Remodeling of Epithelial Adherens Junctions

The intercellular adherens junctions (AJ) are specialized sub-apical structures that function as principle mediators of cell-cell adhesion. Cadherins, the type-I transmembrane proteins of AJs, are principally responsible for homotypic cell-cell adhesion. The extracellular domain of E-cadherin binds calcium and forms complexes with the extracellular domains of E-cadherin molecules on neighboring cells. The cytoplasmic domain of E-cadherin associates with catenins, and provides anchorage to the actin cytoskeleton to form stable cell-cell contacts. Ctnn-β binds through its armadillo repeats to the distal region of the E-cadherin tail. Ctnn-α binds to Ctnn-β and links components of AJs to the actin cytoskeleton. It also binds to vinculin, zyxin and α-actinin, which in turn binds to F-actin. Ctnn-δ binds to the juxtamembrane region of E-cadherin and stabilizes cadherin molecules at the cell surface. Additional proteins and regulators of actin polymerization such as the ARP2/3 complex also occur at AJs. The cadherin-catenin mediated cell-cell adhesion is regulated by IQGAP1, APC and CLIP170, leading to establishment of polarized cell morphology and directional cell migration. But localization of IQGAP1 to sites of cell-cell contact and activation by APC/CLIP70/Mt-BPs reduces E-cadherin-mediated cell-cell adhesion by interacting with Ctnn-β, causing the dissociation of Ctnn-α from the cadherin-catenin complex and formation of weak adhesions.E-cadherins are rapidly removed from the plasma membrane and recycled to sites of new cell-cell contacts. RTKs and non-RTKs along with other PTKs phosphorylate tyrosine residues in the short intra-cytoplasmic tail of E-cadherins, thereby promoting their internalization by endocytosis. Tyrosine kinases also phosphorylate Ctnn-β, causing disassociation of cytoskeletal proteins from junctions. Hakai, an E3-ubiquitin ligase mediates ubiquitination of the E-cadherin complex and induces its endocytosis. E-cadherin bound to Hakai initiates the activation of intracellular signaling pathways, while the E3-ligase function of Hakai mediates the transfer of ubiquitin chains to E-cadherin and Ctnn-β through the E1-E2 ubiquitination system. The ubiquitinated E-cadherin can also undergo deubiquitination. E-cadherin is then recycled back to the cell surface, where it facilitates the reassembly of cell junctions. But ubiquitinated E-cadherin-Hakai complexes are internalized via clathrin-coated endocytic vesicle which are rapidly uncoated and fuse to early endosomes. The modification of E-cadherin by ubiquitin is essential for its sorting to the lysosome, which occurs by a process mediated by Src. Src activates Rab5 and Rab7 which mediate the trafficking of ubiquitinated E-cadherin to the lysosome for degradation.