Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity.
Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity.
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DOI：
10.1083/jcb.200108112
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发表时间：
2001-12-24
期刊：
影响因子：
--
通讯作者：
Seiki M
中科院分区：
文献类型：
--
作者：
Uekita T;Itoh Y;Yana I;Ohno H;Seiki M
1 型膜基质金属蛋白酶 (MT1-MMP) 是一种整合膜蛋白酶，可降解细胞周围的细胞外基质 (ECM)，并在许多迁移细胞（包括侵袭性癌细胞）中表达。 MT1-MMP 已被证明定位于迁移边缘并促进细胞迁移；然而，目前尚不清楚酶在迁移过程中是如何受到调节的。在这里，我们报告 MT1-MMP 从表面内化，并且该事件取决于其细胞质尾部的序列。双亮氨酸（Leu571-572 和 Leu578-579）和酪氨酸 573 残基对于内化很重要，并且接头蛋白 2 的 μ2 亚基（用于膜蛋白内化的网格蛋白包被凹坑的一个组成部分）被发现与 LLY573 序列结合。 MT1-MMP 主要在粘附边缘内化，并被发现与网格蛋白包被的囊泡共定位。干扰内化的突变导致酶在粘附边缘积聚，但净蛋白水解活性并未受到太大影响。有趣的是，尽管 MT1-MMP 的表达增强了细胞迁移和侵袭，但内化缺陷突变体却未能促进这两种活性。这些数据表明，MT1-MMP 在迁移边缘通过内化进行的动态周转对于细胞迁移和侵袭过程中酶的正常功能非常重要。
Membrane-type 1 matrix metalloproteinase (MT1-MMP) is an integral membrane proteinase that degrades the pericellular extracellular matrix (ECM) and is expressed in many migratory cells, including invasive cancer cells. MT1-MMP has been shown to localize at the migration edge and to promote cell migration; however, it is not clear how the enzyme is regulated during the migration process. Here, we report that MT1-MMP is internalized from the surface and that this event depends on the sequence of its cytoplasmic tail. Di-leucine (Leu571–572 and Leu578–579) and tyrosine573 residues are important for the internalization, and the μ2 subunit of adaptor protein 2, a component of clathrin-coated pits for membrane protein internalization, was found to bind to the LLY573 sequence. MT1-MMP was internalized predominantly at the adherent edge and was found to colocalize with clathrin-coated vesicles. The mutations that disturb internalization caused accumulation of the enzyme at the adherent edge, though the net proteolytic activity was not affected much. Interestingly, whereas expression of MT1-MMP enhances cell migration and invasion, the internalization-defective mutants failed to promote either activity. These data indicate that dynamic turnover of MT1-MMP at the migration edge by internalization is important for proper enzyme function during cell migration and invasion.
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影响因子：
7.8
作者：
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通讯作者：
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