Epidermal growth factor receptor and integrins control force-dependent vinculin recruitment to E-cadherin junctions

This study reports novel findings that link E-Cadherin-mediated force-transduction signaling to vinculin targeting to intercellular junctions via epidermal growth factor receptor (EGFR) and integrins. These results build on previous findings, which demonstrated that mechanically perturbed E-Cadherin receptors activate phosphoinositide-3-kinase and downstream integrins, in an EGFR-dependent manner. Results of this study show that this EGFR-mediated kinase cascade controls the force-dependent recruitment of vinculin to stressed E-Cadherin complexes--a key early signature of cadherin-based mechanotransduction. Vinculin targeting requires phosphorylation at tyrosine 822 by Abelson family kinase (Abl), but the origin of force-dependent Abl activation had not been identified. We now present evidence that integrin activation, which is downstream from EGFR signaling controls Abl activation, thus linking E-Cadherin to Abl through a mechanosensitive signaling network. These findings place EGFR and integrins at the center of a positive feedback loop, through which force-activated E-Cadherin signals regulate vinculin recruitment to cadherin complexes, in response to increased intercellular tension.