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

Abstract

This study reports novel findings that link E-cadherin (also known as CDH1)-mediated force-transduction signaling to vinculin targeting to intercellular junctions via epidermal growth factor receptor (EGFR) and integrins. These results build on previous findings that 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 its phosphorylation at tyrosine 822 by Abl family kinases (hereafter Abl), but the origin of force-dependent Abl activation had not been identified. We now present evidence that integrin activation, which is downstream of 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.This article has an associated First Person interview with the first author of the paper.

Distinct roles of VE ‐cadherin for development and maintenance of specific lymph vessel beds

“…Besides an increase in circumferential actin of VE‐cadherin‐deficient pdLECs (Fig and Appendix Fig S11), we detected a decrease of approximately 30% in focal adhesions per cell compared to controls (Fig ). Cell‐ECM traction has been demonstrated to be directly correlated with cell–cell tension (Maruthamuthu et al , ; Sehgal et al , ). In addition, the reduced focal adhesions may indicate increased actin remodeling and the activation of TAZ contributed to the increased motility (Fig ) of VE‐cadherin‐deleted pdLECs.…”

Functional genomic analyses highlights a shift inGpr17-regulated cellular processes in oligodendrocyte progenitor cells (OPC) and underlying myelin dysregulation in the aged forebrain

“…Notably, these processes are interrelated and the ECM plays a major role in the biomolecular and biomechanical regulation of OPC stemness (Nolte et al, 2001). Our data implicated an EGFR-vinculin-gelsolin-Cldn11 axis at the centre of oligodendroglial networks that are altered in aging, which provides a potential mechanism by which the mechanosensitive function of EGFR (Tschumperlin et al, 2004, Müller-Deubert et al, 2017, is transduced via vinculin and gelsolin to regulate cell/integrin/ECM interactions and control oligodendroglial cytoskeleton dynamics and cellular spreading (Hagen, 2017, Sehgal et al, 2018, Rübsam et al, 2017. Several lines of evidence show that EGFR promote oligodendrocyte regeneration and myelin repair (Aguirre et al, 2007), and our findings indicate EGFR signalling is pivotal to multiple transcriptional networks and signalling pathways that regulate age-related changes in oligodendrocytes.…”

Cytoskeletal interactions of eukaryotic initiation factor 6 regulate mechanical responses in cells

“…Phosphorylation of Cas at Y165 (pCas Y165 ) in focal adhesions has been linked to several fundamental cell processes including regulation of F-actin and focal adhesion turnover [67][68][69][70][71] . Crk-like protein (CrkL) is an adaptor protein and binds to Cas and forms part of the mechanical scaffold of the adhesion site; CrkL has been shown to be phosphorylated at Y207 in response to force on Ecadherin 72 . Similar to what we found for FAK, force increased phosphorylation of both pCas Y165 and pCrkL Y207 in control cells (Figure 4b 12 si eIF6 cells.…”