BST-2 Binding MT1-MMP Inhibition Of MMP2 Activity To Prevent Mechanism Of Cell Growth And Migration

MT1-MMP (membrane type1-matrix metalloproteinase) plays important roles in cell growth and tumor invasion via mediating cleavage of MMP2/gelatinase A and a variety of substrates including type I collagen. BST-2(bone marrow stromal cell antigen2) is a membrane tetherin whose expression dramatically reduces the release of a broad range of enveloped viruses including HIV from infected cells. In this study, we provided evidence that both transient and IFN-a induced BST-2could decrease the activity of MMP2via binding to cellular MT1-MMP on its C-terminus and inhibiting its proteolytic activity; and finally block cell growth and migration. Zymography gel and Western-blot experiments demonstrated that BST-2decreased MMP2activity, but no effect on the expression of MMP2and MT1-MMP genes. Confocal and immunoprecipitation data showed that BST-2co-localized and interacted with MTl-MMP. This interaction inhibited the proteolytic enzyme activity of MTl-MMP, and blocked the activation of proMMP2. Experimental results of C-terminus deletion mutant of MTl-MMP showed that activity of MMP2was no change and also no interaction existed between the mutant and BST-2after co-transfection with the mutant and BST-2. It meant that C-terminus of MTl-MMP played a key role in the interaction with BST-2. In addition, cell growth in3-D type I collagen gel lattice and cell migration were all inhibited by BST-2. Taken together, BST-2, as a membrane protein and a tetherin of enveloped viruses, was a novel inhibitor of MT1-MMP and could be considerable as an inhibitor of cancer cell growth and migration on clinic.