MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway

Jose J. Bravo-Cordero, Raquel Marrero-Diaz, Diego Megías, Laura Genís, Aranzazu García-Grande, Maria A. García, Alicia G. Arroyo, María C. Montoya

Research output: Contribution to journalArticle

166 Scopus citations

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 β1 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.

Original languageEnglish (US)
Pages (from-to)1499-1510
Number of pages12
JournalEMBO Journal
Volume26
Issue number6
DOIs
StatePublished - Mar 21 2007

Keywords

  • MT1-MMP
  • Matrix metalloproteinases
  • Membrane traffic
  • Rab8
  • Tumor invasion

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Bravo-Cordero, J. J., Marrero-Diaz, R., Megías, D., Genís, L., García-Grande, A., García, M. A., Arroyo, A. G., & Montoya, M. C. (2007). MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway. EMBO Journal, 26(6), 1499-1510. https://doi.org/10.1038/sj.emboj.7601606