Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by matrilysin.
Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs) implicated in normal and pathological processes that require remodelling of the extracellular matrix. In human prostate tissue, matrilysin is synthesized in ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but not in normal glands. Gelatinase B expression is restricted to inflammatory cells. Gelatinase A can be found in both benign and malignant prostate tissue. MMP activities are regulated by their transition from latent to activated forms, as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We investigated whether matrilysin can activate progelatinases A and B in the presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS-PAGE and enzyme activity assays. TIMP-free gelatinase B was also activated by matrilysin. In addition, activation of progelatinase B by matrilysin was demonstrated in the conditioned medium of phorbol ester-treated HT1080 cells, confirming the results obtained in the in vitro experiments. In contrast, matrilysin did not proteolytically cleave gelatinase A-TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Matrilysin did not enhance the autocatalytic conversion of its own proform. The data presented here suggest that matrilysin participates in a proteolytic cascade and can activate gelatinases in the presence of TIMPs.
von Bredow
D C
DC
Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
Cress
A E
AE
Howard
E W
EW
Bowden
G T
GT
Nagle
R B
RB
D017364:Collagenases / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; C099583:promatrilysin; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate