The Mr 72,000 (MMP-2; gelatinase A) and Mr 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 Mr 72,000 gelatinase A activates progelatinase B to an Mr 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 Mr 62,000 and Mr 45,000 forms, generated after plasma membrane or organomercurial activation of TIMP-2-free progelatinase A. The Mr 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.

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

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