matrix metalloproteinase; trafficking; breast cancer cells; endocytosis; protein-protein interaction
Abstract :
[en] MT4-MMP (MMP17) is a glycosyl-phosphatidyl inositol-anchored membrane-type matrix metalloproteinase expressed at the cell surface of human breast cancer cells. In triple negative breast cancer, MT4-MMP promotes primary tumor growth and lung metastases. Recently, we demonstrated that EGFR activation and signaling are enhanced by MT4-MMP in a non-proteolytic dependent manner. While trafficking and internalization of EGFR was extensively investigated, little is known about MT4-MMP. Here, we investigated the dimerization, internalization and recycling dynamics of MT4-MMP and its mutated inactive form MT4-MMP-E249A. We demonstrate that MT4-MMP forms dimers and oligomers at the cell surface, a process that was not inhibited neither by broad-spectrum MMP inhibitors (GM6001 and BB94) nor TIMP-2. MT4-MMP is internalized in early endosomes from 10 minutes to 60 minutes. Once internalized, some amount of MT4-MMP is auto-degraded, whereas its inert form E249A was found intact. Large part of the internalized enzyme was recycled intact at the cell surface. By exploring its endocytosis, we found that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Overall, we provided a new mechanistic insight on the regulatory mechanisms of MT4-MMP in human breast cancer cells. We also, highlighted unique features of MT4-MMP among membrane-associated MMPs, which may be useful for the design of novel therapeutic strategies for metastatic breast cancer.
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 ; Centre Hospitalier Universitaire de Liège - CHU > Centre d'oncologie
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 :
26 October 2015
Number of pages :
A0
Event name :
Organelle Crosstalk in Membrane Dynamics and Cell Signalling