Adhesion Molecules and Related Proteins

Cadherins
Cadherins are a family of calcium-dependent single-pass transmembrane glycoprotein that mediate cell-cell adhesion. Members are known by their tissue specific distribution: epithelial (E-cadherin, uvomorulin), neural (N-), placental (P-), vascular-endothelial (VE-). They are characterized by five extracellular domains (EC1 to EC5) that co-ordinate with Ca²⁺ forming rod-like structures. Distal EC1 has an HAV (histidine, alanine, valine) region involved in transdimerization between opposing cells where Ca²⁺ is required. The C-terminal cytoplasmic tail (CT) is highly conserved with a binding site for the p120 family proximal to the transmembrane (TM) domain and a β-catenin binding site in the C-terminal 25 amino acid residues.
Lateral cis-dimerization and clustering of E-cadherins is required to stabilize adhesion. Formation of anti-parallel adhesive structures (trans-dimerization) with cadherins on opposing cells is envisioned to take place in a zipper fashion. Cadherin-based adhesion complex (CAC)/cadherin-catenin system is linked to the cytoskeleton via other partners. E-Cadherin binds to β-catenin (alternatively, γ-catenin/plakogobulin), which binds to α-catenin, vinculin, ZO-1, and actin. In this way, cadherin functions to preserve tissue integrity. The CAC also participates in cell signaling, it transduces signals from the extracellular micro-environment that determine differentiation, embryonic morphogenesis and possibly modulate cancer invasiveness. Loss of E-cadherin function has been described in many tumors.
The Rho family of small GTPases (Rho, Rac, cdc42) regulates the CAC. IQGAP1, a RasGAP (GTPase-activating protein), associates with E-cadherins and β-catenins thereby disrupting the complex with α-catenins and blocking cell-cell adhesion. Active GTP-bound Rac1 and cdc42 positively regulates the CAC by suppressing the function of IQGAP1. In addition, calmodulin competes with E-cadherin for interaction with IQGAP1.