Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2).
Human tissue inhibitor of metalloproteinases-2 (TIMP-2) has a potent growth-promoting activity for wide range of human, bovine and mouse cells, having an optimal concentration (10 ng/ml, 0.46 nM) that is ten-times lower than that of TIMP-1 (Hayakawa et al. (1992) FEBS Lett. 298, 29). Neither TIMP-1 complexed with progelatinase B nor TIMP-2 complexed with progelatinase A, both of which have full inhibitory activity against active forms of matrix metalloproteinases (MMPs), showed any cell growth-promoting activity. On the contrary, both reductively alkylated TIMPs had no MMP inhibitory activity, but significantly stimulated cell proliferation. These facts clearly indicate that the cell-proliferation. These facts clearly indicate that the cell-proliferating activity of TIMPs is independent of MMP inhibitory activity. We also demonstrated that [3H]thymidine was significantly incorporated into Raji cells, a Burkitt lymphoma cell line, in the presence of either 4 ng/ml of TIMP-1 or 0.1 ng/ml of TIMP-2. Under steady-state conditions at 4 degrees C, high-(Kd = 0.15 nM) and low-(35 nM) affinity binding sites for TIMP-2 were identified on Raji cells with 20,000 and 1.4 x 10(5) sites/cell, respectively. Both high- and low-affinity binding of 125I-TIMP-2 to Raji cells were competitively inhibited by unlabeled TIMP-2 but not by unlabeled TIMP-1, suggesting the presence of receptors for TIMP-2 independent from those for TIMP-1. TIMP-2 seems to be another new TIMP cell-growth factor in serum, besides TIMP-1.
Department of Biochemistry, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.
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Hayakawa
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Yamashita
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Ohuchi
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Shinagawa
D000478:Alkylation; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D006224:Cricetinae; D004261:DNA Replication / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D011506:Proteins / Q000494:pharmacology*; D013268:Stimulation, Chemical; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004792:Enzyme Precursors; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D011506:Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase