breast cancer cells; endocytosis; matrix metalloproteinase; protein-protein interaction; trafficking
Abstract :
[en] MT4-MMP (MMP17) is a glycosylphosphatidyl inositol (GPI)-anchored membrane-type MMP expressed on the cell surface of human breast cancer cells. In triple negative breast cancer cells, MT4-MMP promotes primary tumor growth and lung metastases. Although trafficking and internalization of the transmembrane MT1-MMP have been extensively investigated, little is known about the regulatory mechanisms of the GPI-anchored MT4-MMP. Here, we investigated the fate and cellular trafficking of MT4-MMP by analyzing its homophilic complex interactions, internalization and recycling dynamics compared to an inert form, MT4-MMP-E249A. Oligomeric and dimeric complexes were analyzed by co-transfection of cells with FLAG- or Myc-tagged MT4-MMP by reducing and non-reducing immunoblots and co-immunoprecipitation experiments. The trafficking of MT4-MMP was studied using an antibody feeding assay and confocal microscopy analysis or cell surface protein biotinylation and Western blot analysis. We demonstrate that MT4-MMP forms homophilic complexes at the cell surface, internalizes in early endosomes, and some of the enzyme is either auto-degraded or recycled to the cell surface. Our data indicate that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Although MT4-MMP localizes with caveolin-1, MT4-MMP internalization was not affected by inhibitors of caveolin-1 or clathrin endocytosis pathways but was reduced by cdc42 or RhoA silencing with siRNA. We provide a new mechanistic insight into the regulatory mechanisms of MT4-MMP, which may have implications in the design of novel therapeutic strategies for metastatic breast cancer. This article is protected by copyright. All rights reserved.
Research center :
Laboratory of Tumor & Development Biology
Disciplines :
Oncology
Author, co-author :
Truong, Alice ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Yip, Cassandre ; Université de Liège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
PAYE, Alexandra ; Centre Hospitalier Universitaire de Liège - CHU > Centre d'oncologie
Blacher, Silvia ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Munaut, Carine ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Deroanne, Christophe ; Université de Liège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Noël, Agnès ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Sounni, Nor Eddine ; Université de Liège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Language :
English
Title :
Dynamics of Internalization and Recycling of the Pro-Metastatic Membrane Type 4-Matrix Metalloproteinase (MT4-MMP) in Breast Cancer Cells
Publication date :
February 2016
Journal title :
FEBS Journal
ISSN :
1742-464X
eISSN :
1742-4658
Publisher :
Blackwell Publishing, Oxford, United Kingdom
Volume :
283
Issue :
4
Pages :
704-22
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Fonds Léon Fredericq [BE]
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