CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain
CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain
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DOI：
10.1093/emboj/cdf411
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发表时间：
2002-08-01
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：
Mori, H;Tomari, T;Seiki, M
膜型基质金属蛋白酶（MT1-MMP）定位于迁移细胞的前部，在癌症侵袭过程中降解细胞外基质屏障。然而，人们对MT1-MMP在迁移前沿的极化分布是如何调控的知之甚少。在这里，我们证明MT1-MMP通过血凝素样（PEX）结构域与CD44H形成复合物。缺乏PEX结构域的突变体MT1-MMP不能结合CD44H，也不能定位于板足。CD44H的细胞质尾部包含与肌动蛋白细胞骨架相关的界面，对于其在板足的定位很重要。缺乏细胞质尾部的CD44H突变体的过表达也阻止了MT1-MMP在板足的定位。细胞松弛素D对f -肌动蛋白的调节表明，CD44H和MT1-MMP都与肌动蛋白细胞骨架紧密共定位，依赖于CD44H的细胞质尾部。因此，CD44H似乎是将MT1-MMP连接到肌动蛋白细胞骨架上的连接器，并在将MT1-MMP引导到迁移前沿中发挥作用。MT1-MMP的PEX结构域在促进细胞迁移和CD44H脱落中是不可或缺的。
Membrane-type I matrix metalloproteinase (MT1-MMP) localizes at the front of migrating cells and degrades the extracellular matrix barrier during cancer invasion. However, it is poorly understood how the polarized distribution of MT1-MMP at the migration front is regulated. Here, we demonstrate that MT1-MMP forms a complex with CD44H via the hemopexin-like (PEX) domain. A mutant MT1-MMP lacking the PEX domain failed to bind CD44H and did not localize at the lamellipodia. The cytoplasmic tail of CD44H, which comprises interfaces that associate with the actin cytoskeleton, was important for its localization at lamellipodia. Overexpression of a CD44H mutant lacking the cytoplasmic tail also prevented MT1-MMP from localizing at the lamellipodia. Modulation of F-actin with cytochalasin D revealed that both CD44H and MT1-MMP co-localize closely with the actin cytoskeleton, dependent on the cytoplasmic tail of CD44H. Thus, CD44H appears to act as a linker that connects MT1-MMP to the actin cytoskeleton and to play a role in directing MT1-MMP to the migration front. The PEX domain of MT1-MMP was indispensable in promoting cell migration and CD44H shedding.