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Ovarian Carcinoma Regulation of Matrix Metalloproteinase-2 and Membrane Type 1 Matrix Metalloproteinase through ß1 Integrin¹

Departments of Obstetrics and Gynecology [S. M. E., D. A. F., A. S. K., L. M. B., M. S. S.] and Cell and Molecular Biology [S. M. E., L. M. B., M. S. S.], Northwestern University Medical School, Chicago, Illinois 60611

Culturing DOV 13 ovarian carcinoma cells on three-dimensional collagen lattice but not on thin-layer collagen induces processing of pro-matrix metalloproteinase (MMP)-2 to a M_r 62,000 form, suggesting that multivalent integrin aggregation may participate in proteinase regulation. To address the role of collagen-binding integrins in this event, we treated DOV 13 cells with soluble ß1 integrin antibodies (clones P4C10 or 21C8) or ß1 integrin antibodies immobilized on latex beads to promote integrin aggregation. Divalent ligation of ß1 integrins with soluble P4C10 antibodies stimulated expression of pro-MMP-2 and its inhibitor, tissue inhibitor of metalloproteinase-2, whereas soluble 21C8 antibodies had no effect. Aggregation of ß1 integrins with immobilized 21C8 or P4C10 antibodies stimulated MMP-dependent pro-MMP-2 activation and accumulation of a M_r 43,000 form of membrane type 1 MMP (MT1-MMP), a cell surface activator of pro-MMP-2, in cell extracts. ß1 integrin-mediated MMP-2 activation required protein synthesis and tyrosine kinase signaling and was reduced by an inhibitor of gene transcription. Treatment of control cells with concanavalin A stimulated MMP-dependent pro-MMP-2 activation and accumulation of M_r 55,000 and 43,000 forms of MT1-MMP in cell extracts. Addition of either the MMP inhibitor GM-6001-X or exogenous tissue inhibitor of metalloproteinase-2 to concanavalin A-treated cells resulted in loss of the M_r 43,000 form of MT1-MMP and accumulation of the M_r 55,000 form of the enzyme in cell extracts, suggesting that the M_r 43,000 form is a product of MMP-dependent M_r 55,000 MT1-MMP proteolysis. Together, these data suggest that ß1 integrin stimulation of pro-MMP-2 activation involves MT1-MMP posttranslational processing and requires multivalent integrin aggregation.

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