Cadherins and growth factor receptors - ligand-selective mechano-switches at cadherin junctions.

Abstract

This study investigated possible mechanisms underlying differences between heterophilic and homophilic cadherin adhesions that influence intercellular mechanics and multicellular organization. Results suggest that homophilic cadherin ligation selectively activates force transduction, such that resulting signaling and mechano-transduction amplitudes are independent of cadherin-binding affinities. Epithelial (E-) and neural (N-)cadherin cooperate with distinct growth factors to mechanically activate force transduction cascades. Prior results have demonstrated that E-cadherin and epidermal growth factor receptor form force-sensitive complexes at intercellular junctions. Here, we show that the reconstitution of N-cadherin force transduction requires the co-expression of N-cadherin and fibroblast growth factor receptor. Mechanical measurements further demonstrated that homophilic ligation initiates receptor tyrosine kinase-dependent force transduction cascades, but heterophilic cadherin ligands fail to activate signaling or generate stereotypical mechano-transduction signatures. The all-or-nothing contrast between mechano-transduction by heterophilic versus homophilic cadherin adhesions supersedes differences in cadherin adhesion strength. This mechano-selectivity impacts cell spreading and traction generation on cadherin substrates. Homophilic ligation appears to be a key that selectively unlocks cadherin mechano-transduction. These findings might reconcile the roles of cadherin recognition and cell mechanics in the organization of multicellular assemblies.