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Activation of Progelatinase B (MMP-9) by Gelatinase A (MMP-2)¹

Departments of Pathology [R. F., M. T, D. P.] and Chemistry [S. M.], Wayne State University, Detroit, Michigan 48201

The M_r 72,000 (MMP-2; gelatinase A) and M_r 92,000 (MMP-9; gelatinase B) gelatinases are two members of the family of matrix metalioproteinases (MMPs). These proteinases are thought to play a critical role in tumor cell invasion and are frequently coexpressed in human cancers. Gelatinases are secreted in a latent inactive form, and their conversion to the active species can be accomplished by other proteolytic enzymes, including other MMPs. We report herein that organomercurial or plasma membrane-activated M_r 72,000 gelatinase A activates progelatinase B to an M_r 82,000 active form in a process inhibited by tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Progelatinase B activation was accomplished by the two active species of gelatinase A, the M_r 62,000 and M_r 45,000 forms, generated after plasma membrane or organomercurial activation of TIMP-2-free progelatinase A. The M_r 45,000 species of gelatinase A lacks both the NH₂-terminal profragment and the COOH-terminal domain known to play a role in plasma membrane activation and the regulation of TIMP-2 inhibition. These results suggest a novel mechanism of activation of progelatinase B mediated by gelatinase A species that may be localized in the surface of tumor cells and enhance matrix degradation during cancer metastasis.

¹ This work was supported in part by Department of Defense Grant DAMD17-94-J-4356 (to R. F.).

² To whom requests for reprints should be addressed, at Department of Pathology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201.

Received 1/13/95. Accepted 4/17/95.

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