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Tyrosine Phosphorylation Mediates ConA-induced Membrane Type 1-Matrix Metalloproteinase Expression and Matrix Metalloproteinase-2 Activation in MDA-MB-231 Human Breast Carcinoma Cells¹

Departments of Cell Biology [M. Y., E. T. B., S. C. M., E. W. T.] and Orthopedic Surgery [E. W. T.] and Lombardi Cancer Center [M. Y., E. T. B., J. S., S. C. M., E. W. T.], Georgetown University Medical Center, Washington DC 20007; Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Ishikawa 920, Japan [H. S.]; and Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108, Japan [M. S.]

ConA-induced cell surface activation of pro-matrix metalloproteinase-2 (pro-MMP-2) by MDA-MB-231 human breast cancer cells is apparently mediated by up-regulation of membrane type 1 MMP (MT1-MMP) through transcriptional and posttranscriptional mechanisms. Here, we have explored the respective roles of cell surface clustering and protein tyrosine phosphorylation in the ConA-induction effects. Treatment with succinyl-ConA, a variant lacking significant clusterability, partially stimulated MT1-MMP mRNA and protein levels but did not induce MMP-2 activation, suggesting that clustering contributes to the transcriptional regulation by ConA but appears to be critical for the nontranscriptional component. We further found that genistein, an inhibitor of tyrosine phosphorylation, blocked ConA-induced pro-MMP-2 activation and ConA-induced MT1-MMP mRNA level in a dose-dependent manner, implicating tyrosine phosphorylation in the transcriptional aspect. This was confirmed by the dose-dependent promotion of pro-MMP-2 activation by sodium orthovanadate in the presence of suboptimal concentrations of ConA (7.5 µg/ml), with optimal effects seen at 25 µg/ml orthovanadate. Genistein did not inhibit the ConA potentiation of MMP-2 activation in MCF-7 cells, in which transfected MT1-MMP is driven by a heterologous promoter, supporting the major implication of phosphotyrosine in the transcriptional component of ConA regulation. These data describe a major signaling event upstream of MT1-MMP induction by ConA and set the stage for further analysis of the nontranscriptional component.

¹ This work was supported in part by United States Public Health Service Grants RO1 CA61344 (to E. W. T.) and RO1 CA61273 (to S. C. M.) and by the Lombardi Cancer Center Microscopy/Imaging and Synthesis/Sequencing Shared Resources Grant IP30 CA51008.

² Present address and to whom requests for reprints should be addressed, at VBCRC Breast Cancer Research Unit, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Melbourne 3065, Australia. Phone: 61-3-9288-2480; Fax: 61-3-9416-2676; E-mail: rik@ariel.its.unimelb.edu.au.

Received 7/31/97. Accepted 10/10/97.

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