serine/threonine kinase 23 [Homo sapiens]
79
531
1
261

H
Serine/threonine kinase 22A (spermiogenesis associated) [Mus text missing or illegible when filed

10
265
1
261

M
Serine/threonine kinase 22B (spermiogenesis associated)
10
265
1
261

H
Serine/threonine kinase 22A (spermiogenesis associated)
25
280
1
261

H
Serine/threonine kinase 22B (spermiogenesis associated) [Mus text missing or illegible when filed

12
272
1
261

H
Serine/threonine kinase 22A (spermiogenesis associated)
12
267
1
261

H
Serine/threonine kinase 22B (spermiogenesis associated)
1
213
7
261

H
Putative protein kinase [Arabidopsis thaliana]
1
329
1
261

M
UNC-51-like kinase (ULK) 2 [Mus musculus]
80
408
1
261

H
UNC-51-like kinase (ULK) 2 [Mus musculus]
8
340
1
261

H
Hypothetical protein DKFZp434C131.1 - human (fragment)
57
313
1
261

H
Unnamed protein product [Homo sapiens]
4
265
1
261

H
Serum-Inducible kinase [Homo sapiens]
1
39
84
124

M
Serine/threonine protein kinase like protein [Arabidopsis thaliane
80
159
1
86

H
KIAA1264 protein [Homo sapiens]
1
246
25
261

M
Tie gene product [Drosphila melanogaster]
9
104
168
261

H
SALIVARY PROLINE-RICH PROTEIN PO(ALLELE K)[HOME text missing or illegible when filed

1
272
16
73

M
testis-specific kinase 1 [Homo sapiens]
68
96
42
71

H
Vaccinia related kinase 3 [Homo sapiens]
247
318
63
136

M
(AB031052) vaccinia related kinase 3 [Homo sapiens]
7
78
63
136

H
MPSK [Homo sapiens]
20
290
1
261

H
CG4523 gene product [Drosphila melanogaster]
156
507
1
261

H
NEK1 (NIMA-RELATED PROTEIN KINASE 1) [Mus musculus]
4
251
1
261

H
(AC007055) unknown [Homo sapiens]
52
305
1
261

H
mitogen-activated protein kinase kinase kinase 6 [Homo sapiens]
376
629
6
261

H
(AB040812) protein kinase PAK5 [Homo sapiens]
449
700
1
261

H
(U40827) protein lyrosine kinase [Mus musculus]
167
453
1
261

M
fibroblast growth factor receptor 3 [Mus musculus]
8
143
123
261

H
SGK2alpha protein kinase [Homo sapiens]
35
292
1
261

H
Cell cycle related kinase [Homo sapiens]
4
267
1
261

H
Testis-specific kinase 2 [Homo sapiens]
62
293
5
261

TABLE 3

T text missing or illegible when filed

-h

1

text missing or illegible when filed

137

721

24705

13163

-h

2

8131
32 text missing or illegible when filed

114237

-h

3

text missing or illegible when filed

3477

267
32237
33 text missing or illegible when filed

-h

4

984
276
105547
42231
4318
1234

text missing or illegible when filed

2293

-h

5

text missing or illegible when filed

23
239783

text missing or illegible when filed

7734

-h

6

text missing or illegible when filed

73
2674

text missing or illegible when filed

-h

7

8358

text missing or illegible when filed

-h

8

8542

text missing or illegible when filed

73
11 text missing or illegible when filed

-h

9

15 text missing or illegible when filed

-h

10

6783
13 text missing or illegible when filed

80242

-h

11

4797

text missing or illegible when filed

837527

31171

-h

12

3477
1794

text missing or illegible when filed

-h

13

3397

text missing or illegible when filed

24129

-h

14

2725

text missing or illegible when filed

429781
37 text missing or illegible when filed

277

11433

-h

15

text missing or illegible when filed

31811

-h

16

8493

text missing or illegible when filed

12319

-h

17

3912
1915

text missing or illegible when filed

11717

-h

18

text missing or illegible when filed

318

11720
12229

text missing or illegible when filed

-h

19

2439

text missing or illegible when filed

7829

-h

20

5184

text missing or illegible when filed

-h

21

2783
4479

text missing or illegible when filed

11589

-h

22

text missing or illegible when filed

49111

-h

23

4121
1921

text missing or illegible when filed

25413
25247
10839
4418

text missing or illegible when filed

7084

-h

24

text missing or illegible when filed

419

3479

-h

25

4642

text missing or illegible when filed

117943

-h

27

text missing or illegible when filed

21139

LC

28

74

text missing or illegible when filed

34171

-h

29

2479
1073
194311

text missing or illegible when filed

LC

30

29

24571
1923

text missing or illegible when filed

3237

42340

-h

31

8274
3082

text missing or illegible when filed

EC

32

7791

text missing or illegible when filed

4775
11713

text missing or illegible when filed

-h

33

text missing or illegible when filed

34729

HCAEC

34

text missing or illegible when filed

-h

35

text missing or illegible when filed

913
41543

text missing or illegible when filed

8149

-h

36

8123
731
47839
19781
20729
9429

text missing or illegible when filed

-h

37

text missing or illegible when filed

77
0

text missing or illegible when filed

9411

-h

38

text missing or illegible when filed

2171

2447
34121

text missing or illegible when filed

-h

39

text missing or illegible when filed

2472

2515

-h

40

text missing or illegible when filed

2472

1592
79722

text missing or illegible when filed

-h

41

2979
0

text missing or illegible when filed

42181

-h

42

text missing or illegible when filed

21473

18311
13419

text missing or illegible when filed

-h

43

text missing or illegible when filed

0
9314
11344
12177
4129
2283

text missing or illegible when filed

-h

44

text missing or illegible when filed

17833

WT2

243

115
357
9191

text missing or illegible when filed

134

WT2

343

0
427
9712

text missing or illegible when filed

0
144

text missing or illegible when filed

WT1

391

0
15
26479
2724
725

text missing or illegible when filed

-13

356
354

23
1684
543114

text missing or illegible when filed

-12

354
354

11259
1283

text missing or illegible when filed

9438

2467

-h

284

0
242

text missing or illegible when filed

1746

-h

342

0
543
20541

text missing or illegible when filed

0
2454
2223

text missing or illegible when filed

R*TEC

334
334

1977
0

text missing or illegible when filed

24733

323
6057

text missing or illegible when filed

-h

322

704
0
1241
7347
7053

text missing or illegible when filed

1180

330

905
0
9314
2447
1944
0
140

text missing or illegible when filed

-h

328

7120
318
191277
49029
19433

text missing or illegible when filed

2972

HT3

327

8223
320

text missing or illegible when filed

832

-h

324

6734
80

text missing or illegible when filed

10538
7917

text missing or illegible when filed

HT1

321

187
61

text missing or illegible when filed

2927
0
139
1743

text missing or illegible when filed

3252
0

text missing or illegible when filed

12132

4353
2348
61918

text missing or illegible when filed

-h

318

4313

text missing or illegible when filed

31221

-h

316

4443
254

text missing or illegible when filed

4790

-h

334

3520
841

text missing or illegible when filed

-h

311

text missing or illegible when filed

447

11249

-h

309

45

text missing or illegible when filed

1434

-h

307

1276
0

text missing or illegible when filed

-h

393

183
907

text missing or illegible when filed

44917

-h

303

1134
700

text missing or illegible when filed

24295
8124

text missing or illegible when filed

-h

292

text missing or illegible when filed

-h

294

4247
11127

text missing or illegible when filed

-h

287

2938
1244

text missing or illegible when filed

-h

298

94
1547

text missing or illegible when filed

9794

-h

234

2252

text missing or illegible when filed

25447
14737

text missing or illegible when filed

3701

-h

282

195
115

text missing or illegible when filed

12005
3217

text missing or illegible when filed

-h

299

1375
1452
417579
27541
12419

text missing or illegible when filed

-h

273

0

text missing or illegible when filed

34547
2711

text missing or illegible when filed

2421

-h

277

0
2174

text missing or illegible when filed

4719
2539

text missing or illegible when filed

HPALC

275
276

991
123
4987

text missing or illegible when filed

532
1082

text missing or illegible when filed

7713

HT2 text missing or illegible when filed

0
59

text missing or illegible when filed

4487
0

text missing or illegible when filed

HT2

253

-11

230
239

1719
4284

text missing or illegible when filed

-

224
231

41

text missing or illegible when filed

8231

HT373-

234

757
0

text missing or illegible when filed

8133

-7

233
233

0

text missing or illegible when filed

7274
2074

text missing or illegible when filed

-4

231
231

291
2454
49149
7943
8703
8477
7340

text missing or illegible when filed

-2

229
229

text missing or illegible when filed

74913

7022
3423

text missing or illegible when filed

-1

227
227

text missing or illegible when filed

4934

11203
4547

text missing or illegible when filed

-h

222

328
459
5047

text missing or illegible when filed

3423
171

text missing or illegible when filed

-h

218

942
0

text missing or illegible when filed

-h

214

text missing or illegible when filed

1512

3792

17311

-h

212

854
647

text missing or illegible when filed

6130

-h

212

522
1972

text missing or illegible when filed

5781
2184

text missing or illegible when filed

1232

HCAEC

211
211

143
0
8183

text missing or illegible when filed

184

1143
24737

text missing or illegible when filed

-h

210

text missing or illegible when filed

3127

HMEC

209

text missing or illegible when filed

8034
8400
0
214

text missing or illegible when filed

-h

206

1
0

text missing or illegible when filed

1141

-h

203

423
16

text missing or illegible when filed

1437
3994
4309
991

text missing or illegible when filed

-h

291

415

text missing or illegible when filed

-h

183

130
134
1142

text missing or illegible when filed

2327

247

-h

187

438
16

text missing or illegible when filed

4851
2304
1218
742

text missing or illegible when filed

4117

196

82
0
4377

text missing or illegible when filed

1231
374
21318

text missing or illegible when filed

-h

193

text missing or illegible when filed

174

0
0

text missing or illegible when filed

2183
0

text missing or illegible when filed

0
21244
1771

text missing or illegible when filed

-h

91

314
273

text missing or illegible when filed

4234

-h

737

-h

57

0
234

text missing or illegible when filed

2152

-h

54

0
1134

text missing or illegible when filed

3702
4377
442
37903

text missing or illegible when filed

-h

53

0
1323

text missing or illegible when filed

732
1175

text missing or illegible when filed

-h

51

277
841

text missing or illegible when filed

4737

-h

1379
744

text missing or illegible when filed

2313

1472

HELA-

-031

2343

4142

HELA-

-031

3757

4922

HELA-

-031

82

935

text missing or illegible when filed

3429

HELA-

-031

83

944

text missing or illegible when filed

HELA-

-031

1271

4751

HELA-

-031

3

323
416

text missing or illegible when filed

HELA-10h-031 text missing or illegible when filed

2

419

text missing or illegible when filed

5137

HELA-11h-031 text missing or illegible when filed

4

0
0

text missing or illegible when filed

312

HELA-12h-031 text missing or illegible when filed

3207

MC1-

148

1454
244

text missing or illegible when filed

MC2-

144

1834
164

text missing or illegible when filed

MC3-

150

913
254

text missing or illegible when filed

-19

152

1113
0

text missing or illegible when filed

1124

-75

154

1194
0

text missing or illegible when filed

3794

-288

156

231
0

text missing or illegible when filed

447

-295

158

0
342

text missing or illegible when filed

892
378

text missing or illegible when filed

CCRY-CRM

160

1991
274

text missing or illegible when filed

317

418

DU-145

162

209
425
7542

text missing or illegible when filed

118

MCT 115

154

121
0
21002

text missing or illegible when filed

1953

mo SAIT
156

13873
0

text missing or illegible when filed

41
16731
12712

text missing or illegible when filed

6334

mo SAVT
153

13427
1232
37438

text missing or illegible when filed

8797
5704

text missing or illegible when filed

MCP

151

15337
1085

text missing or illegible when filed

7
12914
21779
1 text missing or illegible when filed

10792
87 text missing or illegible when filed

0
9415

M14
143

8482
145
2 text missing or illegible when filed

14
17174
16734
183 text missing or illegible when filed

4
2844
63303
4 text missing or illegible when filed

20

UACC-257
142

11438
0
1888 text missing or illegible when filed

7
10437
12037
41 text missing or illegible when filed

2737

UACC-42
143

3456
123
14725
21877
11114
27 text missing or illegible when filed

4
1820
27441
4941

text missing or illegible when filed

MEL-28
144

4479
0
390827
13781
7222
2 text missing or illegible when filed

47
2124
2 text missing or illegible when filed

24

UP-31
143

8347
0
242414
19130

text missing or illegible when filed

7
23333
41 text missing or illegible when filed

230
8343

S text missing or illegible when filed

-MEL-4
142

5444
680
43 text missing or illegible when filed

34
3 text missing or illegible when filed

782
70 text missing or illegible when filed

01
12 text missing or illegible when filed

2

MCM-12
141

6633
377
43670
12 text missing or illegible when filed

4823
71 text missing or illegible when filed

2
3132

SOC-MEL-2
140

29 text missing or illegible when filed

331
391883

text missing or illegible when filed

6
13817
13 text missing or illegible when filed

741
1004
20577
5700

MCT- text missing or illegible when filed

139

1187
0
362064
14372

text missing or illegible when filed

230
11433

text missing or illegible when filed

78
14730
18341

M text missing or illegible when filed

-2

138

0
403464
1 text missing or illegible when filed

70
21371
5334
45000
7827

COLO text missing or illegible when filed

137

6249
0
384338
1 text missing or illegible when filed

8560
11 text missing or illegible when filed

1
4 text missing or illegible when filed

877

136

4339
294
1470004
237 text missing or illegible when filed

3
18725
23414

text missing or illegible when filed

200000
1815

S text missing or illegible when filed

-4

135

11829
0
822854
1 text missing or illegible when filed

4
7213
3 text missing or illegible when filed

1702

TW-10
134

3634
1142
232633
21183
1832

text missing or illegible when filed

041
4 text missing or illegible when filed

MCT 110
133

3482
0
160614
13 text missing or illegible when filed

37000
8317

70 text missing or illegible when filed

-0
132

3284
0
3 text missing or illegible when filed

64
17729
4 text missing or illegible when filed

2
13 text missing or illegible when filed

4
2041
34171

text missing or illegible when filed

7

HCC-23 text missing or illegible when filed

131

70
2737
3 text missing or illegible when filed

8
179 text missing or illegible when filed

3371

130

6662
117
84811

text missing or illegible when filed

10054
6438

text missing or illegible when filed

0
5706

PC-2
129

13 text missing or illegible when filed

0
4 text missing or illegible when filed

24
14104
4879

text missing or illegible when filed

473
3508
343 text missing or illegible when filed

128

33
278
4 text missing or illegible when filed

7110
13004
3324
43444
1004

OL text missing or illegible when filed

127

14823
134
30 text missing or illegible when filed

12131
3150
3 text missing or illegible when filed

0
3261
37777
3307

C text missing or illegible when filed

-1
126

3646
722
71294 text missing or illegible when filed

127140

13345
4217
38247

text missing or illegible when filed

125

35 text missing or illegible when filed

257
420391
13347

text missing or illegible when filed

20
10111
7543
378 text missing or illegible when filed

4327

AC text missing or illegible when filed

124

8123
0
64309
140 text missing or illegible when filed

0
41874
17 text missing or illegible when filed

4314

104
8283

text missing or illegible when filed

123

2276
0
372834
18300
5419
297 text missing or illegible when filed

1191

0043

C
122

6283
217
200477
17102
14334
29787
67 text missing or illegible when filed

32473
1267

ML-40
121

11442
0
137022

text missing or illegible when filed

63201
224 text missing or illegible when filed

3
4184
384440
4200

MCL T-4
120

4384
0
440060
127 text missing or illegible when filed

10231
18 text missing or illegible when filed

4
26300
4478

OVCAR-1
119

3830
364

text missing or illegible when filed

25
14534
5452
41 text missing or illegible when filed

4117
25736

text missing or illegible when filed

34

X- text missing or illegible when filed

118

2180
794
804729
14781

text missing or illegible when filed

5
20028
2300
54213

text missing or illegible when filed

030

OVCAR-4
117

2854
3367
43 text missing or illegible when filed

335
10520
8040
117 text missing or illegible when filed

1
42100
2303

CC text missing or illegible when filed

-CDM
116

4370
0
3 text missing or illegible when filed

707
217 text missing or illegible when filed

7
9518
81543

text missing or illegible when filed

38120
4575

OVCAR-3
115

3371
9
14 text missing or illegible when filed

64
10 text missing or illegible when filed

74
1044
21026
5119
52017
5413

S text missing or illegible when filed

-638
114

4819
0

text missing or illegible when filed

2870
13841
4716
1 text missing or illegible when filed

3
2834
3 text missing or illegible when filed

5
5113

HC text missing or illegible when filed

113

2174
384
345970
13734

text missing or illegible when filed

54
11834
3200
19676
4413

SF-295
112

11905
218
98183
19707

text missing or illegible when filed

0
7154
2946
40830
1 text missing or illegible when filed

2

A text missing or illegible when filed

TCC
111

17217

text missing or illegible when filed

376850
27212
12354
1 text missing or illegible when filed

17
6358
47430
8324

SF-288
110

3084
1353
233341

text missing or illegible when filed

41
11 text missing or illegible when filed

24
2370
30243
3718

MCAH text missing or illegible when filed

109

4147
0
1128384
19211
19185
32502
318 text missing or illegible when filed

3
44011

text missing or illegible when filed

45

w291
108

9538
373
230300
107 text missing or illegible when filed

120

54075
8200

MC- text missing or illegible when filed

107

6777
0
457383
13000

text missing or illegible when filed

3
4430
2 text missing or illegible when filed

5244

SN text missing or illegible when filed

-75
106

7578
630
27880
8030
323
9216
2822
41104
4 text missing or illegible when filed

18

MC- text missing or illegible when filed

105

6471
821
188027
19449
14479
18523
2322
42032
6532

text missing or illegible when filed

M-19
104

7360
0
210001
17 text missing or illegible when filed

44
7 text missing or illegible when filed

4
12434
3100
50664
1744

MC-M224
103

32964
310
106338

text missing or illegible when filed

4
10726
24181
3034
61587

text missing or illegible when filed

3

SM-CM-3
102

8457
0
302788
16547
1470
11077
2287
33178
2004

NCH text missing or illegible when filed

23
101

5414
371
108502
12284
8342
15724

text missing or illegible when filed

3418

ROV1
100

13803
708
313545
14137

text missing or illegible when filed

515

679
2 text missing or illegible when filed

41
41000
3314

text missing or illegible when filed

99

8228
1110
3 text missing or illegible when filed

16
10012
6432
217 text missing or illegible when filed

3010
25017
3824

OVCAR-6
98

12781
814
16774
10381
4170

text missing or illegible when filed

4
3120
31129
4019

MCP- text missing or illegible when filed

2
97

7808
0
397 text missing or illegible when filed

22816
4200
3 text missing or illegible when filed

00
3 text missing or illegible when filed

2
33300
3000

text missing or illegible when filed

3831492

12
48

130 text missing or illegible when filed

0
177631
14183

text missing or illegible when filed

047
3428
3200
4127

in text missing or illegible when filed

C 102142 017
47

4478
137
8972
14410
1 text missing or illegible when filed

0
3 text missing or illegible when filed

4
5 text missing or illegible when filed

20037
3335

in text missing or illegible when filed

2025792

44

13802
230
153425
321 text missing or illegible when filed

14419
3871
29129
1 text missing or illegible when filed

2

TCCP
25

6808
0

text missing or illegible when filed

454
15245
19200
19187
3430
22053
8471

ASCS-1

wt
1421
5421
44209
11710
0
0
0
0
0

ASCS-3

wt
130
4212
28334
6707
0
0
0
0
0

ASCS-4

wt
278
8223
38473
1 text missing or illegible when filed

0
0
0
0
0

ASCS-6

wt
440
2672
28000
10727
0
0
0
0
0

ASCS-7

wt
148
182
18733
6765
0
0
0
0
0

EKVX-1

text missing or illegible when filed

844
1243

text missing or illegible when filed

4
16734
0
0
0
0
0

EKVX-4

text missing or illegible when filed

1480
43 text missing or illegible when filed

22314
0
0
0
0
0

EKVX-3

text missing or illegible when filed

836
834
32907
12511
0
0
0
0
0

EKVX-6

text missing or illegible when filed

0
0
99902
1740
0
0
0
0
0

EKVX-7

text missing or illegible when filed

732
1374

text missing or illegible when filed

2
11042
0
0
0
0
0

MCP-7-1

wt
240
718
88119
10 text missing or illegible when filed

0
0
0
0
0

MCP-7-3

wt
407
6248

text missing or illegible when filed

380
7 text missing or illegible when filed

3
0
0
0
0
0

MCP-7-4

wt
438
1154
140711
14017
0
0
0
0
0

MCP-7-6

wt
224
1050
81148
11019
0
0
0
0
0

MCP-7-7

wt
0
1337
10847
8720
0
0
0
0
0

AD text missing or illegible when filed

-RE

-1

0
3883
51125
1 text missing or illegible when filed

444
0
0
0
0
0

AD text missing or illegible when filed

-RE

-3

123
823
27134
8042
0
0
0
0
0

AD text missing or illegible when filed

-RE

-4

0
941
15870
4440
0
0
0
0
0

AD text missing or illegible when filed

-RE

-6

204
472
33538
7540
0
0
0
0
0

AD text missing or illegible when filed

-RE

-7

980
7302
12023
13042
0
0
0
0
0

WI 3 text missing or illegible when filed

-1

wt
819
0
41827
24007
0
0
0
0
0

WI 3 text missing or illegible when filed

-3

wt
508
217
40570
15233
0
0
0
0
0

WI 3 text missing or illegible when filed

-4

wt
642
751
32719
5317
0
0
0
0
0

WI 3 text missing or illegible when filed

-6

wt
1161
3721
17081
11307
0
0
0
0
0

WI 3 text missing or illegible when filed

-7

wt
218
4817
84181
12200
0
0
0
0
0

H text missing or illegible when filed

-1

HPY E text missing or illegible when filed

523
12821
18493
13319
0
0
0
0
0

H text missing or illegible when filed

-3

HPY E text missing or illegible when filed

480
643
51637
12033
0
0
0
0
0

H text missing or illegible when filed

-4

HPY E text missing or illegible when filed

502
3311
46288
7005
0
0
0
0
0

H text missing or illegible when filed

-6

HPY E text missing or illegible when filed

213
1104
40234
10027
0
0
0
0
0

H text missing or illegible when filed

-7

HPY E text missing or illegible when filed

0
1049
37504

text missing or illegible when filed

0
0
0
0
0

WI 2 text missing or illegible when filed

-1

944
0
88087
14773
0
0
0
0
0

WI 2 text missing or illegible when filed

-3

304
0
80294
14722
0
0
0
0
0

WI 2 text missing or illegible when filed

-4

304
2070
78198
29063
0
0
0
0
0

WI 2 text missing or illegible when filed

-5

204
1404
33234
10427
0
0
0
0
0

WI 2 text missing or illegible when filed

-7

440
0
41806
10304
0
0
0
0
0

AS text missing or illegible when filed

-2

wt
194
4270
37307
1002
0
0
0
0
0

EKVX-2

text missing or illegible when filed

538
2003
23382
15428
0
0
0
0
0

MCT-116-1

wt
428
8497
38339
9130
0
0
0
0
0

MCT-116-2

wt
1123
3794
480330
21130
0
0
0
0
0

MT text missing or illegible when filed

-2

1
1380
62391
13827
0
0
0
0
0

SP text missing or illegible when filed

-1

wt
0
1849
10007
13003
0
0
0
0
0

SP text missing or illegible when filed

-2

wt
112
2474
46281
12141
0
0
0
0
0

SP-268-1

text missing or illegible when filed

962
317
42852
13334
0
0
0
0
0

SP-268-2

text missing or illegible when filed

818
850
74505
12530
0
0
0
0
0

OVCAR- text missing or illegible when filed

-1

wt
332
98
70236
13104
0
0
0
0
0

OVCAR- text missing or illegible when filed

-2

wt
342
1843
101777
10427
0
0
0
0
0

OVCAR- text missing or illegible when filed

-1

220
941
12838
14287
0
0
0
0
0

OVCAR- text missing or illegible when filed

-2

10
10
1110
6476
0
0
0
0
0

MCF-7-2

wt
291
1423
11082
7 text missing or illegible when filed

2
0
0
0
0
0

AD text missing or illegible when filed

-2

0
731
31787

text missing or illegible when filed

442
0
0
0
0
0

M text missing or illegible when filed

-2

HPV E4
518
0
112434
14374
0
0
0
0
0

SW text missing or illegible when filed

-1

328
0
54775
8 text missing or illegible when filed

0
0
0
0
0

SW text missing or illegible when filed

-2

1061
7828
88139
12351
0
0
0
0
0

WI2 text missing or illegible when filed

-2

23
2573
57384
18061
0
0
0
0
0

C33A-1

text missing or illegible when filed

02
18707
9547
18 text missing or illegible when filed

0
0
0
0
0

C33A-2

text missing or illegible when filed

4
1154
43004
11722
0
0
0
0
0

U2C text missing or illegible when filed

-1

110
86
151805
10077
0
0
0
0
0

U2C text missing or illegible when filed

-2

121
0
140671
22177
0
0
0
0
0

M text missing or illegible when filed

-1

wt
287
582
23 text missing or illegible when filed

4
10011
0
0
0
0
0

M text missing or illegible when filed

-2

wt

text missing or illegible when filed

0
985
34277
11870
0
0
0
0
0

WI text missing or illegible when filed

-2

wt
415
2476
38744
25529
0
0
0
0
0

M text missing or illegible when filed

-1

574
283
1294
110430
0
0
0
0
0

M text missing or illegible when filed

-2

1123
3287
36129
1 text missing or illegible when filed

56
0
0
0
0
0

M text missing or illegible when filed

-3

4
894
34711
31829
0
0
0
0
0

M text missing or illegible when filed

-4

1168
0
12352
7 text missing or illegible when filed

0
0
0
0
0

M text missing or illegible when filed

730
0
8477
277577
0
0
0
0
0

M text missing or illegible when filed

872
8439
13002
31582
0
0
0
0
0

M text missing or illegible when filed

1350
1097
14384
24700
0
0
0
0
0

M text missing or illegible when filed

834
0
15325
11034
0
0
0
0
0

text missing or illegible when filed

-7

4281
4123

text missing or illegible when filed

781

7
0
0
0
0
0

text missing or illegible when filed

-4

1603
0
1,28,244
31,888
0
0
0
0
0

text missing or illegible when filed

-0

1704
362
23,137
22, text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-11

2 text missing or illegible when filed

2718

36,367
0
0
0
0
0

text missing or illegible when filed

-12

1421
0
14,3018
14,764
0
0
0
0
0

text missing or illegible when filed

-10

1137
11437

text missing or illegible when filed

,778
2, text missing or illegible when filed

13
0
0
0
0
0

text missing or illegible when filed

-1

87,121
0
0
0
0
0

text missing or illegible when filed

-2

778
282
11,3575
44,171
0
0
0
0
0

text missing or illegible when filed

-3

89,117

0
0
0
0
0

text missing or illegible when filed

-4

64
3575

text missing or illegible when filed

11,740
0
0
0
0
0

text missing or illegible when filed

-5

647
217

text missing or illegible when filed

34,175
0
0
0
0
0

text missing or illegible when filed

-6

1734
0
48,374
16,000
0
0
0
0
0

A text missing or illegible when filed

-0

wt
147
1853
35,454
11,740
0
0
0
0
0

EXVX-8

text missing or illegible when filed

261

74,732
34,175
0
0
0
0
0

HGT-118-7

wt
438
0
48,374
16,076
0
0
0
0
0

HGT-118-8

wt
368
674

text missing or illegible when filed

0
0
0
0
0

HT25-1

text missing or illegible when filed

273
3281
23,164
16,610
0
0
0
0
0

XT25-1

text missing or illegible when filed

78
3147

text missing or illegible when filed

6481
0
0
0
0
0

HT25-6

text missing or illegible when filed

181
457
63,732
14,319
0
0
0
0
0

SF text missing or illegible when filed

-7

wt
107
446
33,067
13,17
0
0
0
0
0

SF538-8

wt
223
0
29,182
14,319
0
0
0
0
0

SF266-7

text missing or illegible when filed

881
1301
72,107
6447
0
0
0
0
0

SF-366-6

text missing or illegible when filed

1384
627
10,500
8738
0
0
0
0
0

OVCAR-4-7

wt
0
320
12,000
13,175
0
0
0
0
0

OVCAR-5-8

text missing or illegible when filed

154
0
17,814
0041
0
0
0
0
0

OVCAR-6-7

text missing or illegible when filed

545
740
24,120
14,422
0
0
0
0
0

OVCAR-6-8

text missing or illegible when filed

422
3013
12,600
21,781
0
0
0
0
0

MCF-7-8

text missing or illegible when filed

0
2343
23,063
10,770
0
0
0
0
0

text missing or illegible when filed

737
1041
24,571
10,657
0
0
0
0
0

text missing or illegible when filed

224
7324
43,102
11,163
0
0
0
0
0

SW489-7

text missing or illegible when filed

102
2330

text missing or illegible when filed

17,722
0
0
0
0
0

SW489-8

text missing or illegible when filed

372
2172
11,400
6104
0
0
0
0
0

H1238-8

text missing or illegible when filed

0
1613
28,317
12,001
0
0
0
0
0

C33A-7

text missing or illegible when filed

70
2184
72,532

text missing or illegible when filed

0
0
0
0
0

C33A-8

text missing or illegible when filed

67
0
15,0,067
10,781
0
0
0
0
0

U203-7

wt
538
4034
38,274
8774
0
0
0
0
0

U308-8

wt
502
4457
8255
13,570
0
0
0
0
0

text missing or illegible when filed

-7

wt
732
47

text missing or illegible when filed

14,777
0
0
0
0
0

text missing or illegible when filed

-8

6548
0

text missing or illegible when filed

10,004
0
0
0
0
0

WI38-8

110
0
8735
7518
0
0
0
0
0

text missing or illegible when filed

64

341
1575

text missing or illegible when filed

7421
15,778
21,839
3228
37 text missing or illegible when filed

7006

CF2,1572, text missing or illegible when filed

1340
405
87 text missing or illegible when filed

2767
887
2381
1237

text missing or illegible when filed

2084

457
516
1 text missing or illegible when filed

4834
12,083
23,343
21,752
2324

HT388

3175
0

text missing or illegible when filed

24,204
4834
5347
715

text missing or illegible when filed

7005

HT345

0
380

text missing or illegible when filed

198

34
7363
15,311
725

text missing or illegible when filed

5768

HT675

40
303
2532
2582
704
7809
2635

text missing or illegible when filed

7837

HT628

01
420
8381
4229
183
2123
2338

text missing or illegible when filed

2764

-3

173

325
0
14,405
12,819
1029
153
723
45,163

text missing or illegible when filed

-6

175

1003
0

text missing or illegible when filed

5200
859
1780
121

text missing or illegible when filed

4314

-8

177

591
0
83 text missing or illegible when filed

5200
1536
1118
115

text missing or illegible when filed

138
0
14,405
12,819
1542
3275
1342

text missing or illegible when filed

1011

10

237

515
0

text missing or illegible when filed

1666
1,8010
2231

text missing or illegible when filed

14,731

HT10

384
37
2723
5219
263
3078
1114

text missing or illegible when filed

8700

405
0
2,00,879
11,083
1553
367
74
44,374
8400

text missing or illegible when filed

1201
0
29,774
11,028
2188
10, text missing or illegible when filed

1479
24,578
4500

text missing or illegible when filed

1883
354
75,223
17,508
3422
1$
1384
27,087
4355

text missing or illegible when filed

wt
420
3054

text missing or illegible when filed

3824
3415
2424
32,124
7705

text missing or illegible when filed

wt
857
0
29,779

text missing or illegible when filed

0
0
0
0
0

HCT-176-3

wt
350
377
30,555
13,023
0
0
0
0
0

HCT-116-4

wt
0
271

text missing or illegible when filed

0
0
0
0
0

HCT-116-5

wt
0
248
2330
7224
0
0
0
0
0

HCT-116-6

text missing or illegible when filed

4538
3330
7224
0
0
0
0
0

AS text missing or illegible when filed

238
3771
3915
0
0
0
0
0
0

NT29-3

text missing or illegible when filed

27
0
62,803
8937
0
0
0
0
0

NT29-3

text missing or illegible when filed

448
0

text missing or illegible when filed

8240
0
0
0
0
0

NT29-4

text missing or illegible when filed

329
1308
23,073
18,179
0
0
0
0
0

NT29-5

wt
661
457
63,479

text missing or illegible when filed

0
0
0
0
0

NT29-6

wt
329
3832
64,009
44,924
0
0
0
0
0

OVCAR-4-3

wt
0
522

text missing or illegible when filed

8741
0
0
0
0
0

OVCAR-4-4

wt
391
0
53,852
13,001
0
0
0
0
0

OVCAR-4-5

wt
291
0
83 text missing or illegible when filed

0
0
0
0
0

OVCAR-4-6

wt
404
617
27,709
14 text missing or illegible when filed

0
0
0
0
0

SF text missing or illegible when filed

-3

wt
259
2513
53,162
9722
0
0
0
0
0

SF text missing or illegible when filed

-4

wt
0
3084
44,663

text missing or illegible when filed

0
0
0
0
0

SF text missing or illegible when filed

-5

648
444
8763
7202
0
0
0
0
0

SF text missing or illegible when filed

-6

wt
0
617
27,709
14 text missing or illegible when filed

0
0
0
0
0

OVCAR-4-3

text missing or illegible when filed

0
892
15,534
7377
0
0
0
0
0

OVCAR-4-4

text missing or illegible when filed

512
2112
90,711
12,219
0
0
0
0
0

OVCAR-4-5

text missing or illegible when filed

82,509

0
0
0
0
0

OVCAR-5-6

text missing or illegible when filed

215
0
82 text missing or illegible when filed

0
0
0
0
0

WCF-7-0

text missing or illegible when filed

711
254
21,094
11,567
0
0
0
0
0

text missing or illegible when filed

-6

0
226
50,552
8767
0
0
0
0
0

H1230-1

text missing or illegible when filed

313
3044

text missing or illegible when filed

17,055
0
0
0
0
0

SW480-3

text missing or illegible when filed

824
0

text missing or illegible when filed

25,234
0
0
0
0
0

SW480-4

text missing or illegible when filed

84
240

text missing or illegible when filed

0
0
0
0
0

SW480-5

text missing or illegible when filed

822
0
40 text missing or illegible when filed

21,184
0
0
0
0
0

SW480-6

text missing or illegible when filed

0
0
42,319
25,174
0
0
0
0
0

C33A-3

text missing or illegible when filed

858
211
77,746
11,233
0
0
0
0
0

C33A-4

text missing or illegible when filed

254
875

text missing or illegible when filed

0
0
0
0
0

C33A-5

text missing or illegible when filed

428
0
9205
7527
0
0
0
0
0

C33A-6

text missing or illegible when filed

144
85
2,17,524
30,812
0
0
0
0
0

text missing or illegible when filed

353
2141
1,45,783
12,529
0
0
0
0
0

UQO3-3

text missing or illegible when filed

367
1378
11,555
17,142
0
0
0
0
0

UQO3-4

text missing or illegible when filed

817
128
11,177
12,775
0
0
0
0
0

UQO3-5

text missing or illegible when filed

825
404

text missing or illegible when filed

0
0
0
0
0

UQO3-6

text missing or illegible when filed

434
4041
57,189
18,944
0
0
0
0
0

text missing or illegible when filed

25
4744

text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-3

wt
232
1334
57,073
17,844
0
0
0
0
0

text missing or illegible when filed

-6

wt
1334
140

text missing or illegible when filed

27,837
0
0
0
0
0

SF-366-3

wt
1761
6402
18,667
21,304
0
0
0
0
0

SF-366-4

text missing or illegible when filed

1145
1850
30,421
12,423
0
0
0
0
0

SF-366-5

text missing or illegible when filed

821
1858
40,854
20,121
0
0
0
0
0

SF-366-6

text missing or illegible when filed

574
1530
1,27,423
12,423
0
0
0
0
0

text missing or illegible when filed

-13

1771
1629
2,35,833

text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-29

1817

text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-21

1349
87
34,349
63,737
0
0
0
0
0

text missing or illegible when filed

-22

1779
2514
1,20,280
25,282
0
0
0
0
0

OVCAR-4-6

text missing or illegible when filed

1023
0
41,280
27,874
0
0
0
0
0

text missing or illegible when filed

-10

1347
15
79,144
73,812
0
0
0
0
0

text missing or illegible when filed

-11

613
0
14 text missing or illegible when filed

87,514
0
0
0
0
0

text missing or illegible when filed

-12

1081
0
1 text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-13

2111
0
24 text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-14

2004
0
58,283

text missing or illegible when filed

0
0
0
0
0

text missing or illegible when filed

-15

739
0
1,04,457
14,747
0
0
0
0
0

text missing or illegible when filed

-16

818
0
96,744
13,838
0
0
0
0
0

text missing or illegible when filed

-17

675
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34117
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174 text missing or illegible when filed

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text missing or illegible when filed

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text missing or illegible when filed

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HCT-114-4

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1405
116
0
17
2754
4357

text missing or illegible when filed

229
229

197

text missing or illegible when filed

1572
17
23

text missing or illegible when filed

227
227

text missing or illegible when filed

54
0

text missing or illegible when filed

1455
2494
2380

text missing or illegible when filed

222

250

text missing or illegible when filed

55
145
322
1082

text missing or illegible when filed

215

0

text missing or illegible when filed

229
17
29
1520
3087
343

text missing or illegible when filed

214

0

text missing or illegible when filed

0
0
0
0

text missing or illegible when filed

1770

213

0

text missing or illegible when filed

0
0

text missing or illegible when filed

2202

212

130

text missing or illegible when filed

0
0
153

text missing or illegible when filed

480

211
211

135

text missing or illegible when filed

412
0
117
454
2312
7793

text missing or illegible when filed

210

0

text missing or illegible when filed

40
0
220

text missing or illegible when filed

209

170

text missing or illegible when filed

0
2108
4178

text missing or illegible when filed

205

0
4
0
483
1052
0

text missing or illegible when filed

203

0
13

text missing or illegible when filed

238

201

0

text missing or illegible when filed

0
0
0
180
2429
124

text missing or illegible when filed

180

385

text missing or illegible when filed

0
2744
304

text missing or illegible when filed

187

0

text missing or illegible when filed

411
2172
2792
380

text missing or illegible when filed

194

0
132
22
534
1518
2052

text missing or illegible when filed

193

0

text missing or illegible when filed

0
0
25
294
1254
42

text missing or illegible when filed

0
204
0

text missing or illegible when filed

2652

0
0
0

text missing or illegible when filed

830
72

text missing or illegible when filed

50

0

text missing or illegible when filed

0
158
84

text missing or illegible when filed

2001
170
34783

text missing or illegible when filed

57

0

text missing or illegible when filed

0
2379
2154
5507
175192

text missing or illegible when filed

1173

1020
2135
3445

text missing or illegible when filed

53

273

text missing or illegible when filed

0
0
0
777

text missing or illegible when filed

176
0
1157
822

text missing or illegible when filed

40

380

text missing or illegible when filed

23343

HELA text missing or illegible when filed

2750
5247
95108

HELA text missing or illegible when filed

0
781
2330
21234

text missing or illegible when filed

HELA

0
50
203
1276
2295

text missing or illegible when filed

HELA

80
2720
1297
4512

text missing or illegible when filed

HELA

0
81
0
1843
4070
23775

HELA text missing or illegible when filed

1744
4304

text missing or illegible when filed

HELA

1781
3048

text missing or illegible when filed

HELA

0
195
192
0

text missing or illegible when filed

7823
78133

HELA text missing or illegible when filed

0
0
0

text missing or illegible when filed

1400
2544

text missing or illegible when filed

4158
1829

text missing or illegible when filed

148

0
703

text missing or illegible when filed

432
2184

text missing or illegible when filed

150

0

text missing or illegible when filed

0
275
0
378
1871
13323
24403

text missing or illegible when filed

152

0
1114
2329

text missing or illegible when filed

154

40
2304
3295
17173
20001

text missing or illegible when filed

154

0

text missing or illegible when filed

432
233
0
1122
1851

text missing or illegible when filed

14348

0
87
434
732
254
2043

text missing or illegible when filed

CCRF

180

0
0
128
821

text missing or illegible when filed

303

145

152

0

text missing or illegible when filed

1957
13480
18145

MC7 text missing or illegible when filed

184

0

text missing or illegible when filed

0
245
0
471
1324
19125
12384

text missing or illegible when filed

5737
154

text missing or illegible when filed

143
111814
7208

text missing or illegible when filed

8343
0

text missing or illegible when filed

MCF-

153

70411
721
387
0

text missing or illegible when filed

0
838

MCF 7
151

text missing or illegible when filed

30804
11834
2980
278

text missing or illegible when filed

0
0

text missing or illegible when filed

148

371
22234
15025
2725
157

text missing or illegible when filed

975
73

UACC-257
147

text missing or illegible when filed

72330
4018
111
0

text missing or illegible when filed

0
311

UACC-42
145

27441

text missing or illegible when filed

202

346
271

text missing or illegible when filed

144

30051
71

text missing or illegible when filed

1402
2016
634
4067
175
274

UO-31
143

34230

text missing or illegible when filed

2316
644
1204
1427
1885
0

text missing or illegible when filed

142

137676
1062
110
280

text missing or illegible when filed

490
134

text missing or illegible when filed

141

297

3025

85
1287
0
329

text missing or illegible when filed

140

30507
0

text missing or illegible when filed

2329
927
495

text missing or illegible when filed

0
180

MCT-15
139

34734
441

text missing or illegible when filed

2790
1872
397

text missing or illegible when filed

842
0

text missing or illegible when filed

138

4322
243
294
12794
224

text missing or illegible when filed

1

COLO text missing or illegible when filed

137

57728
433

text missing or illegible when filed

2580
495
0

text missing or illegible when filed

0
174

LOX text missing or illegible when filed

136

1512

983

248
839

text missing or illegible when filed

135

437

730

100

375

134

43207

text missing or illegible when filed

1719

382
7085
72

text missing or illegible when filed

MCT 114
133

37406
345

text missing or illegible when filed

1175
0
458
3813
721

text missing or illegible when filed

132

34176

text missing or illegible when filed

27523
0
534
757

text missing or illegible when filed

967
14

HCC- text missing or illegible when filed

131

734
17230
0
125

text missing or illegible when filed

0
641

text missing or illegible when filed

130

229
91730
1652
917
303

text missing or illegible when filed

129

34742
33
90087
1005
106
457

text missing or illegible when filed

819
0

text missing or illegible when filed

128

40664
304

text missing or illegible when filed

3145
3477
2041

text missing or illegible when filed

478
0

DU-145
127

37777

text missing or illegible when filed

8182
5183
140
480

text missing or illegible when filed

0
0

text missing or illegible when filed

126

36217
331
61753
9431
94
827

text missing or illegible when filed

110

125

37858

text missing or illegible when filed

7367
1172
961

text missing or illegible when filed

134
0

text missing or illegible when filed

124

38104

text missing or illegible when filed

106212
4214
0
1685
2875
423

text missing or illegible when filed

123

23005
737
8134
2800
3182
625
13014
0
0

SN12C
122

32675

text missing or illegible when filed

64277
634
1472
180
23636
0
637

ML- text missing or illegible when filed

121

36449

text missing or illegible when filed

2018
0
325
771
707

text missing or illegible when filed

, T-4
120

28305
783
17193
961
132
1023
4038
0
0

OVCAR- text missing or illegible when filed

119

25375

text missing or illegible when filed

42224
1995
2371
1966
6812

text missing or illegible when filed

77

X- text missing or illegible when filed

118

34213

text missing or illegible when filed

18143
2124
342
222
6444
0
0

OVCAR-4
117

42145
1500
10042
2320
2728
2583
6751
1276
1110

CCRF-CEM
116

38130
576
10022
2781
831
470
41505
0
0

OVCAR-3
115

63017
548
47001
1242
940
303
19348
2443
0

text missing or illegible when filed

114

30005

text missing or illegible when filed

14022
3425
0
350
18283
0
252

MCF- text missing or illegible when filed

113

19678

text missing or illegible when filed

84330
1645
1196
406
1725
0
100

text missing or illegible when filed

112

40230
257
17808
700
708
1164
8394
417
837

text missing or illegible when filed

TCC
111

47430
0
78724
1670
495
303
17019
1114
472

5F- text missing or illegible when filed

110

30345
64
64487
972
185
76
13642
437

text missing or illegible when filed

NC3-

109

44511
0
81076
585
813
276
4038
0
94

U251
108

54075
431

text missing or illegible when filed

573
134
713
17677
804
0

NCL- text missing or illegible when filed

107

78179
436
405
603
17566
808
132

text missing or illegible when filed

-75
106

41104
0
17012
403
416

text missing or illegible when filed

4792

316

NCI- text missing or illegible when filed

105

40037

text missing or illegible when filed

10280
2064
4822
461
28230

text missing or illegible when filed

-1

104

40554
442
13825
1417
491
2644
32964
166
676

NCI-H23
103

41587
633
6072
2204
1331
604
16328
743
60

S text missing or illegible when filed

-OV-3
102

32170
0
18584
2641
522
200

text missing or illegible when filed

343
61

NCI-H23
101

30431
0
6416
4702
140
243

text missing or illegible when filed

0
481

text missing or illegible when filed

100

41930
442
11790
3091
229
303
11318
0
0

EKVX
99

23917
0
14173
1822
0
642
31477
0
0

OVCAR-3
98

31129
0
7829
48
101
793
9392
11
0

MCP-42
97

33300
0
18542
1074
384
465
12792
482
197

text missing or illegible when filed

48

32440
0
9173
1588
6279
341
401
300
184

text missing or illegible when filed

47

32837

text missing or illegible when filed

0
2785
0
120
0
983
127

text missing or illegible when filed

46

29124

text missing or illegible when filed

23461
1117
0
92
10370
344
0

TOGF
24

22953
700
18106
7310

text missing or illegible when filed

130
6277
1704
111

A545-1

text missing or illegible when filed

0
0
0
348
1134

text missing or illegible when filed

415
571
0

A545-3

text missing or illegible when filed

0
0
0
871
134
4878
830
1033
0

A545-4

text missing or illegible when filed

0
0
0
0
1291

text missing or illegible when filed

0

A545-6

text missing or illegible when filed

0
0
0
0
484

text missing or illegible when filed

134
0
0

A545-7

text missing or illegible when filed

0
0
0
0
813

text missing or illegible when filed

787
0
0

EKVX-1

text missing or illegible when filed

0
0
0
1360
3426

text missing or illegible when filed

476
2338
0

EKVX-4

text missing or illegible when filed

0
0
0

text missing or illegible when filed

4219

330
180
0

EKVX-3

text missing or illegible when filed

0
0
0
1806
0

text missing or illegible when filed

0
706
0

EKVX-6

text missing or illegible when filed

0
0
0
284
1113

text missing or illegible when filed

137
0
0

EKVX-7

text missing or illegible when filed

0
0
0
0
37
7443
867
0
0

MCF-7-1

text missing or illegible when filed

0
0
0
483
801
710
3344
134
0

MCF-7-3

text missing or illegible when filed

0
0
0
18
1045

text missing or illegible when filed

0
482
0

MCF-7-4

text missing or illegible when filed

0
0
0
675
827
2087
218
13 text missing or illegible when filed

0

MCF-7-5

text missing or illegible when filed

0
0
0
1191
2431
1029
0

text missing or illegible when filed

0

MCF-7-7

text missing or illegible when filed

0
0
0
0

text missing or illegible when filed

4028
407
829
0

ADR-RES-1

text missing or illegible when filed

0
0
0
0
2734
433
4006

text missing or illegible when filed

0

ADR-RES-3

text missing or illegible when filed

0
0
0
1145
3482
2797
1066
0
0

ADR-RES-4

text missing or illegible when filed

0
0
0
112
0
4038
637
801
0

ADR-RES-5

text missing or illegible when filed

0
0
0
403
2300
3017
0
0
0

ADR-RES-7

text missing or illegible when filed

0
0
0
2011
2904
842

text missing or illegible when filed

0

WI 34-1

text missing or illegible when filed

0
0
0
0
7754
1845
529
18311
0

WI 34-3

text missing or illegible when filed

0
0
0

text missing or illegible when filed

3848
187
0
0

WI 34-4

text missing or illegible when filed

0
0
0
1631
2095
8250
0
1650
0

WI 34-5

text missing or illegible when filed

0
0
0
1300
7877
6484
683
547
0

WI 34-7

text missing or illegible when filed

0
0
0
1458
3377
3293
312
0
0

text missing or illegible when filed

-1

E4
0
0
0

text missing or illegible when filed

0
5828
0
80
0

text missing or illegible when filed

-3

E4
0
0
0
642
849
1015
644
0
0

text missing or illegible when filed

-4

E4
0
0
0
280
281
4257
335
850
0

text missing or illegible when filed

-5

E4
0
0
0
1177
1708

text missing or illegible when filed

1280
173
0

text missing or illegible when filed

-7

E4
0
0
0
1543
274
4044
0
0
0

H1 text missing or illegible when filed

-1

0
0
0
114
7085
4794
0
237
0

H1 text missing or illegible when filed

-3

0
0
0
0
431
2347
542
906
0

H1 text missing or illegible when filed

-4

0
0
0
767
123
2212
421
817
0

H1 text missing or illegible when filed

-5

0
0
0
0
1456
4474
26
0
0

H1 text missing or illegible when filed

-7

0
0
0
468
1883
2279
10
0
0

text missing or illegible when filed

-2

0
0
0
234
764
1167
204
834
0

EXVX-2

text missing or illegible when filed

0
0
0
1435
830
2012
0
0
0

HCT-114-1

text missing or illegible when filed

0
0
0
1106
330
20773
1648
786
0

HCT-115-2

text missing or illegible when filed

0
0
0
2982
2935

text missing or illegible when filed

148
811
0

HT text missing or illegible when filed

-2

0
0
0
1014
2541
8264

text missing or illegible when filed

0
0

text missing or illegible when filed

-1

0
0
0
213
3130
1816
0
647
0

text missing or illegible when filed

-2

0
0
0
819
5647
1019
793
179
0

text missing or illegible when filed

-1

0
0
0
2143
3277
744
875
0
0

text missing or illegible when filed

-2

0
0
0
326
5072
4430
2855
1204
0

OVCAR-4-1

text missing or illegible when filed

0
0
0
1664
2823
4847
25
867
0

OVCAR-4-2

text missing or illegible when filed

0
0
0
0
1824
19130
406
441
0

OVCAR-5-1

text missing or illegible when filed

0
0
0
1143
6553
13774
483
330
0

OVCAR-5-2

text missing or illegible when filed

0
0
0
1268
3797

text missing or illegible when filed

875
0
0

MCF-7-2

text missing or illegible when filed

0
0
0
768
3082
1725
294
0
0

ADA-RES-2

text missing or illegible when filed

0
0
0
776
1953
0
0
44
0

text missing or illegible when filed

-2

E4
0
0
0
841
1916
845
1522
0
0

SW480-1

text missing or illegible when filed

0
0
0
424
1870
4717

text missing or illegible when filed

0

SW480-2

text missing or illegible when filed

0
0
0
1306
702
6413
0

text missing or illegible when filed

0

HT text missing or illegible when filed

-2

0
0
0
283
0
2907
1014
340
0

C33A-1

text missing or illegible when filed

0
0
0
205
4364
2016
131
440
0

C33A-2

text missing or illegible when filed

0
0
0
204
1142
0
380
373
0

U text missing or illegible when filed

-1

0
0
0
2048
7970

text missing or illegible when filed

443
3787
0

U text missing or illegible when filed

-2

0
0
0
6100
11304
7073
1903

text missing or illegible when filed

0

M text missing or illegible when filed

-1

0
0
0
1432
4561
3320
0

text missing or illegible when filed

0

M text missing or illegible when filed

-2

0
0
0
0
1963
8724
283
0
0

W1 text missing or illegible when filed

-2

0
0
0
2204

text missing or illegible when filed

2835
442
18
0

text missing or illegible when filed

-1

0
0
0
1156
3176
9771
244
0
0

text missing or illegible when filed

-2

0
0
0
4485
2091
0
404
0
0

text missing or illegible when filed

-3

0
0
0
6430
11049
0
0
1371
0

text missing or illegible when filed

-4

0
0
0
6660
41955
13408
0
1037
0

text missing or illegible when filed

-5

0
0
0
4520
2081
4204
282
0
0

text missing or illegible when filed

-6

0
0
0
1704
340
0
143
0
0

text missing or illegible when filed

-7

0
0
0
3347
131
314
4175
110
0

text missing or illegible when filed

-8

0
0
0
48
21722
273
603
0
0

text missing or illegible when filed

0
0
0

text missing or illegible when filed

8479

2724

0
0
0

text missing or illegible when filed

0
0
0
8122
1300

text missing or illegible when filed

1311

0
0
0

text missing or illegible when filed

14381
1851

text missing or illegible when filed

0
0
0
3087
3288

text missing or illegible when filed

1028
0
0

text missing or illegible when filed

0
0
0

text missing or illegible when filed

298

311
238
0

text missing or illegible when filed

0
0
0
3041
12534
1781
833

text missing or illegible when filed

0
0
0
4794
2846
2872
2303
4773
0

text missing or illegible when filed

0
0
0
1944
4731
97

text missing or illegible when filed

933
0

text missing or illegible when filed

0
0
0

text missing or illegible when filed

231
1117

text missing or illegible when filed

0
0
0
12057
5346
0

text missing or illegible when filed

0
0
0
0
1444

text missing or illegible when filed

0
427
0

text missing or illegible when filed

0
0
0
1913
2753

text missing or illegible when filed

17
0

text missing or illegible when filed

0
0
0
742
2307
2043

text missing or illegible when filed

819
0

text missing or illegible when filed

0
0
0
614
8117
2307
761
0
0

HC29-1

text missing or illegible when filed

0
0
0
429
2044

text missing or illegible when filed

0
0

HT29-7

text missing or illegible when filed

0
0
0
444
130
8
0
101
0

HT29-3

text missing or illegible when filed

0
0
0

text missing or illegible when filed

2808
2171
0
1144
0

text missing or illegible when filed

0
0
0
0
4143

text missing or illegible when filed

1075

0
0
0

text missing or illegible when filed

2822
102
0
0

text missing or illegible when filed

0
0
0
771
0001
2712
1138
1044
0

text missing or illegible when filed

0
0
0
1100
4034
0022
384
0
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text missing or illegible when filed

137

180
0
11
0
2207

text missing or illegible when filed

12
4200

text missing or illegible when filed

186

0
0

text missing or illegible when filed

4
0
1347
174
42
23
1813

text missing or illegible when filed

183

110
0
13
0
2304

text missing or illegible when filed

11
0
20071

text missing or illegible when filed

178

0
0
0
0
1139
0
0
400
10

text missing or illegible when filed

81

0
0
0

text missing or illegible when filed

0
0

text missing or illegible when filed

1428
0
0
0

text missing or illegible when filed

1000
0
0

text missing or illegible when filed

0
0
0
4477
2000
24
384
23334

text missing or illegible when filed

4

242
0

text missing or illegible when filed

4
0

text missing or illegible when filed

241
70
0
8333

text missing or illegible when filed

3

0
0
0
0
1711
142
0
137
410

text missing or illegible when filed

1

174
0
23
242
2021
2134
0
187

text missing or illegible when filed

0
0

text missing or illegible when filed

0
3843
824
0
81
12023

text missing or illegible when filed

79

0
0
0
70
4670
341
0
0
37319

text missing or illegible when filed

81

0
0
42
2700
4053
237
0
31
3014

text missing or illegible when filed

83

143
0

text missing or illegible when filed

4007
0
288
1371

text missing or illegible when filed

0
30
0

text missing or illegible when filed

0
0
131

text missing or illegible when filed

200
0
0
343
7318
425
0
0

text missing or illegible when filed

90

0
0
183
0
1780
701
443
0

text missing or illegible when filed

82

53
0
70
12

text missing or illegible when filed

2
731
43
0

text missing or illegible when filed

94

483
0
0
0

text missing or illegible when filed

57
0
230
0
1053

text missing or illegible when filed

0
4334
4121
12
0
1789

text missing or illegible when filed

0
0
0
2707

text missing or illegible when filed

22
0
0
183
27 text missing or illegible when filed

80
143
1739
425

text missing or illegible when filed

150

0
0
30
0
1047
1083
184
730
2441

text missing or illegible when filed

152

2072
0
0
247
2284
0
343
3370
2024

text missing or illegible when filed

154

0
0
0
2623
1100
0

text missing or illegible when filed

3807

0
0
42
207
1432
0
0
114
1632

text missing or illegible when filed

154

0
0
42
570
184
0

text missing or illegible when filed

1114
0

text missing or illegible when filed

109

0
0
52
149
1729
1178
0
0
231

text missing or illegible when filed

-143

142

0
0
43
0
1422
217

text missing or illegible when filed

1034
1800

text missing or illegible when filed

184

12284
0
0
0
1344
0
183
1004
4034

C. text missing or illegible when filed

0
47

text missing or illegible when filed

784

4017
0
0

text missing or illegible when filed

04
0
21342

text missing or illegible when filed

T-4

100

0
0
70
212

text missing or illegible when filed

531
7187

text missing or illegible when filed

3

171

0
0
0

text missing or illegible when filed

373
0
0
241

c text missing or illegible when filed

, 1441

30

181

0
0
0

text missing or illegible when filed

130
203

text missing or illegible when filed

0

7817 text missing or illegible when filed

* c

143

0
0
31
0
447
0
1
212
410

KB text missing or illegible when filed

A*

1 text missing or illegible when filed

4

0
0
0
135

text missing or illegible when filed

24
52
211

text missing or illegible when filed

poly A*

282
0
43
0
2437
0

text missing or illegible when filed

3781

ACI-94

124

0
0
0
0
2832
208
171
8742

text missing or illegible when filed

UACC-02

209

304
0
34
131
1204
0
0
1277
1373

MCF-7 text missing or illegible when filed

202

0
0
34
0
1347
700
0
1434
1030

UTOS ( text missing or illegible when filed

204

0
0
171
22
0
0
0
0
3433

WISM (C text missing or illegible when filed

A*

206

0
0
0
0
742
843
44
42
1191

454 text missing or illegible when filed

208

41
0
0
0
7137
0
0
0

text missing or illegible when filed

CC1, 137

218

0
0
80
141
1184
3
100
0
8.27

W text missing or illegible when filed

10% PBS

219

0
0
0
0
2120
0
77
0

text missing or illegible when filed

1441 * TFA text missing or illegible when filed

220

0
0
0
234

text missing or illegible when filed

03
0
0
0

text missing or illegible when filed

-1

221

text missing or illegible when filed

0
0
16
1672
0
0
0
1347

text missing or illegible when filed

-2

223

0
0
0
0
3225
300

text missing or illegible when filed

-4

224

734
0
172
0

text missing or illegible when filed

0
0
0
1331

MCP-02

241

124
0
0
3
1134
372
0
0
1724

text missing or illegible when filed

, T-4

242

1229
0
0
0
41 text missing or illegible when filed

1234
0
2 text missing or illegible when filed

DXYX

243

text missing or illegible when filed

0
0

text missing or illegible when filed

2700

317

10
1440

L-40

244

0
0
0
0
3432

text missing or illegible when filed

614
14 text missing or illegible when filed

10317

MC-4423

245

237
0

text missing or illegible when filed

183

321
3342
6330

text missing or illegible when filed

8226

0
0

text missing or illegible when filed

413
2047
711 text missing or illegible when filed

182
0
736

AS text missing or illegible when filed

A TCC

247

0
0

text missing or illegible when filed

0
2108
1 text missing or illegible when filed

10
33
241

text missing or illegible when filed

SA

248

0
0
0
0
2709
1310
23
261

text missing or illegible when filed

CVCAR-3

249

0
0
17
247
3481
0
41
183

text missing or illegible when filed

44

MCT-14

250

1042
0
0
62

text missing or illegible when filed

1387
283

text missing or illegible when filed

OVC

-4

251

83
0
83
1 text missing or illegible when filed

542
0
7

text missing or illegible when filed

7

UO-31

252

347
0
0

text missing or illegible when filed

0
0

text missing or illegible when filed

1047

OVCAR-5

253

0
0

text missing or illegible when filed

727

0
362
4789

text missing or illegible when filed

32

SM12C

254

811
0
0
0
355 text missing or illegible when filed

OVCAR-4

256

322
0
0
13

text missing or illegible when filed

872
0

text missing or illegible when filed

1742

LOX text missing or illegible when filed

0
0
77
343
8301

text missing or illegible when filed

2950
8100

X3 text missing or illegible when filed

OV1

257

text missing or illegible when filed

37

SX text missing or illegible when filed

-2

258

0
0
176
0
23 text missing or illegible when filed

401
338
1574

text missing or illegible when filed

04

SX-OV-3

259

0
0
0
0
1164
0
184
14 text missing or illegible when filed

1437

SX-MEL-4

260

0
0
0
472
1378

text missing or illegible when filed

SF-

261

1373
0

text missing or illegible when filed

434

73
3291
0
7434

text missing or illegible when filed

262

67
0
0
0
3780

text missing or illegible when filed

41
0

text missing or illegible when filed

3063

K-962

263

157
0
85
31
8144
4336
276
2537
1782

UACC-287

264

text missing or illegible when filed

0
0
0

text missing or illegible when filed

0
42
0
1200

M14

265

0
0
74
0

text missing or illegible when filed

27
151
181
0
1430

MCF7

267

5820
0
0
24
8234
0
0
17404

text missing or illegible when filed

MOA-M-436

269

0
0
80
227
1834
0
0
744
1343

MT279

270

1743
0
0
0
1534
2 text missing or illegible when filed

3
87
0

text missing or illegible when filed

MOA-N

271

0
0
17
0
4727

text missing or illegible when filed

283
1282
3025

v10 poly A*

273

text missing or illegible when filed

006
0
137
0
7232
1800
43
854
18372

XHOS poly A*

text missing or illegible when filed

370

0
14

text missing or illegible when filed

3301
32
384
579
4284

HT2.34 24th TPA RHA text missing or illegible when filed

23

300

0
0
19
0
2942

text missing or illegible when filed

171

HELA-EXP-031000

313

0
0
19
49
2177
949
24
0
104 text missing or illegible when filed

HT384

322

630
0
0

text missing or illegible when filed

4154

424
773
4214

HT347

323

442
0
5
0
244 text missing or illegible when filed

2412
0

text missing or illegible when filed

54352

456 text missing or illegible when filed

324

0
55
0
3464
0
11
761
1101

NCI- text missing or illegible when filed

224

334

0
0
0
34

text missing or illegible when filed

0
100
0
1100

text missing or illegible when filed

337

0
0
0
357
3132
381
181

text missing or illegible when filed

222

479

-231

338

7140
0
22
0
8113
4366
0

text missing or illegible when filed

28631

U251

339

16344
0

text missing or illegible when filed

0
116 text missing or illegible when filed

18310
202
141005
34705

FT text missing or illegible when filed

poly A*

340

0
0
0
0

text missing or illegible when filed

0
0

text missing or illegible when filed

2606

FC-3

341

0
0
0
227
3879

text missing or illegible when filed

63
584
419

HCC-2 text missing or illegible when filed

343

31
0
0
0
2399
0
138
0

text missing or illegible when filed

SW-420

345

0
0
72
83
2872
0
106

text missing or illegible when filed

0

MT102

346

575
0
80
25
4309

text missing or illegible when filed

0
3475
10731

COLO 204

347

0
0
24
43
703

text missing or illegible when filed

0
0
0

MT218

348

4211
0
0
0
1703
0
0
0
1866

text missing or illegible when filed

-12

349

0
0
44
137
1734
842
102
0
1130

MT131

350

0
0
34
202
3787

text missing or illegible when filed

9
0

text missing or illegible when filed

774

A text missing or illegible when filed

351

7840
0
0

text missing or illegible when filed

0
200
0
0

MT282

352

250
0
0
0
8001
0
0
0
18131

ROO text missing or illegible when filed

3

353

0
0
134
0
2870
0
0
0
179

TH-19

356

text missing or illegible when filed

0
0
0
7868
2226
0
3008
17089

text missing or illegible when filed

-3M

357

2843
0
0
0
24100
16870
313
37531
7453

text missing or illegible when filed

T

360

0
0
0
0
1834
0
0

text missing or illegible when filed

1100

MT213

60

0
0
162
0
13822
1275
37
0
43 text missing or illegible when filed

62

195
0
107
0
5482
437
0
429
4 text missing or illegible when filed

48

HT text missing or illegible when filed

64

0
0
0
31
3341
0
0
0
2704

HT134

54

0
0
114
0
3041
0
0
0
12179

HT143

58

337
0
35

text missing or illegible when filed

0
0
248

HT170

60

0
0
2 text missing or illegible when filed

0
8332
0
0
0
12 text missing or illegible when filed

50

HT172

62

0
0
5
0
4071
0
94
104
2202

HT130

63

1302
0
0
0
3671
121
0
0
2 text missing or illegible when filed

HT1

64

0
0
0
701
5034
0
0
0
2831

HT154

65

1836
0
0
0
8174
1 text missing or illegible when filed

63
0
0
1773

HT140

66

0
0
73
0

text missing or illegible when filed

0
0
0
2924

HT text missing or illegible when filed

67

0
0
0
0

text missing or illegible when filed

343
13 text missing or illegible when filed

HT149

68

0
0
24
5
4352
0
440
0

text missing or illegible when filed

HT143

69

5
0
0
1176
3334
0

text missing or illegible when filed

HT183

70

text missing or illegible when filed

0
61
0
4240

text missing or illegible when filed

HT148

71

340
0
0
0

text missing or illegible when filed

0
0
0
3 text missing or illegible when filed

4

HT227

72

0
0
30
114
4034
0
0
0
4727

HT302

73

420
0
0
123
5413

text missing or illegible when filed

7
32
41 text missing or illegible when filed

HT314

74

429
0
0
0
4709
6214
0
0

text missing or illegible when filed

HT317

76

243
0
27
0

text missing or illegible when filed

2971
0
0
20750

text missing or illegible when filed

0
33

text missing or illegible when filed

2199

220

2212

HT323

78

83
0
110
0

text missing or illegible when filed

197
0
5230

HT327

80

0
0
124
0
3771
177 text missing or illegible when filed

14
7320

HT235

82

0
0
71
0

text missing or illegible when filed

0
422
17130

HT146

84

432
0
120
0
1141
0
419
0
364

HT343

87

0
0
0
0
5314

text missing or illegible when filed

0
304
21 text missing or illegible when filed

HT311

170

text missing or illegible when filed

0
3141

text missing or illegible when filed

234
0

text missing or illegible when filed

185

0
0

text missing or illegible when filed

0
3240
0
22 text missing or illegible when filed

HT140

187

0
0
0
0
812
0
0
0
303

HT291

1 text missing or illegible when filed

0
0
244
0
2857
1134
0
0

text missing or illegible when filed

47

HT372

191

0
0

text missing or illegible when filed

242
33 text missing or illegible when filed

23
247
0
431

TCGP

207

0
0
0
212

text missing or illegible when filed

0
811

text missing or illegible when filed

17

HT100

276

131
0
0
0
801
0
202
429
2730

HT307

217

0
0
115
0
1318
0
0
0
4418

HT300

234

0
0
45
15

text missing or illegible when filed

0
827
33 text missing or illegible when filed

HT370

224

1027
0
22
0

text missing or illegible when filed

44
134
644
11858

HT371

229

0
0

text missing or illegible when filed

27
4211
0
0
281
9410

HT377

230

405
0
23
0
3712
779
292
0

text missing or illegible when filed

HT342

236

text missing or illegible when filed

408
0
627
7080

text missing or illegible when filed

281

0
0
0

text missing or illegible when filed

7
0
0
0
0
0

HT334

text missing or illegible when filed

0
0
32
0
4472
0
0
0
32015

HT338

301

0
0
0
3
3010
0
202
0
6382

HT342

315

544
0
0
71
2100
0
0
0
2019

HT304

317

0
0
0
102
2127
19712
2
0

text missing or illegible when filed

HT312

319

2077
0
0
104
2504
65
0

text missing or illegible when filed

6517

HT162

325

0
0
10
0
1411
0
193
0
0

HT text missing or illegible when filed

334

0
0
0
0
6212
294
0
182
4313

HT137

3 text missing or illegible when filed

0
6
324
2314
426
0
374
1 text missing or illegible when filed

T-410
143

text missing or illegible when filed

0
0
0
4107

text missing or illegible when filed

253

MDA-N
141

22 text missing or illegible when filed

0
49
0

text missing or illegible when filed

MOA-

-4.34
108

1148
0
68
130

text missing or illegible when filed

814

MOA-

-231
157

3 text missing or illegible when filed

1
0
0
103
4223
381
200
141

text missing or illegible when filed

153

0
84
0
4775
0
870
1534
13305

MCF-7/AC text missing or illegible when filed

153

0
0

text missing or illegible when filed

0
110

text missing or illegible when filed

MCF/
151

3033
0

text missing or illegible when filed

2
0

text missing or illegible when filed

149

0
0

text missing or illegible when filed

3
0

text missing or illegible when filed

LIACC-257
147

0
0
0
0

text missing or illegible when filed

0
0
813

text missing or illegible when filed

LIACC-

145

0
0
47

text missing or illegible when filed

144

0
101
0

text missing or illegible when filed

LO-31
143

756
0
0
0

text missing or illegible when filed

142

0
14
0

text missing or illegible when filed

-12
141

text missing or illegible when filed

0
0
29

text missing or illegible when filed

0
437

text missing or illegible when filed

140

0
0
4
0

text missing or illegible when filed

0
177

text missing or illegible when filed

NCT-1

139

0
0
0
0

text missing or illegible when filed

139

1 text missing or illegible when filed

0
0
0

text missing or illegible when filed

0
3 text missing or illegible when filed

C₂O

O20

137

2
0
232

text missing or illegible when filed

0
311

text missing or illegible when filed

LOX

138

0
0
121

text missing or illegible when filed

0
0

text missing or illegible when filed

135

0
37
0

text missing or illegible when filed

134

1 text missing or illegible when filed

0
0
10

text missing or illegible when filed

0
304

text missing or illegible when filed

HCT

133

0
107
104

text missing or illegible when filed

0
204

text missing or illegible when filed

132

791
0
7
110

text missing or illegible when filed

0
180

text missing or illegible when filed

HCC-

131

1371
0
0
0

text missing or illegible when filed

0
370

text missing or illegible when filed

130

0
0
0
104

text missing or illegible when filed

0
2 text missing or illegible when filed

C-2

129

0
0
0
0

text missing or illegible when filed

0
102

text missing or illegible when filed

129

0
11
212

text missing or illegible when filed

0
220

text missing or illegible when filed

127

454
0
0
82

text missing or illegible when filed

126

0
0
132
160

text missing or illegible when filed

128

0
2
0

text missing or illegible when filed

124

2 text missing or illegible when filed

0
124
245

text missing or illegible when filed

8228
121

0
0
0
64

text missing or illegible when filed

0
0

text missing or illegible when filed

122

0
0
0

text missing or illegible when filed

0
732

text missing or illegible when filed

HS-40
12 text missing or illegible when filed

0
0
0
104

text missing or illegible when filed

0
102

text missing or illegible when filed

MCL, T-4
120

text missing or illegible when filed

0
24
0

text missing or illegible when filed

OVCAR-5
119

576
0
14
30

text missing or illegible when filed

0
203

text missing or illegible when filed

X-562

119

0
0
0
0

text missing or illegible when filed

0
83

text missing or illegible when filed

OVCAR

-4
117

text missing or illegible when filed

0
0
0

text missing or illegible when filed

-CEM
118

text missing or illegible when filed

0
70
0

text missing or illegible when filed

0
372

text missing or illegible when filed

OVCAR-3
115

2334
0

text missing or illegible when filed

0
302

text missing or illegible when filed

5F-539

114

941
0
2
0

text missing or illegible when filed

0
1013

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HI text missing or illegible when filed

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0
17277
0
3974
0
3412
1982

text missing or illegible when filed

-4

wt
0

text missing or illegible when filed

0
23072
0
3413

text missing or illegible when filed

-3

0
11184
0
1910

text missing or illegible when filed

18347

-4

0
13125
0

text missing or illegible when filed

0
1248
1137

text missing or illegible when filed

-5

0
4084
0
0
0
814

text missing or illegible when filed

2400

-6

0
318

text missing or illegible when filed

32104

-13

0

text missing or illegible when filed

740

20303

-20

0
14080
0

text missing or illegible when filed

0
2419 text missing or illegible when filed

777
18057

text missing or illegible when filed

21

0
13873
0
3178
0

text missing or illegible when filed

22

0

text missing or illegible when filed

18178

OVCAR4-5

text missing or illegible when filed

0
4712
0

text missing or illegible when filed

7830

-10

0
4712
0
3078

text missing or illegible when filed

7
1837

text missing or illegible when filed

-11

0
8270
0
4705
0

text missing or illegible when filed

4271

-12

0
10544
0

text missing or illegible when filed

0
2390

text missing or illegible when filed

42037

-13

0

text missing or illegible when filed

0
1883
810
43027

text missing or illegible when filed

-14

0
18318
0

text missing or illegible when filed

0
432
1228

text missing or illegible when filed

17823

-15

0
70792
0

text missing or illegible when filed

0
834

text missing or illegible when filed

13732

-16

0
7517
0
54
0
1777
710
18220
12001

text missing or illegible when filed

-17

0
9720
0

text missing or illegible when filed

0
1273
874

text missing or illegible when filed

-18

0

text missing or illegible when filed

0
734
0
2844
1438

text missing or illegible when filed

21852

-19

0

text missing or illegible when filed

0
0
0
1173
649
22782
14100

adrenal gland- text missing or illegible when filed

1

0
238
14723
24 text missing or illegible when filed

724
3477
13 text missing or illegible when filed

13731

lymph node- text missing or illegible when filed

2

0

text missing or illegible when filed

22295
2 text missing or illegible when filed

336

8
281
22 text missing or illegible when filed

3

0

text missing or illegible when filed

34
2 text missing or illegible when filed

724
447

text missing or illegible when filed

gland-

4

0
0
4322
2741
3 text missing or illegible when filed

3
30
24
100
2044

text missing or illegible when filed

5

0
0
114 text missing or illegible when filed

2076
13 text missing or illegible when filed

8167
3530
51
1 text missing or illegible when filed

108

6

0
530

text missing or illegible when filed

17022

24
2091
1052
241
115 text missing or illegible when filed

7

0
234
1244 text missing or illegible when filed

1638

237

28
4341

text missing or illegible when filed

211

gland-

8

127
162

text missing or illegible when filed

271

067
4 text missing or illegible when filed

1
23
11637

text missing or illegible when filed

9

171
364
10 text missing or illegible when filed

39
23 text missing or illegible when filed

45
91 text missing or illegible when filed

55
23 text missing or illegible when filed

10

317
3 text missing or illegible when filed

10004
742 text missing or illegible when filed

7
63 text missing or illegible when filed

338
301

text missing or illegible when filed

11

254
634
2011 text missing or illegible when filed

241

311

3
234

text missing or illegible when filed

12

51

text missing or illegible when filed

11313

47
232 text missing or illegible when filed

4
21 text missing or illegible when filed

74
11 text missing or illegible when filed

13

434
207
16229

text missing or illegible when filed

11634
10 text missing or illegible when filed

41
435
2 text missing or illegible when filed

14

0
523
13 text missing or illegible when filed

40
77 text missing or illegible when filed

1022

3
2034
7 text missing or illegible when filed

15

0

text missing or illegible when filed

277

719
15 text missing or illegible when filed

75
177
13041

text missing or illegible when filed

16

791
1 text missing or illegible when filed

154

110

194712

38
22 text missing or illegible when filed

4
3341

text missing or illegible when filed

17

2 text missing or illegible when filed

1054
11 text missing or illegible when filed

7
229 text missing or illegible when filed

1
0
4 text missing or illegible when filed

18

230
2 text missing or illegible when filed

25312
141 text missing or illegible when filed

40
23 text missing or illegible when filed

132

757

19

218

text missing or illegible when filed

142
18 text missing or illegible when filed

91241
3 text missing or illegible when filed

5
340
779 text missing or illegible when filed

11044
84347
7 text missing or illegible when filed

41
3 text missing or illegible when filed

21

372
254

text missing or illegible when filed

34
13 text missing or illegible when filed

31
1 text missing or illegible when filed

77
1734
354
100
3 text missing or illegible when filed

22

79
2 text missing or illegible when filed

2
14 text missing or illegible when filed

0
22 text missing or illegible when filed

4
345
233

text missing or illegible when filed

23

179
542
16 text missing or illegible when filed

2203
337
143
5791

text missing or illegible when filed

24

0
2 text missing or illegible when filed

12342
12134
71122

text missing or illegible when filed

1227

3742

25

0
373
21347
23 text missing or illegible when filed

43
1 text missing or illegible when filed

2
2 text missing or illegible when filed

27

177
496
21278
27103
112750
3483
700
290
3 text missing or illegible when filed

28

28

0
124
6795
13179

text missing or illegible when filed

764
209

text missing or illegible when filed

39
2 text missing or illegible when filed

131

gland-

29

0
229
13 text missing or illegible when filed

11034

0
14 text missing or illegible when filed

C

30

30

122
0
0
4 text missing or illegible when filed

1
1157 text missing or illegible when filed

0
11
372
7

text missing or illegible when filed

31

0
438
19832
13704

text missing or illegible when filed

718
2751
147 text missing or illegible when filed

162
11043

text missing or illegible when filed

C

32

0
797
167 text missing or illegible when filed

112
15 text missing or illegible when filed

44
1037
304
471
20117

text missing or illegible when filed

33

105
1371
61570
11723
84250
3429
1 text missing or illegible when filed

4
81
18387

HCA text missing or illegible when filed

C

34

30
0
11 text missing or illegible when filed

02
3716
222 text missing or illegible when filed

4
200
230
0

text missing or illegible when filed

100

35

0
130
20403
2248
127701
2304
1034
0
7344

lymph node

36

0
154
2145
4941
17824

text missing or illegible when filed

76
0
54
2943

text missing or illegible when filed

37

0
0
23 text missing or illegible when filed

6
1 text missing or illegible when filed

79
157218
302
613
0
3016

text missing or illegible when filed

38

436
37
37
63

text missing or illegible when filed

411
8
0
05

Heart

39

124
232
20524
4904
128875

text missing or illegible when filed

23
233
4434

text missing or illegible when filed

40

362
0
3423
14731
15 text missing or illegible when filed

423
184
0
4404

C text missing or illegible when filed

41

0
0
0
4472
83230
76

text missing or illegible when filed

4
82 text missing or illegible when filed

42

534
204
1307
19012
1837
1024
330
2 text missing or illegible when filed

0
7734

Sal text missing or illegible when filed

43

4
170
4203

text missing or illegible when filed

25
1 text missing or illegible when filed

0729
1547

text missing or illegible when filed

4
167
33 text missing or illegible when filed

lymph-

44

441
218

text missing or illegible when filed

77
17243
23307
40 text missing or illegible when filed

4
37 text missing or illegible when filed

304

257

HT21- text missing or illegible when filed

154
34
0
1327
1011
0
384
40
2473

HT21- text missing or illegible when filed

0
0
0
1256
0
0
308

text missing or illegible when filed

2
5 text missing or illegible when filed

3

HT157- text missing or illegible when filed

1

44
0
0
3044
0
234
15
67
4 text missing or illegible when filed

-13

364
356

2341
0
0
4870
3 text missing or illegible when filed

18
47
1438
140

text missing or illegible when filed

-12

364
354

4181
44
1 text missing or illegible when filed

004
3 text missing or illegible when filed

3
530
475
243
1 text missing or illegible when filed

145

344

76
41
0
3534
0
418
80
0
2922

text missing or illegible when filed

342

258
148
230
2481
0
228
97
0
2043

RFTEC

334
334

290
0
0
8453
4946
0
423
0
2443

lymph node- text missing or illegible when filed

332

15
0
0
19034
0
104
92
0
564

text missing or illegible when filed

SACC

330

0
0
823
6104
0
129
0
0
1081

text missing or illegible when filed

329

031
2 text missing or illegible when filed

43113
442

text missing or illegible when filed

147
7317

HT text missing or illegible when filed

327

0
272
2277
0
0
114
148
2 text missing or illegible when filed

326

2058
25
417
11256
201 text missing or illegible when filed

125
871
0

text missing or illegible when filed

321

9
20
0
2 text missing or illegible when filed

34
0
0
24 text missing or illegible when filed

0
2382

text missing or illegible when filed

3rd

320

253
0

text missing or illegible when filed

611
77802
1049
307
294
1 text missing or illegible when filed

319

447
3490
5764
177 text missing or illegible when filed

110677
52 text missing or illegible when filed

9031
12 text missing or illegible when filed

132

315

227
290
29285

text missing or illegible when filed

9
19054
2424

text missing or illegible when filed

3
79
9214

text missing or illegible when filed

314

230
470
20 text missing or illegible when filed

2
1 text missing or illegible when filed

3
1002
273
14207

text missing or illegible when filed

311

90
52
42
73 text missing or illegible when filed

314
173
9
162
1713

text missing or illegible when filed

309

0
21
308
2 text missing or illegible when filed

37
0
145
49
0
1645

text missing or illegible when filed

gland

307

24 text missing or illegible when filed

0
225
54 text missing or illegible when filed

19
169
57 text missing or illegible when filed

190
144 text missing or illegible when filed

304

0
11
194
4771
847

text missing or illegible when filed

36
19
0
2 text missing or illegible when filed

gland

303

146
734
3409
7475
735
1902
150
34
9057

text missing or illegible when filed

27084
14441
141733
106
400
10
3863

text missing or illegible when filed

296

1134
7043

text missing or illegible when filed

9706
3876
2877

text missing or illegible when filed

19783

344
14347

text missing or illegible when filed

12364
1179
1089
384

text missing or illegible when filed

296

0
344
702

text missing or illegible when filed

2347
132
153
7683

text missing or illegible when filed

294

485

text missing or illegible when filed

546
4105
13000
4373

text missing or illegible when filed

311
11648

text missing or illegible when filed

292

136
84
1830
4123
279
479
231
134
5612

text missing or illegible when filed

230

833
1439
38493
18470
4733
3133
1374
124
15783

homo text missing or illegible when filed

279

0
0
0
1113
0
15
0
143
1019

text missing or illegible when filed

277

0
0
442

text missing or illegible when filed

143
29
0
0
2444

Hpaec

278
273

110
124
87
2787
172
0
0
73
1917

Ht text missing or illegible when filed

294

0
0
0
1285
0
113
82
109

text missing or illegible when filed

266

0
0
0
0909
0
0
13
0
7422

text missing or illegible when filed

-11

239
336

0
1002
0
8324
587
10
11
31
1434

text missing or illegible when filed

238

527
98
213
4743
1703
313
11
130
8438

HT372- text missing or illegible when filed

234

158
0
0
4079
2761
734
0
52
2234

text missing or illegible when filed

-7

233
233

192
112
0
2948
0
134
64
0
8712

text missing or illegible when filed

-6

231
231

0
0
184

text missing or illegible when filed

0
50
82
0

text missing or illegible when filed

-2

239
279

0
0
347
3473
0
50
50
171

text missing or illegible when filed

-1

227
227

308
52
0
1773
205
10
0
32
9127

text missing or illegible when filed

322

41
0
1051
3212
0
183
133
40
2036

text missing or illegible when filed

216

200
0
0
7296
876
0
131
0
1579

text missing or illegible when filed

214

0
204
0
8474
0
1257
315
108
2857

text missing or illegible when filed

213

35
8
0

text missing or illegible when filed

1
0
123
0
0

text missing or illegible when filed

212

0
93
243

text missing or illegible when filed

196

113
75
3834

HCAEC

211
211

0
0
0
3921
1
190
0
28
1167

text missing or illegible when filed

210

186
143
0
4763
0
873
109
182
1473

text missing or illegible when filed

209

115
0
54
2295
0
1 text missing or illegible when filed

0
70
2718

text missing or illegible when filed

205

236
50
125
2870
0
1785
72
15
2 text missing or illegible when filed

203

124
15
329
3074
183
53
38
0
831

text missing or illegible when filed

201

0
0
194
27 text missing or illegible when filed

0
83
101
7
2100

text missing or illegible when filed

35
0
3811
0
154
63
0
1438

text missing or illegible when filed

197

33
49
2102
2 text missing or illegible when filed

125

183
113
0

text missing or illegible when filed

HEPM 34 TOPS1 text missing or illegible when filed

444
135
213
1914
0
364
0
70
3531

text missing or illegible when filed

183

0
444
135
213
0
349
71
0
712

text missing or illegible when filed

81

0
87
0
1834
0
0
172
0
1302

text missing or illegible when filed

86

409
3 text missing or illegible when filed

447
1283
0
1374
867
31
13412

text missing or illegible when filed

87

0
213
181
1330
0
977
476
112

text missing or illegible when filed

155
184
3427
2343
0

text missing or illegible when filed

281

4283

3

149
113
105
34
0
0
0
21
834

text missing or illegible when filed

81

0
83
204
1747
18
382

text missing or illegible when filed

0
2902

text missing or illegible when filed

49

0
78
290
5454
1233
275
218
0
1413

HELA- text missing or illegible when filed

-031

79

213
587
121
3227
805
81
190
0
8484

HELA- text missing or illegible when filed

-031

81

72
174
0
3329
0
0

text missing or illegible when filed

0
5479

HELA- text missing or illegible when filed

-031

83

0
253
215
2 text missing or illegible when filed

204
0
315
0

text missing or illegible when filed

HELA-

-031

84

83
0
257
2475
0
0
296
0

text missing or illegible when filed

47

HELA- text missing or illegible when filed

-031

140
340
0
9084
37 text missing or illegible when filed

0
247
0
4351

HELA- text missing or illegible when filed

-031

342
203
0
6775
0
94
0
183
7038

HELA- text missing or illegible when filed

-031

82

33
813
616
8034
0
184
0
0
7091

HELA- text missing or illegible when filed

-031

134
143
234
4109
0
0
0
0
3438

HELA- text missing or illegible when filed

-031

43
0
384
1916
0
103
47
0
3000

H text missing or illegible when filed

146

0
18
8702
747
1508
1734
34
0
1485

H text missing or illegible when filed

148

0
74
9 text missing or illegible when filed

1557
241
11
0
34
2372

SA text missing or illegible when filed

19

150

0
74
9783
1557
241
71
0
34
2372

text missing or illegible when filed

152

0
138

text missing or illegible when filed

30
4181
818
0
0
3485

text missing or illegible when filed

154

91
109
34338

text missing or illegible when filed

300
1174

text missing or illegible when filed

194
8211

SF text missing or illegible when filed

154

242
0
3482
0

text missing or illegible when filed

37
102
0
1189

SF- text missing or illegible when filed

154

52
0
1743
201
0
87
3
27
937

CCRF-CEM

150

0
0

text missing or illegible when filed

83
443
3
247
0
121
1419

DY- text missing or illegible when filed

152

0
1041
173
6033
184
302
87

text missing or illegible when filed

HCT 116

184

0
20
1437
817
372
0
0
1437
791

text missing or illegible when filed

279
236

text missing or illegible when filed

781
1322
0
782
0
0

text missing or illegible when filed

4542
3083
4163
138
0
3600

T470

text missing or illegible when filed

0
236
13838
3870

text missing or illegible when filed

2368
454
0
1 text missing or illegible when filed

171

43
0
0
1622

text missing or illegible when filed

0
61
0
2573

text missing or illegible when filed

1441

181

0
264
0
0
1781
0
1
128
543

text missing or illegible when filed

183

28
0
0
321
111
0
0
0
384

text missing or illegible when filed

184

114
0
141
2325
0
0
136
0
3700

text missing or illegible when filed

194

218
0
1383
3226
0
0
101
130
3434

text missing or illegible when filed

198

0
172
10072
1171

text missing or illegible when filed

147
130
83
1431

text missing or illegible when filed

200

0
3877
0
2173
364
0
183
4827

text missing or illegible when filed

202

100
0

text missing or illegible when filed

402
215
140
0
0
3477

text missing or illegible when filed

204

112
0
0
300
0
79
252
134
438

text missing or illegible when filed

0
300
813
237
216
0
0
0
1376

text missing or illegible when filed

1140
0
2134
2643
526
800
0
197
8071

text missing or illegible when filed

216

0
0
382
1884
0
25
143
8
3126

text missing or illegible when filed

219

0
0
901
3083
414
626
184
0
3255

C text missing or illegible when filed

1441-

220

0
154
0
177
0
0
8
71
1173

text missing or illegible when filed

-1

221

18

text missing or illegible when filed

0
2117
0
0

text missing or illegible when filed

1
84
2344

text missing or illegible when filed

-2

223

text missing or illegible when filed

0
45
1182
104
0
133
0
2280

text missing or illegible when filed

-4

225

0
230
0
622
0
0
34
0
1273

text missing or illegible when filed

241

0
0
1700
1800
183
136
216
0
2325

HCL T-4

242

text missing or illegible when filed

143

63
1036
3006
183
160
10
1276

text missing or illegible when filed

243

0
0
32076
1884

text missing or illegible when filed

311
300
0

text missing or illegible when filed

244

0
228
14080
2061
0
64
215
0
4264

text missing or illegible when filed

245

0
1087
77132
1403
0
700
225
1
3648

text missing or illegible when filed

1226

246

0
0
0
011
838
57
0
7
34

text missing or illegible when filed

TCC

247

0
0
4447
255
0
168
98
0
2344

SR

248

0
183
18413
954
1882
638
17
0
2103

DVC- text missing or illegible when filed

249

0
144
8806
1324
168
0
80
218
4234

HCT-15

250

129
0
45225
1488
201
500
0
95
8063

text missing or illegible when filed

-4

251

171
0
2381
54
0
180
0
187
98323

UC-31

252

208
0
307
460
0
38
0
131
1431

DVC-AR-6

253

0
10
577
3408
0
1477
0
0
4318

text missing or illegible when filed

254

486
0
6634
173
0
0
322
1821
4185

DVC-AR- text missing or illegible when filed

255

181
94
17088
486
0
54
128
0
1781

text missing or illegible when filed

256

0
2036
82875
1863
1303
1383
0
134
5348

text missing or illegible when filed

257

140
0
32874
1309
176
178
0
326
4434

text missing or illegible when filed

-2

258

0
187
4482
224
0
0
48
547
1206

SLOV-3

259

0
13
4761
313
681
681
0
71
1009

SX-VCL-4

260

0
101
3676
172
38
29
0
41
1811

text missing or illegible when filed

261

0
73832
1603
821
927
456
174
4154

text missing or illegible when filed

262

187
0
14342
144
0
0
34
0
1278

X-342

263

0
118
36631
926
1876
432
74
63
2880

LACC-257

264

0
83
8654
1800
175
81
108
6
1257

M14

265

0
21
1254
873
3737
0
121
0
2308

MCF7

267

128
258
23780
6300
1000
0
215
0
14382

MDA- text missing or illegible when filed

-425

268

0
0
8781
383
0
147
250
136
4085

MT276

270

30
36
0
1064
0
67
170
25
3872

MDA-N

271

0
0
14736
415
0
441
336
0
4136

text missing or illegible when filed

273

11
341
8084
4474
0
1320
0
345
12179

text missing or illegible when filed

280

25
360
15640
6370
1854
2113
1061
0
11610

WT838 text missing or illegible when filed

TPA

823

300

71
0
0
8304
0
0
40
483
786

HELA-EXP- text missing or illegible when filed

313

37
42
0
4774
0
0
185
97
3084

text missing or illegible when filed

322

344
0
616
6852
16719
0
800
0
4427

HT347

323

text missing or illegible when filed

0
50
4108
170
377
142
83
8447

text missing or illegible when filed

324

942
94
0
8137
8287
481
385
170
1663

MCL-H text missing or illegible when filed

336

31
11483
1317
1815
8
171
0
0

HOP-42

337

0
0
10827
3205
0
226
138
0
3071

MOA-MB-231

338

text missing or illegible when filed

1127
138008
18086
38722
8586
1087
45
13418

U251

339

text missing or illegible when filed

1786
720047
9036
80293
30873
1374
0
19432

PT text missing or illegible when filed

340

0
112
8025
778
0
446
136
37
2086

PC-3

341

673
215
29876
7064
78117
1417
1087
0
9562

HCC-2000

343

0
3
7508
1213
708
179
829
0
3085

text missing or illegible when filed

345

80
6
32834
1180
5491
27
343
0
5447

HT182

346

48
0
1998
1007
0
13
381
0
3808

COLO 20 text missing or illegible when filed

347

17
96
3856
946
834
0
481
0
940

HT316

348

1
0
512
6443
0
72
0
0
2341

MO4-12

349

0
81
9886
3008
913
0
188
0
1130

HT151

350

32
302
252
7132
0
782
306
22
4497

A438

351

137
11
8123
3278
2335
0
308
0
2252

HT383

352

235
131
0
14919
186
0
183
0
1887

PGG text missing or illegible when filed

353

350
0
8021
2130
3003
112
219
0
1887

T text missing or illegible when filed

355

2370
1831
58083
4438
38183
4039
184
173
6282

text missing or illegible when filed

357

1422
1373
942135
14400
51277
9086
947
84
6236

MS 8787

358

184
48
21180
1286
1187
1033
180
12
628

HT313

50

0
0
707
2163
0
600
338
0
14318

HT344

52

144
0
947
3338
0
98
160
0
18288

HT130

53

174
0
0
3229
0
84
307
27
9584

HT156

54

0
0
13
2383
0
0
80
0
18006

HT163

58

376
0
118
1859
0
412
181
117
9434

HT170

60

713
0
2417
9484
1368
0
710
0
13123

HT172

62

111
0
95
2328
0
0
29
0

text missing or illegible when filed

HT178

63

384
34
83
3079
0
0
0
0
8428

HT179

64

0
78
147
3414
0
821
40
0
6827

HT184

65

text missing or illegible when filed

0
374
2820
0
0
907
0
12319

HT180

66

43
122
4371
3000
0
0
0
48
3831

HT188

67

0
118
0
1861
0
0
340
182
2359

HT190

68

43
638
2823
3580
0
984
83
78
8023

HT143

69

327
0
0
2961
0
0
182
0
432

HT1 text missing or illegible when filed

0

70

382
71
1386
8686
0
209
388
0
1551

HT144

71

84
88
2044
4734
0
0
230
0
428

HT227

72

12
0
215
3473
0
1015
484
0
2054

HT302

73

143
0
2818
7388
1860
4134
721
174
25415

HT314

74

230
0
674
6547
0
838
340
0
15481

HT317

76

285
0
348
7398
705
978
585
235
15104

text missing or illegible when filed

77

0
0
0

text missing or illegible when filed

2
0
52
0
87

HT323

79

0
0

text missing or illegible when filed

0
9443

HT327

80

0
83
230

text missing or illegible when filed

1133
0

text missing or illegible when filed

HT336

82

0
0
0

text missing or illegible when filed

0
0

text missing or illegible when filed

HT1

83

4 text missing or illegible when filed

5
93
0
0

text missing or illegible when filed

0
132
1344

HT3 text missing or illegible when filed

0
1429
0
1017
0
0
3434

HT311

170

23 text missing or illegible when filed

0
0
317 text missing or illegible when filed

0
130

text missing or illegible when filed

117

185

73
0
0
11 text missing or illegible when filed

1414
0

text missing or illegible when filed

HT1

187

230
117
0
0
0
0
1 text missing or illegible when filed

144

HT text missing or illegible when filed

189

303
0
0
1304

text missing or illegible when filed

0
3 text missing or illegible when filed

1
0
4 text missing or illegible when filed

HT372

191

43
220
0
2713
0
2 text missing or illegible when filed

144
43 text missing or illegible when filed

TCOP

207

text missing or illegible when filed

4
17
0
14 text missing or illegible when filed

0
0
0
10
0
3112

HT1 text missing or illegible when filed

0

215

0
0

text missing or illegible when filed

0
13 text missing or illegible when filed

304
0
40
0
1331

HT text missing or illegible when filed

07

217

0

text missing or illegible when filed

0
0
3222
0
44
14 text missing or illegible when filed

0
41 text missing or illegible when filed

HT3

4

224

343
0
0

text missing or illegible when filed

13719
127
327
11 text missing or illegible when filed

4916

HT370

225

114
0
0
1343
0
0
0
0

text missing or illegible when filed

HT371

228

170

text missing or illegible when filed

71
0
0
12 text missing or illegible when filed

22

HT377

230

30
181
122

text missing or illegible when filed

7
135

text missing or illegible when filed

3
0

text missing or illegible when filed

234

1 text missing or illegible when filed

1
0
4305
142
820

text missing or illegible when filed

132

1

0
0
103

text missing or illegible when filed

0
30
41
0
283

HT334

text missing or illegible when filed

0
127
0
8791
1302

text missing or illegible when filed

123
0

text missing or illegible when filed

HT334

301

text missing or illegible when filed

52
0
2712
0
185
341
279

text missing or illegible when filed

315

1 text missing or illegible when filed

4
0
22 text missing or illegible when filed

322

107
31
308
3177

HT text missing or illegible when filed

317

83
2474
0

text missing or illegible when filed

0
77 text missing or illegible when filed

HT312

318

309

text missing or illegible when filed

0
17

text missing or illegible when filed

180

743

HT182

325

415
0
22 text missing or illegible when filed

2191
0
0
0
0
20

HT text missing or illegible when filed

354

100
0
3119
0
0
0
0
2471

HT1 text missing or illegible when filed

7

3 text missing or illegible when filed

0

4 text missing or illegible when filed

0
0
4418

text missing or illegible when filed

0
145

T-470
143

437
128
35100

text missing or illegible when filed

174

70
3414
112
0

text missing or illegible when filed

485
135

text missing or illegible when filed

0419

015
157 text missing or illegible when filed

1441
123
114
4 text missing or illegible when filed

1

MO text missing or illegible when filed

-435
154

79
0
142 text missing or illegible when filed

4
404 text missing or illegible when filed

2831
197
0

text missing or illegible when filed

-231
157

text missing or illegible when filed

15
282

text missing or illegible when filed

7911
328
441
4471

text missing or illegible when filed

153

235
125
122345
4402
291883
3072
334
43
9383

MCF- text missing or illegible when filed

152

464
0
82988
3783
172347
408
234
71
4902

MCF7
151

0
90
23491
3643
218251
402
407
54
6604

M14
149

34
0

text missing or illegible when filed

5725
99836
734
734
78

text missing or illegible when filed

UACC-2

148

0
130

text missing or illegible when filed

4088
49506
1177
1177
77
3942

UACC- text missing or illegible when filed

147

9
33

text missing or illegible when filed

8515
47918
123
1123
0

text missing or illegible when filed

146

0
133

text missing or illegible when filed

6315
14330
128
127
24

text missing or illegible when filed

VO-31
145

304
100
36141
6315
73374
120
120
27
4746

text missing or illegible when filed

144

105
0
20849
9249
73371
1853
1055
11
2380

text missing or illegible when filed

143

416
0
28587
2364
80993
198
190
182
2792

text missing or illegible when filed

142

171
0
3464
2306
130029
27
27
132
7404

HCT-13
141

0
47
22819
3813
194839
100
100
163
3750

text missing or illegible when filed

140

140
130
12009
5785
137883
877
877
0
8273

COLO text missing or illegible when filed

139

0
213
23499
5643
114681
942
942
74
4536

Lax text missing or illegible when filed

138

158
1464
21811
3350
112345
1470
1476
0
7443

text missing or illegible when filed

137

188
0
90087
3417
164917
796
796
210
9336

TK- text missing or illegible when filed

136

0
137
11994
4148
19124
1900
1183
0

text missing or illegible when filed

HCT 11

135

1080
90

text missing or illegible when filed

2016
118724
162
182
283

text missing or illegible when filed

134

225
0
7185
3038
103477
1314
3314
42
2382

HCC- text missing or illegible when filed

132

0
180
28315
4509
127191
485
495
0
1400

ACM
131

0
130
17047
4256
97808
473
473
144
1600

PC-3
130

100
104
28733
2713
90476
1017
1017
0
3677

text missing or illegible when filed

129

134
204
8373
2502
98863
377
377
85
1233

DU-145
128

0
70
34000
2431
17433
256
1258
0
10013

C text missing or illegible when filed

127

0
141
8334
2645
64342
3136
3136
0
4275

SR
126

0
79
60187
2501
34429
1649
1619
47

text missing or illegible when filed

125

0
153
8483
2800
31346
19
15
9
10134

RPM text missing or illegible when filed

124

34
0
28456
2614
12834
102
102
163
24438

SN12C
123

0
0
80
7382
38811
142
142306
43
3934

text missing or illegible when filed

122

813
100
34753
8301
489
365
1346
173
9433

MOLT-4
121

0
0
825
5372
83742
1349
4613
0
8579

OVCAR-5
120

425
0
908
4872
41219
4613
2277
171
3791

X- text missing or illegible when filed

119

254
0
820
4997
198477
2277
8057
70
6240

OVCAR-4
118

854
246
10918
2514
133148
4057
9077
9
3661

CCAF-CON
117

0
0
21540
3482
113796
9077
1905
9
6605

OVCAR-3
116

464
37
14296
2885
98833
1921
2383
0
5443

text missing or illegible when filed

115

217
0
13067
1330
95279
2383
2098
0
13804

MOP-42
114

404
153
14168
3873
72198
2088
3313
0
8445

SF-285
113

201
0
34834
4034
89199
3313
3808
6
4124

text missing or illegible when filed

TCC
112

1006
321
21130
2917
128199
3808
990
0
7211

SF-295
111

0
0
44884
7405
134794
990
3557
416
4202

NCA- text missing or illegible when filed

110

264
213
23877
1108
81138
3557
1164
113
6291

SNS-75
109

232
0
33099
2890
1448017
1164
3814
253
1418

MC text missing or illegible when filed

108

178
216
24583
1042
40575
3414
1006
5
4176

SNB-19
107

0
335
27031
4126
69012
1006
1194
0
10000

MCA-224
106

212
0
8081
2982
72818
1194
1803
0
5661

SK-OV-3
105

138
14
23147
5630
17279
1103
4093
87
9011

NCH-33
104

211
119
8406
2381
11321
4083
1944
298
12724

text missing or illegible when filed

103

0
0
2151
2994
18030
9544
1016
171
8783

BCVX
102

319
432
8434
2107
2371
1016
1772
54
9100

OVCAR-4
101

0
242
61716
4544
18131
1772
613
2151
12000

MOP-42
100

62
122
6156
8395
5728
913
7072
0
4886

text missing or illegible when filed

48

109
23
26183
7181
2989
3072
19079
0
4283

text missing or illegible when filed

47

0
234
3123
8754
380
19079
4488
9
4773

text missing or illegible when filed

46

315
280
19007
7246
120641
4968
634
9
6700

TCOP
76

0
0
22446
1182
122383
634
119
294
14122

ASeq-1

wt
0
0
1880
6235
188916
116
341
8
110

ASeq-3

wt
0
16
13008
83185
81496
341
3042
9
966

ASeq-4

wt
0
48
11008
48136
0
3072
0
40
734

ASeq-5

wt
0
22
2553
48247
0
0
1843
276
1182

ASeq-7

wt
0
82
0
72997
0
1843
2142
243
9377

EXVX-1

text missing or illegible when filed

0
308
118
38990
0
2142
889
9
300

EXVX-4

text missing or illegible when filed

0
66
2509
99934
0
800
4794
9
1000

EXVX-3

text missing or illegible when filed

0
291
831
190881
0
4794
18041
122
824

EXVX-6

text missing or illegible when filed

0
225
2409
17798
0
46061
6764
129
3203

EXVX-7

text missing or illegible when filed

0
360
714
37831
0
6781
898
0
4100

MCF-7-1

wt
0
16
49
74388
0
808
703
157
1196

MCF-7-3

wt
0
1153
1208
41681
0
703
232
0
574

MCF-7-4

wt
0
530
80
37949
0
332
0
0
891

MCF-7-6

wt
0
234
0
32082
0
0
649
124
990

MCF-7-7

wt
0
182
0
25875
0
948
0
91
997

ADR_RES-1

text missing or illegible when filed

0
0
1621
27895
0
199
2747
429
1776

ADR_RES-3

text missing or illegible when filed

0
264
0
88425
0
0
880
0
1127

ADR_RES-4

text missing or illegible when filed

0
144
20
46817
0
2747
1142
912
1423

ADR_RES-5

text missing or illegible when filed

0
811
1810
30547
0
990
1779
175
742

ADR_RES-7

text missing or illegible when filed

0
449
2457
27945
0
1142
1095
9
924

WI 39-1

wt
0
0
218
87821
0
1779
11090
24
3042

WI 39-3

wt
0
473
0
49671
0
1095
10250
0
1300

WI 39-4

wt
0
453
4304
44081
0
19098
8330
110
1232

WI 39-5

wt
0
382
3384
48543
0
10250
1404
0
1057

WI 39-7

wt
0
0
1018
22973
0
8330
10729
0
1000

H text missing or illegible when filed

-1

0
14
1422
38078
0
1404
857
0
1118

H text missing or illegible when filed

-3

0
27
1554
40780
0
10729
764
189
847

H text missing or illegible when filed

-4

0
247
385
41446
0
857
803
140
173

H text missing or illegible when filed

-5

0
143
0
73772
0
764
1303
0
673

H text missing or illegible when filed

-7

0
80
1254
40004
0
803
800
0
1152

H1 2 text missing or illegible when filed

-1

0
148
3030
72779
0
1303
1805
0
949

H1 2 text missing or illegible when filed

-3

0
0
864
26134
0
989
4889
181
441

H1 2 text missing or illegible when filed

-4

0
687
149
36830
0
1906
14941
0
1922

H1 2 text missing or illegible when filed

-5

0
1745
230
13450
0
4889
6836
0
1628

H1 2 text missing or illegible when filed

-7

0
3504
1070
23000
0
14941
1127
64
577

A text missing or illegible when filed

-2

wt
0
0
1823
34870
0
68341
1186
0
911

BXVX-2

text missing or illegible when filed

0
613
80
13387
0
1127
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HCAEC

211
211

0

text missing or illegible when filed

210

0

MMEC

209

0

text missing or illegible when filed

201

0

text missing or illegible when filed

190

0

text missing or illegible when filed

49

0

MELA text missing or illegible when filed

79

0

MELA text missing or illegible when filed

MELA

87

MELA text missing or illegible when filed

MELA

120

140

150

152

154

0

SF text missing or illegible when filed

137

SF text missing or illegible when filed

0

CC text missing or illegible when filed

185

OU-145

1 text missing or illegible when filed

2

0

MCT text missing or illegible when filed

4

0

text missing or illegible when filed

4

766-4

text missing or illegible when filed

0

T-47D

text missing or illegible when filed

177

CPI 1441

181

0

79T text missing or illegible when filed

183

100

text missing or illegible when filed

A*

184

47

text missing or illegible when filed

poly A*

114

0

AC text missing or illegible when filed

114

62

text missing or illegible when filed

CC-42

200

0

MCF-7 text missing or illegible when filed

222

UTC (

)

234

0

text missing or illegible when filed

poly

34

444 text missing or illegible when filed

200

230

CCI, T37 RMA 37 text missing or illegible when filed

218

0

text missing or illegible when filed

200 10% FBS

218

4

text missing or illegible when filed

239

242

text missing or illegible when filed

-1

221

text missing or illegible when filed

-2

223

79

text missing or illegible when filed

-4

224

0

text missing or illegible when filed

241

0

text missing or illegible when filed

T-4

242

0

text missing or illegible when filed

243

0

text missing or illegible when filed

244

0

text missing or illegible when filed

245

0

text missing or illegible when filed

246

TCC

247

241

SR

248

0

OVCAR-3

249

85

HCT-15

250

0

OVCAR-4

251

0

UO-31

252

0

OVCAR-4

253

248

text missing or illegible when filed

12C

254

0

OVCAR-5

255

0

LCD text missing or illegible when filed

256

0

text missing or illegible when filed

257

0

text missing or illegible when filed

-2

258

153

text missing or illegible when filed

-3

259

0

text missing or illegible when filed

-4

260

0

SF- text missing or illegible when filed

261

0

text missing or illegible when filed

262

0

text missing or illegible when filed

263

22

UACC-257

264

33

text missing or illegible when filed

14

265

0

MCF7

267

43

MCA-A text missing or illegible when filed

-435

100

T270

270

0

MCA-4

271

0

Y79 poly A*

273

0

IO text missing or illegible when filed

poly A*

34

HT836 text missing or illegible when filed

TPA

300

147

text missing or illegible when filed

313

83

text missing or illegible when filed

322

0

44T347

333

0

text missing or illegible when filed

334

127

text missing or illegible when filed

234

0

text missing or illegible when filed

337

0

text missing or illegible when filed

61

U29

330

8

PT text missing or illegible when filed

A*

300

0

PC-3

341

0

MCC-7000

343

0

SW-420

345

0

text missing or illegible when filed

TT82

346

148

CCLO 293

347

0

HT294

348

0

text missing or illegible when filed

-12

34349

0

XT151

350

20

AA95

351

0

HT text missing or illegible when filed

352

140

text missing or illegible when filed

353

0

TK-19

355

363

text missing or illegible when filed

357

241

text missing or illegible when filed

578T

350

0

HT13

50

312

HT text missing or illegible when filed

52

0

HT130

54

0

HT166

56

0

HT183

58

165

HT170

60

61

HT172

62

133

HT130

63

0

HT176

64

32

HT154

65

19

HT183

66

40

HT100

67

140

HT100

68

0

HT143

69

0

HT180

70

text missing or illegible when filed

71

130

HT227

72

111

HT322

73

0

HT314

74

0

HT317

76

0

text missing or illegible when filed

77

0

HT323

78

21

HT327

80

137

HT335

82

0

HT144

85

text missing or illegible when filed

HT346

87

29

HT311

170

18

HT text missing or illegible when filed

185

0

HT140

187

0

HT201

190

236

HT372

191

75

TCCP

207

40

HT text missing or illegible when filed

214

44

HT307

217

82

HT text missing or illegible when filed

224

258

HT370

226

0

HT371

228

114

HT377

230

125

HT382

text missing or illegible when filed

112

445

HT334

290

231

HT328

301

0

HT302

315

text missing or illegible when filed

3

HT304

317

0

HT312

318

0

HT162

325

0

HT304

354

45

HT187

300

13

T-47D
103

83

text missing or illegible when filed

101

0

text missing or illegible when filed

-423
154

0

text missing or illegible when filed

157

151

144

143

0

text missing or illegible when filed

142

141

4

text missing or illegible when filed

140

139

138

137

134

0

text missing or illegible when filed

133

0

text missing or illegible when filed

132

131

130

PC-3
129

0

text missing or illegible when filed

128

127

126

125

0

text missing or illegible when filed

124

137

text missing or illegible when filed

123

0

text missing or illegible when filed

122

138

text missing or illegible when filed

121

0

text missing or illegible when filed

120

118

OVCAR-4
119

0

text missing or illegible when filed

118

34

OVCAR-4
117

text missing or illegible when filed

116

OVCAR-3
115

text missing or illegible when filed

114

47

text missing or illegible when filed

113

0

text missing or illegible when filed

112

141

text missing or illegible when filed

111

110

text missing or illegible when filed

110

109

0

text missing or illegible when filed

108

107

0

text missing or illegible when filed

106

20

text missing or illegible when filed

105

430

text missing or illegible when filed

104

78

text missing or illegible when filed

103

92

text missing or illegible when filed

102

0

text missing or illegible when filed

101

777

text missing or illegible when filed

100

0

text missing or illegible when filed

99

54

OVCAR-4
98

0

text missing or illegible when filed

97

43

text missing or illegible when filed

48

148

text missing or illegible when filed

47

210

text missing or illegible when filed

-1

-3

379

-4

-5

-7

73

EXVX-1

text missing or illegible when filed

94

EXVX-4

text missing or illegible when filed

EXVX-5

0

EXVX-6

text missing or illegible when filed

EXVX-7

677

MCF-7-1

text missing or illegible when filed

0

MCF-7-3

text missing or illegible when filed

MCF-7-4

318

MCF-7-6

text missing or illegible when filed

0

MCF-7-7

text missing or illegible when filed

-1

-3

198

-4

-6

-7

WI 34-1

0

WI 34-3

text missing or illegible when filed

283

WI 34-4

text missing or illegible when filed

WI 34-6

WI 34-7

-1

-3

-4

-5

-7

105

-1

-3

-4

-5

-7

-2

-1

-2

-1

-2

-1

204

-2

831

OVCAR-4-1

text missing or illegible when filed

0

OVCAR-4-2

text missing or illegible when filed

0

OVCAR-4-1

text missing or illegible when filed

123

OVCAR-4-2

text missing or illegible when filed

234

-2

271

-2

173

-1

-2

-1

-2

-1

271

-2

-1

-2

-1

0

text missing or illegible when filed

-2

0

text missing or illegible when filed

-4

2301

text missing or illegible when filed

-9

-11

2522

text missing or illegible when filed

-12

-10

300

text missing or illegible when filed

-1

474

text missing or illegible when filed

-2

0

text missing or illegible when filed

-3

222

text missing or illegible when filed

-4

0

text missing or illegible when filed

-5

0

text missing or illegible when filed

-6

0

text missing or illegible when filed

-8

wt
0

EXVX-8 text missing or illegible when filed

50

HCT-1 16-1

wt
0

HCT-1 14-6

wt
0

WT29-1

text missing or illegible when filed

310

WT29-7

text missing or illegible when filed

WT29-8

0

SF434-7

wt
155

SF434-8

wt
228

SF200-7

text missing or illegible when filed

218

SF300-8

text missing or illegible when filed

OVCAR-4-7

wt
493

OVCAR-4-8

wt
0

OVCAR-5-7

text missing or illegible when filed

531

OVCAR-5-8

text missing or illegible when filed

-7-

wt
33

text missing or illegible when filed

-8

837

-8

HPV E8
0

SW420-7

text missing or illegible when filed

0

SW430-8

text missing or illegible when filed

0

Wt200-5

text missing or illegible when filed

0

C33A-7

text missing or illegible when filed

0

C33A-8

text missing or illegible when filed

0

U2OA-7

text missing or illegible when filed

720

U2OA-8

text missing or illegible when filed

-7

wt
0

text missing or illegible when filed

-8

wt
0

WI30-8

wt
0

text missing or illegible when filed

, 1572,

4

64

221

WT268

80

WT376

183

WT395

88

WT320

0

text missing or illegible when filed

-3

173

487

text missing or illegible when filed

-6

176

117

text missing or illegible when filed

-9

177

481

text missing or illegible when filed

233

0

text missing or illegible when filed

Mar. 31, 2002 text missing or illegible when filed

0

HCT-114-3

wt

text missing or illegible when filed

HCT-114-4

wt
0

HCT-114-5

wt
0

HCT-114-6

wt
0

text missing or illegible when filed

-6

wt
0

WT28-3

text missing or illegible when filed

874

EXVX-6

text missing or illegible when filed

129

WT29-4

text missing or illegible when filed

640

WT29-5

text missing or illegible when filed

0

WT29-6

text missing or illegible when filed

177

OVCAR-4-3

wt
220

OVCAR-4-4

wt
0

OVCAR-4-5

wt

text missing or illegible when filed

OVCAR-4-6

wt
0

SF text missing or illegible when filed

-3

wt
728

SF text missing or illegible when filed

-4

wt
83

SF text missing or illegible when filed

-5

wt
0

SF text missing or illegible when filed

-6

wt
0

OVCAR-5-3

text missing or illegible when filed

2718

OVCAR-5-4

text missing or illegible when filed

296

OVCAR-5-5

text missing or illegible when filed

0

OVCAR-5-6

text missing or illegible when filed

0

MCF-7-6

wt
270

text missing or illegible when filed

HPV E5
371

text missing or illegible when filed

0

SW400-3

text missing or illegible when filed

61

SW400-4

text missing or illegible when filed

0

SW400-5

text missing or illegible when filed

293

SW400-6

text missing or illegible when filed

225

C33A-3

text missing or illegible when filed

173

C33A-4

text missing or illegible when filed

C33A-5

0

C33A-6

text missing or illegible when filed

-6

wt
0 text missing or illegible when filed

U2O3-3

630

U2O3-4

text missing or illegible when filed

U2O3-5

544

U2O3-6

text missing or illegible when filed

0

Wt 30- text missing or illegible when filed

wt
0

text missing or illegible when filed

-3

wt

text missing or illegible when filed

-4

wt

text missing or illegible when filed

SF-200-3

277

SF-200-4

text missing or illegible when filed

0

SF-200-5

text missing or illegible when filed

123

SF-200-6

text missing or illegible when filed

-13

21

text missing or illegible when filed

-20

-21

0

text missing or illegible when filed

-22

0

OVCAR-5-6

text missing or illegible when filed

-10

-11

-12

-13

320

text missing or illegible when filed

-14

150

text missing or illegible when filed

-15

332

text missing or illegible when filed

-16

0

text missing or illegible when filed

-17

123

text missing or illegible when filed

-18

0

text missing or illegible when filed

-19

172

TABLE 4

Gene Name
SP
ID# na
ID# aa
Family
Group
Length_AA
Extra-Catalytic Domains (Amino acid positions)

X69117_h beta_adrene
H
1
122
AGC
GRK
688
Regulator of G protein signating domain 54-175;

PH domain 559-652

AA144574_m
M
2
123
AGC
GRK
378
PH domain 249-337

AA210825_h
H
9
130
AGC
PKC
978
Phorbol esters/diacylglycerol binding domain

(C1 domain) 238-287; PH domain 497-577

AA316804_h
H
11
132
AGC
PKC
890
Phorbol esters/diacylglycerol binding domain

(C1 domain) 155-204 and 272-321; PH domain 417-532

AA887763_h
H
21
142
AGC
SGK
446
PX domain 13-120

AA021445_h 3
H
32
152
CAMK
EMK
1311
Vitamin K-dependent carboxylation/gamma-carboxyglutamic

(GLA) domain 1072-1113

R31237_1_h, AAC3348
H
34
154
CAMK
EMK
729
UBA domain 327-365

408786.5_h
H
36
156
CAMK
EMK
1330
PAS domain 133-186, 247-280, 354-386

Z36720_h
H
41
161
CAMK
MLCK
874
WD domain, G-beta repeat 674-711

SGK088_h
H
42
162
CAMK
Trio
2287
Immunoglobulin domain 1-62, 97-153, 221-277,

518-578, 1617-1678; Fibronectin type III domain 301-390,

1697-1779

R19772_h
H
44
164
CAMK
Trio
1287
RhoGEF domain 235-405; Fibronectin type III domain

870-955; Immunoglobulin domain 786-851; PH

domain 419-528

17000139801197_h, IRA
H
76
195
Other
IRAK
596
Death domain 26-106

AA088547_h
H
78
197
Other
IRE
922
PQQ enzyme repeat 39-76

AA232253_h
H
82
201
Other
MLK
800
SAM domain (Sterlie alpha motif) 337-408

AA599286_h
H
89
208
Other
SLOB
649
PX domain 16-122

AA838348_h
H
113
232
STE
NEK
836
Regulator of chromosome condensation (RCC1) 387-427,

427-480, 483-532, 598-650

PAK6_h
H
115
234
STE
STE20-02
719
P21-Rho-binding domain 11-69

	Number	Date	Country
Parent	09979167	Jul 2002	US
Child	11377316	Mar 2006	US

Protein kinases

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Provisional Applications (1)

Divisions (1)