Cleavage and shedding of E-cadherin after induction of apoptosis

Apoptotic cell death induces dramatic molecular changes in cells, becoming apparent on the structural level as membrane blebbing, condensation of the cytoplasm and nucleus, and loss of cell-cell contacts. The activation of ca spases is one of the fundamental steps during programmed cell death. Here w e report a detailed analysis of the fate of the Ca2+-dependent cell adhesio n molecule E-cadherin in apoptotic epithelial cells and show that during ap optosis fragments of E-cadherin with apparent molecular masses of 24, 29, a nd 84 kDa are generated by two distinct proteolytic activities. In addition to a caspase-3-mediated cleavage releasing the cytoplasmic domain of E-cad herin, a metalloproteinase sheds the extracellular domain from the cell sur face during apoptosis, Immunofluorescence analysis confirmed that concomita nt with the disappearance of E-cadherin staining at the cell surface, the E -cadherin cytoplasmic domain accumulates in the cytosol, In the presence of inhibitors of caspase-3 and/or metalloproteinases, cleavage of E-cadherin was almost completely blocked. The simultaneous cleavage of the intracellul ar and extracellular domains of E-cadherin may provide a highly efficient m echanism to disrupt cadherin-mediated cell-cell contacts in apoptotic cells , a prerequisite for cell rounding and exit from the epithelium.