Fig. 9. Hypothetical model for the E-cadherin endocytosis-mediated activation of Rap1. In confluent epithelial cells both Src kinase and Rap1 activity are reduced to basal levels. Rap1 is diffusely distributed into the cytoplasm, where it associates with endosomal compartments, while AJs are stabilized by p120^ctn binding to the E-cadherin juxtamembrane domain. Upon stimuli that induce the weakening of cell-cell adhesion, Src kinase activity is enhanced and may in turn activate the endocytic machinery underling E-cadherin internalization. Major known targets for Src tyrosine kinase activity in response to stimuli that weaken AJs are E-cadherin itself and p120^ctn. However, at least two Rap1GEFs, one of which (C3G) is known to be regulated by tyrosine phosphorylation, have been reported to bind to either the E-cadherin cytoplasmic domain or ß-catenin, suggesting that Rap1GEF directly or indirectly linked to the E-cadherin cytoplasmic domain may also be activated upon cell-cell adhesion weakening. Internalized E-cadherin must proceed through the endocytic pathway in order to induce Rap1 activation, which probably occurs upon E-cadherin transit from early to recycling endosomes where a protein complex containing E-cadherin and Rap1 may form. Activated Rap1 may in turn control the polarized redistribution of integrins and/or integrin regulators to new adhesion sites, leading to the formation of enhanced integrin-mediated cell-matrix adhesion (see text for details).