TY - JOUR
T1 - MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway
AU - Bravo-Cordero, Jose J.
AU - Marrero-Diaz, Raquel
AU - Megías, Diego
AU - Genís, Laura
AU - García-Grande, Aranzazu
AU - García, Maria A.
AU - Arroyo, Alicia G.
AU - Montoya, María C.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/3/21
Y1 - 2007/3/21
N2 - 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.
AB - 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.
KW - MT1-MMP
KW - Matrix metalloproteinases
KW - Membrane traffic
KW - Rab8
KW - Tumor invasion
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U2 - 10.1038/sj.emboj.7601606
DO - 10.1038/sj.emboj.7601606
M3 - Article
C2 - 17332756
AN - SCOPUS:33947597433
VL - 26
SP - 1499
EP - 1510
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 6
ER -