Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes.

We present evidence that the association of Epithelial (E)-cadherin (CHD1) extracellular domain and epidermal growth factor receptor (EGFR, ErbB1) is obligatory for cadherin force transduction signaling. E-cadherin and EGFR associate at cell surfaces, independent of their cytoplasmic domains, and tension on E-cadherin activates EGFR signaling. Using engineered cadherin mutants that disrupt co-immunoprecipitation with EGFR, but not adhesion, we show that the hetero-receptor complex is required to mechanically activate signaling and downstream cytoskeletal remodeling at cadherin adhesions. The mutants localized the essential region on E-cadherin to the extracellular region and domain 4, EC4. The ectodomain is also required for hetero-receptor co-localization at intercellular junctions. Although the E-cadherin mutants disrupt EGFR signaling, integrin pre-activation together with tension rescues cytoskeletal reinforcement at cadherin adhesions, confirming the role of integrins in intercellular force transduction. Furthermore, although E-cadherin suppresses EGFR-mediated proliferation, in response to extracellular matrix stiffening, the force-sensitive hetero-receptor complex regulates growth factor-dependent epithelial proliferation. These findings support the hypothesis that E-cadherin complexes with EGFR are mechano-switches at cell-cell contacts that directly couple intercellular force fluctuations to mitogen-dependent signaling.