Rap1: a turnabout for the crosstalk between cadherin and integrin signaling

The coordinate modulation of the cellular functions of cadherins and integrins plays an essential role in fundamental physiological and pathological processes, including morphogenesis, tissue differentiation and renewal, wound healing, immune surveillance, inflammatory response, tumour progression, and metastasis. However, the molecular mechanisms underlying the fine-balanced relationship between cadherin and integrin functions are still elusive. We found that the small GTPase Rap1, a crucial regulator of the inside-out activation of integrins, is a target for E-cadherin-mediated outside-in signaling. In particular, a strong activation of Rap1 occurs upon adherens junction disassembly and is triggered by E-cadherin internalization and trafficking along the endocytic pathway. Moreover, the activation of Rap1 is associated with and controlled by an increased Src kinase activity, and is paralleled by the colocalization of Rap1 and E-cadherin at the perinuclear recycling endosome compartment, and the association of Rap1 with a subset of E-cadherin-catenin complexes that does not contain p120ctn. Importantly, the E-cadherin endocytosis-dependent activation of Rap1 is associated with and is required for the formation of integrin-based focal adhesions. Our findings point to Rap1 as a pivotal player in the functional crosstalk between cadherins and integrins, suggesting that in physiological conditions this small GTPase may couple AJ disassembly with increased integrin-mediated cell-matrix adhesion in order to prevent uncontrolled cell dissemination.