An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase

Membrane type-1 matrix metalloproteinase (MT1-MMP) and alpha(v)beta(3), integrin are both essential to cell invasion. Maturation of integrin pro-alpha(v) chain (pro-a(v)) involves its cleavage by proprotein convertases (PC) to form the disulfide-bonded 125-kDa heavy and 25-kDa light a chains. Our report presents evidence of an alternative pathway of pro-av processing involving MT1-MMP. In breast carcinoma MCF7 cells deficient in MT1-MMP, pro-a, is processed by a conventional furin-like PC, and the mature a, integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp(891). In contrast, in cells co-expressing alpha(v)beta(3) and MT1-MMP, MT1-MMP functions as an integrin convertase. MT1-MMP specifically cleaves pro-av, generating a 115-kDa heavy chain with the truncated C terminus and a 25-kDa light chain commencing from the N-terminal Leu(892). PC-cleavable a. and a, but not the PC-resistant alpha(2) integrin subunit are also susceptible to MT1-MMP cleavage. These novel mechanisms involved in the processing of integrin a subunits underscore the significance and complexity of interactions between MT1-MMP and adhesion receptors and suggest that regulation of integrin functionality may be an important role of MT1-MMP in migrating tumor cells.