CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase
CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase
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DOI：
10.1038/sj.onc.1208258
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发表时间：
2005-01-27
期刊：
影响因子：
8
通讯作者：
Seiki, M
中科院分区：
文献类型：
--
作者：
Suenaga, N;Mori, H;Seiki, M
膜型1型基质金属蛋白酶（MT1-MMP）是通过其蛋白水解活性调节细胞周围环境的有效调节剂，并促进肿瘤细胞的迁移、侵袭和增殖。在细胞迁移过程中，MT 1-MMP通过血联蛋白样（HPX）结构域与主要透明质酸受体CD 44 H结合，并定位在迁移前沿。MT1-MMP还负责脱落CD44 H，其支持CD44 H介导的细胞迁移。在这项研究中，我们问MT1-MMP与CD44 H的结合是否是连续脱落的先决条件。HPX结构域的缺失剥夺了MT1-MMP的脱落活性。此外，通过过表达HPX片段破坏CD44 H/MT1-MMP复合物导致对脱落的抑制。因此，复合物中的CD44 H似乎是MT1-MMP脱落的直接底物。有趣的是，MT-MMP家族的其他成员显示不同程度的CD44 H脱落。MT1-MMP和其他MT-MMP之间的结构域交换揭示了HPX结构域结合CD44 H的能力在它们之间是保守的。然而，脱落活性取决于催化结构域而不同。HPX结构域的保守结合能力表明，CD44 H可能作为一个核心分子组装在细胞表面的多个MT-MMP。
Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a potent modulator of pericellular environment through its proteolytic activity and promotes migration, invasion, and proliferation of tumor cells. During cell migration, MT1-MMP binds to CD44H, a major hyaluronan receptor, through the hemopexin-like (HPX) domain and localizes at the migration front. MT1-MMP is also responsible for shedding CD44H, which supports CD44H-mediated cell migration. In this study, we asked whether the binding of MT1-MMP to CD44H is a prerequisite step for the successive shedding. Deletion of the HPX domain deprived MT1-MMP of its shedding activity. Furthermore, disruption of the CD44H/MT1-MMP complex by overexpressing the HPX fragments resulted in inhibition of the shedding. Thus, the CD44H in the complex appears to be the direct substrate of MT1-MMP for shedding. Interestingly, other members of the MT-MMP family showed varied extents of CD44H shedding. Domain swapping between MT1-MMP and other MT-MMPs revealed that the ability of the HPX domains to bind CD44H is conserved among them. However, the shedding activity was different depending on the catalytic domains. The conserved binding ability of the HPX domains suggests that CD44H may act as a core molecule assembling multiple MT-MMPs on the cell surface.