Research Project
10113715
Project Summary E-cadherin is the primary mediator of strong cell-cell adhesion between epithelial cells and plays an essential role in the morphogenesis and maintenance of epithelial tissues. E-cadherin adhesion is modulated by multiple biochemical and biophysical cues. The long term goal of the project is to understand how the mechanical regulation of E-cadherin adhesion leads to a cohesive yet dynamic multi-cellular architecture in epithelial tissues. The goal of the proposed project is to uncover how the epithelial cell- specific viscoelastic microenvironment of E-cadherin modulates its adhesion and how E-cadherin- dependent Rho GTPase activity and tension in turn modulate this viscoelasticity. Firstly, E-cadherin is known to be a mechanosensor and resides in a microenvironment formed by the adjoining epithelial cells. However, how epithelial cell-like viscoelastic properties modulate E-cadherin adhesion is not known. Secondly, it is not clear how E-cadherin dependent biochemical signals in turn modulate its microenvironmental viscoelasticity. In particular, the effect of Rho and Rac, known modulators of the actin cytoskeleton, on E-cadherin microenvironment viscoelastic properties is unclear. This effect is essential to understand in order to delineate the role of these Rho GTPases in mediating cell-cell contact formation. Thirdly, E-cadherin adhesions transmit cell-generated as well as external forces imposed on epithelial tissues. How the level of this tension transmitted across cells determines the viscoelastic properties close to cell-cell junctions is unknown. Knowledge of cell viscoelastic properties near cell-cell junctions is important not only to understand E-cadherin mechanobiology, but more generally to also understand cell deformation in response to forces transmitted at cell-cell adhesions. We will use an array of tools including E-cadherin biomimetic substrates with tunable viscoelastic properties similar to epithelial cells, flow assays with such E- cadherin soft substrates, magnetic pulling cytometry and high resolution traction force microscopy in the presence and absence of external stretch, to answer these questions at the sub-cellular, cellular and supra- cellular levels. Results of the proposed project will be crucial in understanding the context-dependent biophysical control of E-cadherin adhesion. Knowledge gained from the project will be essential to better understand the functional basis of the role of E-cadherin in mediating epithelial tissue integrity, mechanical coherence and its dysregulation in disease states like cancer.
