cadherins

Cadherins - Calcium Dependent Adhesion Molecules:

Cadherins are developmentally regulated, calcium-dependent homophilic cell-cell adhesion molecules (CAMs), through which cell-cell and cell-matrix interactions are mediated.[]im[]

The classic cadherins are defined by a conserved intracellular (i) domain which mediates interactions with cytoplasmic proteins termed catenins: α- and β-catenin. β-catenin (5) binds to both the C-terminus of the cadherin intracellular domain (6) and the N-terminus of α-catenin (4). α-catenin binds to a number of proteins involved in actin binding, bundling and polymerisation, as well as binding directly to F-actin (1) of the cytoskeleton, here through α-actin (3) in association with vinculin (2).

Absence of α- or β-catenin results in defective cell adhesion and failure of cadherin-catenin complexes to associate with the actin cytoskeleton. β-catenin is the common target for signal transduction pathways mediated by the EGF and proto-oncogenes src and Wnt-1. Several cytoplasmic Wnt regulators (β-catenin, Bcl-9/Lgs, APC, Axin) appear transiently in the nucleus.

At intercellular adherens junctions, β-catenin is an integral component of E-cadherin complexes. β-Catenin also recruits chromatin remodeling complexes, activating transcription in the nucleus. When the Wnt signaling pathway is inactive, the cytoplasmic pool of β-catenin is degraded by a complex including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK), APC and Axin, which phosphorylate β-catenin (PPPP). The phosphorylated β-catenin is recognized by the ubiquitin ligase component β-TrCP, which together with Skp1, Cul1 and the E1 and E2 ubiquitination components, mediates the ubiquitylation of β-catenin, directing it to degradation by the 26S proteasome.)[s] A third protein, p120 catenin (not shown), binds to the classic cadherin intracellular domain at a site distinct from β-catenin. Classic cadherins together with the three catenins (α-, β-, p120) form a core functional unit, the cadherin-catenin complex (CCC), which is a major component of the apical junctions formed between epithelial cells.

Members of the cadherin superfamily are grouped according to the presence of one or more cadherin repeats in their extracellular (e) domains. Arrays of these (approx. 110 residue) domains form the intermolecular surfaces that mediate cadherin-mediated cell-cell interactions. Patel et al., 2003). The extracellular domains of type I and II (chordate) cadherins consist of five cadherin repeats (CRs). Type III (invertebrate and non-mammalian vertebrate) cadherins have variable numbers of CRs and also contain a region termed the primitive classical cadherin domain (PCCD) which, together with variable numbers of EGF-like and laminin G repeats, lies between the CRs and the transmembrane helix.

E-cadherin is the prototypic member of the cadherin transmembrane protein family, and regulates cell-to-cell adhesion by interacting with (homotype) E-cadherin molecules on opposing cell surfaces. E-cadherin's function in cell adhesion is also critically dependent on its ability to interact, through its cytoplasmic domain, with catenin proteins. A diverse collection of defects alter cadherin-catenin function in cancer cells. [1, 2] The E-cadherin/catenin complex serves cell-cell adhesion and also transduces signals to the nucleus and to the cytoskeleton, either directly or through its connections with multiple other complexes. [3] The E-cadherin/catenin defects associated with malignancy include inactivating mutations and defects in the expression of E-cadherin and certain catenins, such as α-catenin.[a] Frequent inactivating mutations have been identified for the E-cadherin gene (CDH1) in diffuse gastric cancers and lobular breast cancers.[b] Members of several families of adhesion molecules appear to be important in the progression of ovarian carcinoma, including CD44, integrins, and E-cadherin. CD44 and the beta 1 integrin subunit play fundamental roles in the adhesion and migration of ovarian carcinoma cells to mesothelial cells and to their associated pericellular matrix. [4] . micro- cadherin 11 in chick embryo .



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