Cadherins are adhesion molecules that regulate tissue integrity and signalling. Although much is known about the adhesion properties of cadherins, the molecular mechanisms linking cadherin-specific adhesion to force transduction and signalling remain unclear. Here (Vu et al., 2025), Deborah Leckband and colleagues show that force-activated cadherin signalling requires two levels of molecular specificity – homophilic ligation and activation of specific receptor tyrosine kinases (RTKs). Using a combination of biophysical and cell biological approaches, the authors demonstrate that tension on homophilic E-cadherin or N-cadherin adhesions activates epidermal growth factor receptor and fibroblast growth factor receptor, respectively, forming signalling ‘mechano-switches’. These mechano-switches regulate cytoskeletal remodelling and cell contractility via RTK activation, RhoA, α-catenin unfolding and vinculin recruitment. Notably, homophilic cadherin ligation transduces force much more effectively than heterophilic interactions, despite both supporting adhesion. The authors propose a model in which tension at homophilic junctions activates signals that stabilise cadherin adhesions by enhancing cytoskeletal and contractile activity, whereas heterophilic junctions do not, resulting in weaker adhesion. Together, this work highlights the dual role of cadherins as adhesive molecules and force transduction hubs and demonstrates how selective cadherin binding and specific interactions with RTKs regulate local cytoskeletal dynamics and intercellular mechanics.
