Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion
Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion
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DOI：
10.1093/emboj/20.17.4782
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发表时间：
2001-09-03
期刊：
影响因子：
11.4
通讯作者：
Seiki, M
中科院分区：
文献类型：
--
作者：
Itoh, Y;Takamura, A;Seiki, M
MT1-MMP 激活 proMMP-2 被认为是癌细胞侵袭的关键事件。在激活步骤中，TIMP-2 与细胞表面的 MT1-MMP 结合，充当 proMMP-2 的受体。随后，邻近的无 TIMP-2 的 MT1-MMP 激活三元复合物中的 proMMP-2。在这项研究中，我们证明 MT1-MMP 通过血红素结合蛋白样 (PEX) 结构域形成亲同性复合物，该结构域充当保持 MT1-MMP 分子紧密相连以促进 proMMP-2 激活的机制。删除 MT1-MMP 中的 PEX 结构域，或将该结构域与 MT4-MMP 衍生的结构域交换，会消除激活细胞表面 proMMP-2 的能力，而不影响蛋白水解活性。此外，缺乏催化结构域的突变体 MT1-MMP (MT1PEX-F) 的表达可有效抑制全长酶的复合物形成和 proMMP-2 的激活。此外，MT1PEX-F的表达抑制侵袭性人纤维肉瘤HT1080细胞的proMMP-2激活和Matrigel侵袭活性。这些发现阐明了 PEX 结构域的一个新功能：调节细胞表面的 MT1-MMP 活性，从而加速组织中的细胞侵袭性。
Activation of proMMP-2 by MT1-MMP is considered to be a critical event in cancer cell invasion. In the activation step, TIMP-2 bound to MT1-MMP on the cell surface acts as a receptor for proMMP-2. Subsequently, adjacent TIMP-2-free MT1-MMP activates the proMMP-2 in the ternary complex. In this study, we demonstrate that MT1-MMP forms a homophilic complex through the hemopexin-like (PEX) domain that acts as a mechanism to keep MT1-MMP molecules close together to facilitate proMMP-2 activation. Deletion of the PEX domain in MT1-MMP, or swapping the domain with the one derived from MT4-MMP, abolished the ability to activate proMMP-2 on the cell surface without affecting the proteolytic activities. In addition, expression of the mutant MT1-MMP lacking the catalytic domain (MT1PEX-F) efficiently inhibited complex formation of the full-length enzymes and activation of proMMP-2. Furthermore, expression of MT1PEX-F inhibited proMMP-2 activation and Matrigel invasion activity of invasive human fibrosarcoma HT1080 cells. These findings elucidate a new function of the PEX domain: regulating MT1-MMP activity on the cell surface, which accelerates cellular invasiveness in the tissue.