An Alternative Processing of Integrin αv Subunit in Tumor Cells by Membrane Type-1 Matrix Metalloproteinase*

Membrane type-1 matrix metalloproteinase (MT1-MMP) and αvβ3 integrin are both essential to cell invasion. Maturation of integrin pro-αvchain (pro-αv) involves its cleavage by proprotein convertases (PC) to form the disulfide-bonded 125-kDa heavy and 25-kDa light α chains. Our report presents evidence of an alternative pathway of pro-αv processing involving MT1-MMP. In breast carcinoma MCF7 cells deficient in MT1-MMP, pro-αv is processed by a conventional furin-like PC, and the mature αv integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp891. In contrast, in cells co-expressing αvβ3 and MT1-MMP, MT1-MMP functions as an integrin convertase. MT1-MMP specifically cleaves pro-αv, generating a 115-kDa heavy chain with the truncated C terminus and a 25-kDa light chain commencing from the N-terminal Leu892. PC-cleavable α3 and α5 but not the PC-resistant α2 integrin subunit are also susceptible to MT1-MMP cleavage. These novel mechanisms involved in the processing of integrin α 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.

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