6 Molecular Basis for Cell Adhesion and Adhesion-Mediated Signaling

Scheme depicting the structure of a typical integrin molecule. Integrins are composed of two noncovalently associated subunits designated α and β. Sixteen different α variants and eight different β variants have been identified in mammals to date. The integrin heterodimer has a globular head containing a ligand-binding pocket formed by both subunits. Two extended stalks correspond to the C-terminal parts of the α and β subunits. Some α subunits are cleaved posttranslationally to give heavy (extracellular) and light (transmembrane) chains linked by SMS bonding. The majority of integrin ligands contain the Arg-Gly-Asp (RGD) motif as the minimal sequence necessary for the integrin binding. Divalent cations, especially calcium, play an important role in the regulation of ligand binding, and the extracellular domain of the α subunit contains multiple repeats of EF-hand Ca2+-binding sites. The adhesion plaque proteins talin, α-actinin, paxillin, and FAK interact with the short cytoplasmic domain of the β subunit.

Scheme depicting classical cadherins involved in the formation of cellcell adherens junctions. (A) A classical cadherin molecule contains five homologous extracellular domains, denoted EC1 through EC5. Ca2+ ions bind to the regions between the EC domains and probably contribute to the rigid elongated shape of the molecule. The cytoplasmic domain of the classical cadherin is highly conserved and contains a binding site for the armadillo family proteins β-catenin and plakoglobin, while another family member, p120 ctn protein, binds to the juxtamembrane region of the cadherin tail. (B) Cadherin molecules exist as parallel dimers. It is thought that cadherin dimers on one cell make homophilic contacts with the dimers on a neighboring cell, forming a zipper-like structure. The EC1 domain participates both in dimer formation and in homophilic adhesive interactions. According to one model, adhesive specificity depends on this domain of cadherin. According to another model, EC1 through EC3 domains are involved in homophilic adhesion, as shown in Figure 6.9 .

Model depicting role of conformation changes in integrin, talin, and vinculin at the early stages of formation of integrin-mediated matrix adhesions. In the low-affinity state, the C-terminal portions of integrin α and β subunits interact with each other, which prevents interaction of the integrin β subunit with the talin head. In nonactive talin, the head interacts with the C-terminal portion of the rod, which masks the integrin-binding site in the head. The vinculin molecule consists of a globular head domain with the binding sites for talin, C-terminal tail domain with the binding sites for actin, and junctional domain with the binding site for the Arp2/3 complex. In closed conformation (left), the vinculin tail is attached to the head in such a way that the binding sites to talin, Arp2/3, and actin are masked. The signaling molecule PIP2 binds vinculin and talin and induces a transition from the closed conformation to an extended one, rendering the binding sites accessible (middle). Integrin transition from a low-affinity to high-affinity state is accompanied by moving the α and β subunit cytoplasmic tails away from one another, allowing interaction of β subunit with talin. Conversely, talin activation may in turn promote integrin activation. Vinculin in the opened conformation can link actin nucleator Arp2/3 to talin (right), promoting the assembly of adhesion complexes in association with Arp2/3-induced actin polymerization and branching (right).

Protein interactions at adherens junctions (see text).

The dual role of β-catenin in cell adhesion and transcriptional activation. β-Catenin (β) and plakoglobin (Pg) bind to cadherin adhesion receptors, and via α-catenin (α) they associate with the actin cytoskeleton to form AJs. When the Wnt signaling pathway is inactive, free β-catenin is degraded by a complex including glycogen synthase kinase (GSK), adenomatous polyposis coli (APC), and Axin, which phosphorylate β-catenin (PP). This protein complex recruits β-TrCP, which, together with Skp1, Cul1, and the E1 and E2 ubiquitination components, mediates the ubiquitination of β-catenin (Ub) and directs it to degradation by the 26S proteasome. The binding of Wnt to Frizzled (Frz) receptors activates Wnt signaling, and disheveled (Dsh) inhibits β-catenin phosphorylation by GSK. This results in β-catenin accumulation in the nucleus, where it complexes with T-cell factor (TCF) and transactivates target genes such as Cyclin D1 and Myc (adapted from Conacci- PKI-CHECK NLNG PO KC PATI S PDF PUTOL UNG CAPTION N ITO..