Epithelial Adherens Junctions
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Epithelial Adherens Junctions

Adhesion between neighboring epithelial cells is a crucial and tightly controlled process. The integrity of cell-cell contacts is essential for the regulation of electrolyte absorption and for the prevention of tumor metastasis. In polarized epithelia, specialized structures such as Adherens Junctions (AJs) and Tight Junctions (TJs) are responsible for the establishment of contacts between neighboring cells. The establishment and stability of Adherens Junction is tightly regulated-in particular, by Growth Factors, Cytokines and hormones. Such regulation, although poorly understood, is quite essential for the modulation of paracellular permeability in various epithelia, for the epithelium mesenchyme transition, and for development, morphogenesis and wound healing (Ref.1). The Adherens Junctions in epithelial cells are specialized structures for the cell-cell adhesion machinery and consist of Nectin and Cadherin family cell adhesion molecules, which are linked to the Actin cytoskeleton through their binding proteins Afadin and Catenins, respectively (Ref.2). Nectin comprises a family of at least four members, Nectin-1 to Nectin-4, all of which, except Nectin-4, have two or three splice variants and these Nectins bind to the PDZ domain of Afadin. Afadin has two splice variants; l-Afadin (larger splice variant) and s-Afadin (smaller splice variant). l-Afadin is a Nectin- and F-Actin-binding protein and binds along the side of F-Actin but not to the ends of F-Actin, although it does not have cross-linking activity. s-Afadin, the smaller splice variant, lacks the F-Actin-binding domain and the third proline-rich domain. The binding of Afadin and F-Actin at Nectin-Nectin junctions induce major cytoskeletal regulators like ZO1 (Zona Occludens-1), LMO7 (LIM Domain-7), ADIP (Afadin- and Alpha-Actinin-Binding Protein), Alpha-Actinin, Ctnn-Alpha (Catenin-Alpha), Zyx (Zyxin), Ponsin, Vcl (Vinculin), KEAP1 (Kelch-like ECH-Associated Protein-1), Epsin, Tubulin and Myosin to modulate cytoskeletal reorganization and Actin polymerization, leading to formation of  Adherens Junctions (Ref.3). Nectin recruits and activates c-Src, which then phosphorylates FRG, a CDC42 (Cell Division Cycle-42)-GEF (GDP/GTP Exchange Factor), and Vav2, a Rac-GEF, and it also activates Rap1 (Ras-Related Protein-1) through the Crk (v-Crk Avian Sarcoma Virus Ct10 Oncogene Homolog)-C3G (or RapGEF1 (Rap Guanine Nucleotide Exchange Factor-1)) complex. The activation of both c-Src and Rap1 is necessary for the activation of FRG, followed by the activation of CDC42. Similarly, the activation of both c-Src and CDC42 is necessary for the activation of Vav2, eventually causes the activation of Rac. The entire relationship in the Nectin-induced activation of CDC42 and Rac leads to subsequent formation of filopodia and lamellipodia, respectively. Activated CDC42 and Rac bind to and specifically activate their downstream effectors, which include scaffolding proteins like IRSp53 (Insulin Receptor Substrate p53), WASP (Wiskott-Aldrich Syndrome Protein), N-WASP (Neural Wiskott-Aldrich Syndrome Protein) and IQGAP1 (IQ Motif Containing GTPase Activating Protein-1). This allows signals to flow through WAVE (WASP Family Verprolin Homology Domain-Containing Protein) and Actin-related proteins, ARP2/3 complex to coordinate the initiation of new filaments. Filopodia induced in this way increase the number of cell-cell contact sites at the initial stage of the formation of Adherens Junctions. On the other hand, lamellipodia induced in this way efficiently expand the cell-cell adhesion between filopodia, acting like a “zipper”. Thus, the Nectin-induced formation of filopodia and lamellipodia significantly increase the velocity of the formation of Adherens Junctions. At expanded junctions Nectin-induced activation of PAR-3 (Partitioning Defective-3) and CDC42 enhance cell-adhesion through regulation of Tight Junctions in a highly controlled manner (Ref.4 & 5).

In contrast to Nectins, the intercellular adhesion activity of Cadherins is Ca2+ (Calcium) dependent. However, in common with E-Cadherin (or Epithelial Cadherin), it is likely that Nectin first forms a cis-dimer and then a trans-dimer. E-Cadherin and N-Cadherin (or Neuronal Cadherin) functions as a Ca2+-dependent cell adhesion molecules at Adherens Junctions in epithelial cells (inclusive of neuroepithelial cells) (Ref.3). Cadherins comprise a major group of cell-cell adhesion molecules that mediate intercellular adhesion by engaging in Ca2+-dependent, homophilic, trans-interactions. By forming cis-homodimers, Cadherins cluster through a zipper-like mechanism, with their intracellular domains anchored to the Actin cytoskeleton through Ctnn-Beta (Catenin-Beta), Ctnn-Gamma (Catenin-Gamma) and Ctnn-Alpha. Anchorage of Cadherins to the Actin cytoskeleton and their clustering are indispensable for the development of strong and rigid adhesion. The cytoplasmic regions of classical Cadherins comprise two domains; the C-terminal distal Ctnn-Beta-binding domain (D-Beta-D); and the Juxtamembrane domain (JMD), which is the p120Ctn (p120-Catenin)-binding site and is thought to regulate clustering, transport and endocytosis of Cadherins (Ref.6). To facilitate strong adhesion (chiefly regulated by extracellular Ca2+ levels), E-Cadherin binds to protein 4.1, F-Actin, Catenins (Alpha-, Beta-, Gamma- and Delta or p120), whereas, N-Cadherin binds to Ctnn-Beta. These proteins in turn bind to Vcl, F-Actin, MAGIs (Membrane Associated Guanylate Kinases), ZO1, Afadin, Fer (Fps/Fes-Related Tyrosine Kinase) and RhoA (through RhoA Signaling), to regulate Actin polymerization (that is formation of F-Actin (filamentous form) from G-Actin (globular form)), thereby enhancing Adherens Junction formation. Fer kinase, a cytosolic non-receptor PTK (Protein Tyrosine Kinase) apparently contributes to the normal functioning of the E-Cadherin/Catenin complex during Adherens Junction assembly by phosphorylating p120Ctn and PTPs (Protein Tyrosine Phosphatases). PTPs like PTP1B along with RPTPs (Receptor Protein Tyrosine Phosphatases) dephosphorylate Ctnn-Beta and p120Ctn, leading to an increase in cell adhesion (Ref.7). Adherens Junctions are thus multi-protein complexes with one of the highest cellular concentrations of signaling proteins. Among these signaling proteins, scaffold proteins like the members of the membrane-associated guanylate kinase family, MAGI1 and MAGI2, play a critical role in signal transduction by optimizing the functional activity and stability of their ligands. MAGI2/Beta-Catenin interaction at E-Cadherin junctions prevents PTEN degradation, which significantly decreases the cell proliferation activity of the Akt (v-Akt Murine Thymoma Viral Oncogene Homolog) through conversion of PIP3 (Phosphatidylinositol-3,4,5-Trisphosphate) to PIP2 (Phosphatidylinositol-4,5-Bisphosphate) (Ref.8). Similarly, MAGI1/Beta-Catenin/N-Cadherin accumulates around the termini of apically extending processes in neuro-epithelial Adherens Junctions and is partially co-localized with DLL1 (Delta-Like-1). DLL1 is recruited to these through binding to MAGI1. DLL1 is presented on the surface of Adherens Junctions and through interaction with MAGI1 activates Notch on neighboring cells resulting in lateral inhibition of cell differentiation and firm adhesion (Ref.2).

However, the Cadherin-Catenin mediated cell-cell adhesion is regulated by IQGAP1, both positively and negatively. IQGAP1 captures and stabilizes Microtubules/Tubulins through the Mt-BPs (Microtubule-Plus-End-Binding Proteins) and CLIP170 (Cytoplasmic Linker Protein-170Alpha-2), leading to establishment of polarized cell morphology and directional cell migration. Furthermore, Rac and CDC42 link the APC (Adenomatous Polyposis Coli) protein to F-Actin filaments through IQGAP1 thereby regulating polarization and directional migration. This also impinges a positive feedback on Rac and CDC42. Again p120Ctn activated Rac1 and CDC42 positively regulate E-Cadherin-mediated cell-cell adhesion by inhibiting the interaction of IQGAP1 with Ctnn-Beta. But localization of IQGAP1 to sites of cell-cell contact and activation by APC/CLIP170/Tubulins through the Mt-BPs reduces E-Cadherin-mediated cell-cell adhesion by interacting with Beta-Ctnn, causing the dissociation of Alpha-Ctnn from the Cadherin-Catenin complex. Hence, IQGAP1 negatively regulates E-Cadherin-mediated cell-cell adhesion (Ref.6). Weak adhesions are also formed due to Growth Factor induced activation of RPTKs (Receptor Protein Tyrosine Kinases), like Met (Met Proto-oncogene), ErbB (v-ErbB Avian Erythroblastic Leukemia Viral Oncogene Homolog)-1/2, FGFR1 (Fibroblast Growth Factor Receptor-1) and TGF-BetaR (Transforming Growth Factor-Beta-Receptor). Met causes phosphorylation and activation of non-receptor PTKs (that includes Fer, c-Src and Fyn (Fyn Oncogene Related to Src, FGR, YES)) which along with Yes1 (v-Yes-1 Yamaguchi Sarcoma Viral Oncogene Homolog-1) phosphorylate p120Ctn and Ctnn-Beta dissociating them from the Cadherin/Catenin complex, causing a loss of cell adhesion function. Free E-Cadherin is subjected to endocytosis and is either degraded or is recycled back to the cell surface. Whereas release of free Ctnn-Beta results in the translocation of the molecule to the nucleus or it gets disintegrated through interaction with APC-GSK3Beta (Glycogen Synthase Kinase-3-Beta) during signaling by WNTs (Wingless-Type MMTV Integration Site Family Members). WNT signaling leads to binding of Ctnn-Beta to TCF (Transcription Factor-3)/LEF (Lymphoid Enhancer-Binding Factor) that promotes changes in the transcriptional machinery which lead to activation of several target genes including the activation of transcription factors like SNAI2 (Snail Homolog-2)/Slug (Ref.5 & 9). RPTKs like ErbB1/2 and Met also act in concert with Ctnn-Beta/TCF/LEF complex to activate SNAI2/Slug via Ras-MAPK route; other RPTKs like FGFR1 and TGF-BetaR utilize the same route only to enhance SNAI1 (Snail Homolog-1) mediated gene expression. Alternate routes of SNAI1 activation also includes signaling through TGF-Beta/TGF-BetaR . TGF-Beta signaling further stimulates transcriptional activation of Ctnn-Beta by enhancing the interaction between histone acetyl transferase CBP (CREB-Binding Protein) and SMAD3 (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-3) and SMAD4 proteins. Activation of SNAI1 and SNAI2 weaken Adherens Junctions as they interfere with trafficking and transport of E-Cadherin by inhibiting its gene expression. IQGAP1 and Growth Factors are very much vital for recycling of Adherens Junction proteins and it is conceivable that the dysregulation of Cadherin-mediated cell-cell adhesion and the misregulation of cell polarization by IQGAP1 and RhoGTPases promote tumor metastasis and intractable inflammatory diseases that often lead to death. If so, modulation of the Adherens Junction signaling pathways linking IQGAP1 and Cadherins might provide the basis for therapies for the tumor-related and inflammatory diseases (Ref.10 & 11).