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Volume 272, Number 41, Issue of October 10, 1997 pp. 25628-25635
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Dog Mast Cell -Chymase Activates Progelatinase B by Cleaving the Phe⁸⁸-Gln⁸⁹ and Phe⁹¹-Glu⁹² Bonds of the Catalytic Domain

(Received for publication, February 4, 1997, and in revised form, August 4, 1997)

Kenneth C. Fang ^§ , Wilfred W. Raymond , John L. Blount and George H. Caughey ^§

From the  Cardiovascular Research Institute and ^§ Department of Medicine, University of California, San Francisco, California 94143-0911

In prior work we showed that a metallogelatinase is secreted from dog mastocytoma cells and directly activated by exocytosed mast cell -chymase. The current work identifies the protease as a canine homologue of progelatinase B (92-kDa gelatinase, MMP-9), determines the sites cleaved by -chymase, and explores the regulation of gelatinase expression in mastocytoma cells. To obtain a cDNA encoding the complete sequence of mastocytoma gelatinase B, a 2.3-kilobase clone encoding progelatinase was isolated from a BR mastocytoma library. The sequenced cDNA predicts a 704-amino acid protein 80% identical to human progelatinase B. Regions thought to be critical for active site latency, such as the Cys-containing propeptide sequence, PRCGVPD, and the catalytic domain sequence, HEFGHALGLDHSS, are entirely conserved. Cleavage of progelatinase B by purified dog -chymase yielded an ~84-kDa product that contained two NH₂-terminal amino acid sequences, QTFEGDLKXH and EGDLKXHHND, which correspond to residues 89-98 and 92-101 of the cDNA predicted sequence, respectively. Thus, -chymase cleaves the catalytic domain of gelatinase B at the Phe⁸⁸-Gln⁸⁹ and Phe⁹¹-Glu⁹² bonds. Like BR cells, the C2 line of dog mastocytoma cells constitutively secrete progelatinase B which is activated by -chymase. By contrast, non-chymase-producing C1 cells secrete a gelatinase B (which remains in its proform) only in response to 12-O-tetradecanoylphorbol-13-acetate. Whereas 12-O-tetradecanoylphorbol-13-acetate stimulation of BR cells produced a ~15-fold increase in gelatinase B mRNA expression, dexamethasone down-regulated its expression by ~5-fold. Thus, extracellular stimuli may regulate the amount of mast cell progelatinase B expressed by mast cells. These data further support a role for mast cell -chymase in tissue remodeling involving gelatinase B-mediated degradation of matrix proteins.

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