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Carcinogenesis Advance Access published online on July 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn159
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impaired tyrosine phosphorylation of membrane-type 1 matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice

Carine Nyalendo1,3, Edith Beaulieu1, Hervé Sartelet2, Marisol Michaud1,3, Nicolas Fontaine1, Denis Gingras1 and Richard Béliveau1,3,*

1 Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, CHU Sainte-Justine
2 Département de Pathologie, CHU Sainte-Justine
3 Centre de Recherches Biomédicales de l'Université du Québec à Montréal

* To whom correspondence should be addressed: Laboratoire de médecine moléculaire Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec (Canada), H3T 1C5 Phone: (514) 345-2366. FAX: (514) 345-2359. E-mail: molmed{at}recherche-ste-justine.qc.ca

Pericellular proteolysis of the extracellular matrix by membrane-type 1 matrix metalloproteinase (MT1-MMP) confers tumor cells with the ability to proliferate within three-dimensional (3D) matrices and sustains tumor growth in mice. In this study, we show that in addition to its matrix-degrading activity, phosphorylation of MT1-MMP on its unique tyrosine residue located within its cytoplasmic sequence (Tyr573) may also participate to these processes. Fibrosarcoma cells expressing a proteolytically active but non phosphorylable mutant of MT1-MMP showed a markedly reduced proliferation rate when embedded within 3D type I collagen matrices, this antiproliferative effect being correlated with arrest in the G0/G1 phase of the cell cycle. Impaired tyrosine phosphorylation of MT1-MMP also inhibits anchorage-independent growth of HT-1080 cells in soft agar as well as their invasion of collagen barriers, two prominent attributes of tumor cells, suggesting a broad inhibitory effect of the MT1-MMP mutant on tumorigenesis. Accordingly, whereas HT-1080 cells formed well vascularized tumors containing tyrosine phosphorylated MT1-MMP, tumor growth was completely abolished by expression of the non phosphorylable MT1-MMP mutant. These findings thus indicate a close cooperation between the matrix-degrading activity of MT1-MMP and tyrosine phosphorylation of its intracellular domain for tumor cell invasion and proliferation and suggest that the targeting of the intracellular signaling pathways leading to tyrosine phosphorylation of MT1-MMP may represent an unexpected alternative strategy for the inhibition of this enzyme.

Supported by a grant from the Canadian Institutes for Health Research to R.B. and D.G.

Received March 24, 2008; revised June 27, 2008; accepted July 2, 2008.


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