Functional activation of integrin alpha V beta 3 in tumor cells expressingmembrane-type 1 matrix metalloproteinase

Matrix metalloproteinases (MMPs) and integrins have been implicated in a va riety of processes involved in tumor progression. To evaluate the individua l roles of integrin alpha v beta 3 and membrane-type I matrix metalloprotei nase (MTI-MMP), as well as the effects of their joint expression on tumor c ell functions, MCF7 breast carcinoma cells were transfected stably with eit her the MTI-MMP, the beta 3 integrin subunit or both MTI-MMP and beta 3 cDN As. MTI-MMP expression is accompanied by the functional activation of integ rin alpha v beta 3, thereby increasing vitronectin-mediated adhesion and mi gration of MCF7 cells transfected with MTI-MMP and integrin alpha v beta 3. MTI-MMP-dependent functional activation of alpha v beta 3 correlates with modification(s) of the beta 3 subunit, including its higher electrophoretic mobility and affected the LM609-binding site. MCF7 cells jointly expressin g MTI-MMP and alpha v beta 3 were the most efficient in adhesion to the rec ombinant C-terminal domain of MMP-2 as well as in generating soluble and ce ll surface associated mature MMP-2 enzyme. These findings suggest a mechani sm of selective docking of MMP-2 at tumor cell surfaces, specifically at th e sites that include MTI-MMP and activated integrin alpha v beta 3. These m echanisms may provide a link between spatial regulation of focal proteolysi s by the cell surface associated MMPs and the regulation of integrin-mediat ed motility of tumor cells. Int. J. Cancer 86:15-23, 2000. (C) 2000 Wiley-L iss, Inc.