Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1

The function of many transmembrane molecules can be altered by cleavage and subsequent release of their ectodomains. We have investigated ectodomain c leavage of the cell-cell adhesion and signal-transducing molecule E-cadheri n, The E-cadherin ectodomain is constitutively shed from the surface of MCF -7 and hIDCKts,srcC12 cells in culture, Release of the 80 kDa soluble E-cad herin fragment is stimulated by phorbol-12-myristate-13-acetate and is inhi bited by overexpression of the tissue inhibitor of metalloproteinases-2. Th e metalloproteinases matrilysin and stromelysin-1 both cleave E-cadherin at the cell surface and release sE-CAD into the medium, The soluble E-cadheri n fragment thus released inhibits E-cadherin functions in a paracrine way, as indicated by induction of invasion into collagen type I and inhibition o f E-cadherin-dependent cell aggregation. Our results, therefore, suggest a novel mechanism by which metalloproteinases can influence invasion.