Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210097, PR China.
J Cell Biochem. 2012 Mar;113(3):1013-21. doi: 10.1002/jcb.23433.
MT1-MMP (membrane type 1-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 antigen 2) 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-α induced BST-2 could decrease the activity of MMP2 via 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-2 decreased MMP2 activity, but no effect on the expression of MMP2 and MT1-MMP genes. Confocal and immunoprecipitation data showed that BST-2 co-localized and interacted with MT1-MMP. This interaction inhibited the proteolytic enzyme activity of MT1-MMP, and blocked the activation of proMMP2. Experimental results of C-terminus deletion mutant of MT1-MMP showed that activity of MMP2 was no change and also no interaction existed between the mutant and BST-2 after co-transfection with the mutant and BST-2. It meant that C-terminus of MT1-MMP played a key role in the interaction with BST-2. In addition, cell growth in 3D 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.
MT1-MMP（膜型 1 基质金属蛋白酶）通过介导 MMP2/明胶酶 A 和包括 I 型胶原在内的多种底物的裂解，在细胞生长和肿瘤侵袭中发挥重要作用。BST-2（骨髓基质细胞抗原 2）是一种膜结合蛋白 tetherin，其表达显著降低了包括 HIV 在内的多种包膜病毒从受感染细胞中的释放。在本研究中，我们提供了证据表明，瞬时表达和 IFN-α诱导的 BST-2 可以通过与细胞表面的 MT1-MMP 的 C 端结合并抑制其蛋白水解活性来降低 MMP2 的活性；最终阻断细胞生长和迁移。明胶酶谱和 Western blot 实验表明，BST-2 降低了 MMP2 的活性，但对 MMP2 和 MT1-MMP 基因的表达没有影响。共聚焦和免疫沉淀数据显示，BST-2 与 MT1-MMP 共定位并相互作用。这种相互作用抑制了 MT1-MMP 的蛋白水解酶活性，并阻断了 proMMP2 的激活。MT1-MMP C 端缺失突变体的实验结果表明，MMP2 的活性没有变化，并且突变体与 BST-2 共转染后，突变体与 BST-2 之间也不存在相互作用。这意味着 MT1-MMP 的 C 端在与 BST-2 的相互作用中起着关键作用。此外，BST-2 抑制了 3D 型 I 胶原凝胶格子中的细胞生长和细胞迁移。综上所述，BST-2 作为一种包膜病毒的膜蛋白和 tetherin，是 MT1-MMP 的新型抑制剂，在临床上可能是抑制癌细胞生长和迁移的有前途的抑制剂。
