Epithelial Adherens Junction Signaling

The adherens junctions in epithelial cells are specialized structures for the cell-cell adhesion machinery and consist of nectin and cadherin cell adhesion molecules, which are linked to the actin cytoskeleton. The nectin family comprises of four members. Nectins bind to afadin, which then induces major cytoskeletal regulators like LMO7, ADIP, α-actinin, Ctnn-α, Zyxin, tubulins and myosins to modulate cytoskeletal reorganization and actin polymerization, leading to formation of adherens junctions. Nectin also activates Src, which then phosphorylates FRG and Vav2 eventually leading to the activation of Cdc42 and Rac. Activated Cdc42 and Rac activate their downstream effectors such as WASP, N-WASP and IQGAP1. This allows signals to flow through WAVE and the ARP2/3 complex to coordinate the initiation of new filaments.E-cadherin and N-cadherin function at adherens junctions in epithelial cells. By forming homodimers, cadherins anchor to the actin cytoskeleton through the catenins. E-cadherin binds to Ctnn-β, Ctnn-γ and Ctnn-α whereas, N-cadherin binds to Ctnn-β. These proteins in turn bind to Vinculin, F-actin, MAGI, Fer and RhoA to regulate actin polymerization, thereby enhancing adherens junction formation. Fer kinase contributes to the normal functioning of the E-cadherin/catenin complex during adherens junction assembly by phosphorylating Ctnn-δ. MAGI2-Ctnn-β interaction at E-cadherin junctions prevents PTEN degradation, which decreases the cell proliferation activity of AKT. MAGI, Ctnn-β and N-cadherin accumulate around the termini of apically extending processes in neuro-epithelial adherens junctions. Cadherin-catenin mediated cell-cell adhesion is regulated by IQGAP1, both positively and negatively. IQGAP1 captures and stabilizes microtubules/tubulins through Mt-BPs and CLIP170. IQGAP1 activation by APC-CLIP70 reduces E-cadherin-mediated cell-cell adhesion by interacting with Ctnn-β, causing the dissociation of Ctnn-α from the cadherin-catenin complex. Ctnn-δ activated Rac1 and Cdc42 positively regulate E-cadherin-mediated cell-cell adhesion by inhibiting the interaction of IQGAP1 with Ctnn-β.Free E-cadherin is subjected to endocytosis and is either degraded or is recycled back to the cell surface, whereas the release of free Ctnn-β results in the translocation of the molecule to the nucleus or its disintegration through interaction with APC-GSK3β during WNT signaling. Various growth factors such as HGF, FGF and TGFβ2 regulate the expression of E-cadherin indirectly via the transcription factor SNAI2/Slug. SNAI1 and 2 weaken adherens junctions as they interfere with trafficking and transport of E-cadherin by inhibiting its gene expression. Dysregulation of cadherin-mediated cell-cell adhesion and the dysregulation of cell polarization by IQGAP1 and Rho GTPases promote tumor metastasis and intractable inflammatory diseases that can lead to death. (Upgraded 03/2021)