The E-Cadherin/Catenin Complex in Invasion: The Role of Ectodomain Shedding

The E-cadherin/catenin complex is an invasion suppressor in epithelial cells. E-cadherin is a glycoprotein with an extracellular, a transmembrane and a cytoplasmic part. The cytoplasmic part is connected with the actin cytoskeleton via the catenins. s-catenin appears to be a functional modulator of the complex, because its association is not restricted to E-cadherin only. (s-catenin is also found in cytoplasmic (e.g. with the Adenomatous Polyposis Coli gene product, glycogen synthase kinase 3s and axin) and nuclear (e.g. lymphoid enhancer binding factor-1 and pontin 52) complexes, that compete with its availability for the E-cadherin/catenin complex. The extracellular part of E-cadherin contains a histine-alanine-valine sequence responsible for homophilic interactions. Enzymatic cleavage of this extracellular part yield a 80 kDa fragment coined ectodomain. Ectomain shedding is a phenomenon described for many peptide receptors at the plasma membrane, and is mainly ascribed to the activity of two families of proteases: matrix metalloproteinases (MMPs) and adamilysins (ADAMs). Ectodomain shedding of E-cadherin seems to be instrumental in the functional downregulation of the E-cadherin/catenin complex: it can lead to loss of cell-cell adhesion and induction of invasion. The enzymes implicated in this process are considered as targets for anti-invasive strategies.