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

EMBO J. 2007 Mar 21;26(6):1499-510. doi: 10.1038/sj.emboj.7601606. Epub 2007 Mar 1.


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 beta1 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / physiology
  • Collagen / metabolism
  • Exocytosis / physiology*
  • Female
  • Genetic Vectors
  • Humans
  • Integrin beta1 / metabolism
  • Matrix Metalloproteinase 14 / metabolism*
  • Microscopy, Fluorescence
  • Microspheres
  • Models, Biological
  • Neoplasm Invasiveness / physiopathology*
  • Photobleaching
  • Protein Transport / physiology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Transport Vesicles / physiology
  • rab GTP-Binding Proteins / metabolism*


  • Integrin beta1
  • RNA, Small Interfering
  • Collagen
  • MMP14 protein, human
  • Matrix Metalloproteinase 14
  • RAB8A protein, human
  • rab GTP-Binding Proteins