We present evidence that binding between epithelial (E)-cadherin (CHD1) and epidermal growth factor receptor (EGFR, ErbB1) is obligatory for force-activated signaling at intercellular contacts and the mechanical regulation of proliferation. Here, we used engineered cadherin mutants that disrupt co-immunoprecipitation of E-cadherin and EGFR, but not adhesion, to show that this hetero-receptor complex is required for force-activated EGFR signaling and downstream cytoskeletal reinforcement at intercellular adhesions. The mutants localized the essential binding region on E-cadherin to extracellular domain 4, EC4 of the ectodomain region, independent of the cytoplasmic domain. The E-cadherin ectodomain is also required for hetero-receptor co-localization at intercellular junctions. Furthermore, in epithelia, E-cadherin and EGFR cooperate to regulate proliferation in response to matrix stiffening. These results now show that the hetero-receptor complex is a force-sensitive switch that controls the mechanical regulation of growth signaling in response to matrix stiffening. These findings support the hypothesis that E-cadherin complexes with EGFR are essential mechano-switches at cell-cell contacts that directly couple intercellular force fluctuations to mitogen-dependent signaling.
Leckband et al. (Sun,) studied this question.