Fig. 3

Dynamics of E-cadherin-mediated cell-cell adhesion Epithelial AJs are constructed on a foundation of homophilic contacts between E-cadherin clusters. Previous contacts between nectins inhibit non-trans-interacting E-cadherin endocytosis through afadin, Rap1, and p120-ctn, and increase their concentration at cell-cell adhesion sites. Immediately after E-cadherin trans-interaction, the junction complexes trigger activation of the phosphatidylinositol-3-kinase (PI3K)–Akt–protein kinase B pathway. Phosphatidylinositol-(3,4,5)-triphosphate (PIP3) is generated, and guanine nucleotide exchange factors are recruited to the membrane, activating Rac1 or Cdc42 and reducing Rho activation, which stimulates membrane and actin dynamics adjacent to the initial site of contact, increasing the probability of additional E-cadherin engagements. Alpha-catenin homodimerizes and is released from the cadherin-catenin complexes to bind at and antagonize with Arp2/3, facilitating the belt formation of unbranched actin filaments. While vinculin, afadin and alpha-actinin link with actin cytoskeleton, β-catenin and p120-ctn also link with tubulin cytoskeleton to route both vesicles of newly synthesized E-cadherin-catenin and E-cadherin-recycling-endosomes to the cell-cell contact sites. Down-stream of Rac and Cdc42, IQGAP1 binds β-catenin, which could localize in membrane ruffles and control cadherin internalization via SNX-1 preventing E-cadherin lysosomal degradation and recycling of E-cadherin back to the cell surface for AJ maintenance. P120-ctn binding covers cadherin juxtamembrane domain inhibiting RhoA locally and adaptor complex-binding that recruits cadherins into a coated pit. Thus, E-cadherin becomes withheld in plasma membrane junction domains. Meanwhile, PtdIns(3,4,5)P3 accumulation in the membrane signals for the formation and expansion of the baso-lateral surface, while Rac1 promotes cell polarity and lumen formation, cell cycle arrest of confluent epithelial cells, and survival of polarized epithelial cells. In parallel, E-cadherin downregulates ligand-dependent receptor tyrosine kinase activation, such as EGFR stabilizing cell-cell contacts. Insert: traffic of E-cadherin vesicles via p120-ctn or β-catenin coupled to kinesin for delivering to newly forming or remodeling junctions