MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway
MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway
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DOI：
10.1038/sj.emboj.7601606
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发表时间：
2007-03-21
期刊：
影响因子：
11.4
通讯作者：
Montoya, Maria C.
中科院分区：
文献类型：
--
作者：
Bravo-Cordero, Jose J.;Marrero-Diaz, Raquel;Montoya, Maria C.
基质金属蛋白酶1（MT 1-MMP）是肿瘤细胞侵袭机制中最关键的因子之一。亚细胞定位于侵袭性结构是MT 1-MMP促侵袭活性的关键。然而，驱动这种两极化分布的机制仍然不清楚。我们现在报告，极化胞吐MT 1-MMP发生在MDA-MB-231腺癌细胞迁移到胶原蛋白I型三维矩阵。MT 1-MMP的极化运输由β 1-整合素介导的与胶原的粘附触发，并且是侵入性结构处的蛋白酶定位所需的。MT 1-MMP在VSV-G/Rab 8阳性囊泡内的定位，而不是在侵袭性细胞的Rab 11/Tf/TfRc阳性隔室中，表明参与了胞吐交通途径。此外，组成型活性Rab 8突变体诱导MT 1-MMP胞吐交通，胶原降解和入侵，而Rab 8-而不是Rab 11-敲低抑制这些过程。总之，这些数据揭示了一种新的途径MT 1-MMP重新分布到侵入性结构，胞吐囊泡运输，这是至关重要的，它的作用，肿瘤细胞的侵袭性。从机制上讲，MT 1-MMP向侵袭性结构的递送及其促侵袭活性受Rab 8 GT3调节。
MT1-matrix metalloproteinase (MT1-MMP) is one of the most critical factors in the invasion machinery of tumor cells. Subcellular localization to invasive structures is key for MT1-MMP proinvasive activity. However, the mechanism driving this polarized distribution remains obscure. We now report that polarized exocytosis of MT1-MMP occurs during MDA-MB-231 adenocarcinoma cell migration into collagen type I three-dimensional matrices. Polarized trafficking of MT1-MMP is triggered by beta 1-integrin-mediated adhesion to collagen, and is required for protease localization at invasive structures. Localization of MT1-MMP within VSV-G/Rab8-positive vesicles, but not in Rab11/Tf/TfRc-positive compartment in invasive cells, suggests the involvement of the exocytic traffic pathway. Furthermore, constitutively active Rab8 mutants induce MT1-MMP exocytic traffic, collagen degradation and invasion, whereas Rab8- but not Rab11-knockdown inhibited these processes. Altogether, these data reveal a novel pathway of MT1-MMP redistribution to invasive structures, exocytic vesicle trafficking, which is crucial for its role in tumor cell invasiveness. Mechanistically, MT1-MMP delivery to invasive structures, and therefore its proinvasive activity, is regulated by Rab8 GTPase.