Impaired tyrosine phosphorylation of membrane type 1-matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice.
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 G(0)/G(1) 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 co-operation 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.
Nyalendo
Carine
C
Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, CHU Sainte-Justine, 3175 Chemin Côte-Ste-Catherine, Montréal, Québec, Canada.
Beaulieu
Edith
E
Sartelet
Hervé
H
Michaud
Marisol
M
Fontaine
Nicolas
N
Gingras
Denis
D
Béliveau
Richard
R
D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D005354:Fibrosarcoma / Q000473:pathology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D019000:Phosphotyrosine; D051381:Rats; D014443:Tyrosine / Q000378:metabolism*
D019000:Phosphotyrosine; D014443:Tyrosine; D020781:Matrix Metalloproteinase 1