Decoding the E-cadherin mediated mechano-chemical signalling during cell-cell adhesion

The formation of cell-cell adhesions is crucial for the formation and maintenance of tissues in higher organisms, such as the epithelium. Key molecules in initiating and establishing connections between cells are cadherins that form so-called adherens junctions. The extracellular domain of cadherins of adjacent cells can bind to each other, followed by the accumulation of further cadherins and recruitment of adapter proteins at the intracellular site such as alpha- and beta- catenin linking these adhesion sites to the actin cytoskeleton of the cell. This process is mechano-sensitive, meaning that the strength of binding between cadherins and the mechanical forces that act on the adhesion molecules determines how strong cells stick to each other and whether the correct signalling cascades are activated to sustain and reinforce cell-cell adhesion. Recent works have highlighted the importance of this mechano-chemical signalling controlling actin network polymerisation and contractility in understanding how tissues form and how alterations during cancer formation led to the weakening of cell adhesion and migration of cancer cells, known as metastasis.
Despite recent advances, we have yet limited understanding about key mechanisms of this cadherin-mediated mechano-chemical signalling and how it is controlled in space and time. Focusing on E-cadherin, which is the prominent adhesion molecule in epithelial cells, we could show that cells show different patterns of actin cortex activation and organisation depending on how easy it is to drag the E-cadherins on the opposite site along the membrane. For this, we established a novel assay allowing to visualise the interface between a cell and a cell-mimicking substrate at high spatio-temporal resolution using total internal reflection fluorescence and confocal microscopy. Building on this work, the proposed PhD project will employ a combination of molecular cell biology tools, quantitative fluorescence microscopy techniques, and biophysics to investigate the molecular mechanisms leading to the activation of different actin network regulation pathways (linked to the GTPases RhoA and Roc1).