Receptor protein tyrosine phosphatase RPTPα controls epithelial adherens junctions, linking E-cadherin engagement to c-Src signaling to cortactin

Abstract

Epithelial junctions are fundamental determinants of tissue organization, subject to regulation by tyrosine phosphorylation. E-cadherin homophilic binding activates tyrosine kinases, such as Src, that controls junctional integrity. Protein tyrosine phosphatases (PTPs) also contribute to cadherin-based adhesion and signaling, but little is known about their specific identity or functions at epithelial junctions. We report here that the receptor-PTP RPTPα is recruited to epithelial adherens junctions at the time of cell-cell contact, where it is in molecular proximity to E-cadherin. RPTPα is required for appropriate cadherin-dependent adhesion, and for cyst architecture in 3-dimensional culture. Loss of RPTPα impairs adherens junction integrity, manifested by defective E-cadherin accumulation and perijunctional F-actin density. These effects correlate with a role for RPTPα in c-Src activation at sites of E-cadherin engagement. Mechanistically, RPTPα is required for appropriate tyrosine phosphorylation of cortactin, a major Src substrate and a cytoskeletal actin organizer. Expression of a phosphomimetic cortactin mutant in RPTPα-depleted cells partially rescues F-actin and E-cadherin accumulation at intercellular contacts. These findings indicate that RPTPα controls cadherin-mediated signaling by linking homophilic E-cadherin engagement to cortactin tyrosine phosphorylation via c-Src.