Article
- The EMBO Journal (2007) 26, 1499 - 1510
- doi:10.1038/sj.emboj.7601606
Published online: 1 March 2007
Subject Categories:
MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway
Jose J Bravo-Cordero1, Raquel Marrero-Diaz1, Diego Megías1, Laura Genís2, Aranzazu García-Grande1, Maria A García1, Alicia G Arroyo2 and María C Montoya1
- Confocal Microscopy and Cytometry Unit, Biotechnology Programme, Spanish Nacional Cancer Research Center (CNIO), Madrid, Spain
- Matrix metalloproteinases Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Correspondence to:
María C Montoya, Confocal Microscopy and Cytometry Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), C/Melchor Fernández Almagro 3, Madrid E-28029, Spain. Tel.: +34 91 7328012; Fax: +34 91 2246980; E-mail: mmontoya@cnio.es
Received 26 June 2006; Accepted 24 January 2007
Abstract
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 
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.
Keywords:
- matrix metalloproteinases,
- membrane traffic,
- MT1-MMP,
- Rab8,
- tumor invasion
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