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.