Sunday, June 3, 2012

E-cadherin is a classic cadherin that acts as an adhesion molecule and a cellular regulator



E-cadherin (epithelial cadherin) is a member of the cadherin superfamily of proteins, a group of 80 glycoproteins that are broadly involved in cell to cell adhesion via calcium-mediated homotypic interactions. It is considered to be a tumor suppressor gene because its interactions strongly bind cells together, limiting migration. E-cadherin is a type I "classic cadherin" along with neural (N) and placental (P) cadherins and is coded by the CDH1 gene. All classic cadherins contain a highly conserved transmembrane domain with a cytoplasmic tail that binds to the actin cytoskeleton via an alpha- and beta- catenin "bridge" that binds to the C-terminus. Type I and II cadherins contain an extracellular domain consisting of five identical 110 amino acid repeats, which form the basis for their role as adhesion molecules.

E-cadherin is important during early development, expressing throughout the cells soon after the first mitotic division and initiating compaction by the 8-cell stage. Soon afterwards, its expression is restricted to areas in contact with neighboring cells. In addition to its role as an adhesion molecule, E-cadherin has broad signaling properties that influence the fate of cells, especially during early differentiation. When E-cadherin is disrupted, embryonic cells lose their pluripotency and prematurely differentiate. The pattern of E-cadherin expression can be assessed via either a transgenic fluorophore tag (primarily for in vivo work) or an E-cadherin antibody for immunohistochemistry. An analysis of this expression indicates that E-cadherin is important in the establishment of left-right symmetry during morphogenesis.

The viral-mediated overexpression of E-cadherin has been used to "reprogram" embryonic cells, whereas its deletion inhibits reprogramming. Interestingly, E-cadherin is often downregulated in many cancers. It is unknown whether this has any influence over the undifferentiation often seen in metastatic tumors.

After embryonic differentiation, E-cadherin is seen largely in the epithelial cells of the gut and lungs but is also present in the kidney, skin, and liver to some extent. In these tissues, cadherin is responsible for binding cells together, often forming "belt desmosomes", which circumscribe the cell's soma. This allows the cell to both maintain its position relative to neighboring cells and, by forming a cellular seal across the entire epithelial layer, carefully control the transport of nutrient and waste particles across the membrane.

When binding to beta-catenin is disrupted (such as via dephosphorylation at the beta-catenin binding site), the E-cadherin molecule is no longer anchored to the cytoskeleton. This results in destabilization and rapid turnover, decreasing the number of cadherin-cadherin interactions at the intercellular junction, consequently reducing its strength and integrity. Similarly, the prevention of calcium binding at the extracellular domain results in a conformational change that disrupts E-cadherin's homotypic interactions.

The assessment of E-cadherin is often of clinical significance, as it is dysregulated in several forms of cancer. A good E-cadherin antibody can be used to visualize the level and pattern of protein expression via immunofluorescence or similar techniques. During metastasis, many cancers of the breast, skin, and gut substantially downregulate their E-cadherin expression. The effects of this downregulation are twofold: first, the cell to cell adhesion of the tumor cells is reduced, which lets the cancer cells spread and metastasize distant tissues; furthermore, the loosened cancer cells create holes in the basement membrane, which allows the egress of tumor cells from the lumen.


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