TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism.
Tissue inhibitors of metalloproteinases (TIMPs) suppress matrix metalloproteinase (MMP) activity critical for extracellular matrix turnover associated with both physiologic and pathologic tissue remodeling. We demonstrate here that TIMP-2 abrogates angiogenic factor-induced endothelial cell proliferation in vitro and angiogenesis in vivo independent of MMP inhibition. These effects require alpha 3 beta ... 1 integrin-mediated binding of TIMP-2 to endothelial cells. Further, TIMP-2 induces a decrease in total protein tyrosine phosphatase (PTP) activity associated with beta1 integrin subunits as well as dissociation of the phosphatase SHP-1 from beta1. TIMP-2 treatment also results in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR-1 and KDR. Our findings establish an unexpected, MMP-independent mechanism for TIMP-2 inhibition of endothelial cell proliferation in vitro and reveal an important component of the antiangiogenic effect of TIMP2 in vivo.
Mesh Terms:
Angiogenesis Inhibitors, Animals, Binding, Competitive, Cell Division, Cells, Cultured, Dose-Response Relationship, Drug, Embryo, Mammalian, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Inhibitors, Fibroblast Growth Factor 2, Fibroblasts, Humans, Integrin alpha3beta1, Intracellular Signaling Peptides and Proteins, Matrix Metalloproteinases, Mice, Neovascularization, Physiologic, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Recombinant Proteins, Tissue Inhibitor of Metalloproteinase-2, Vanadates, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Inhibitors, Animals, Binding, Competitive, Cell Division, Cells, Cultured, Dose-Response Relationship, Drug, Embryo, Mammalian, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Inhibitors, Fibroblast Growth Factor 2, Fibroblasts, Humans, Integrin alpha3beta1, Intracellular Signaling Peptides and Proteins, Matrix Metalloproteinases, Mice, Neovascularization, Physiologic, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Recombinant Proteins, Tissue Inhibitor of Metalloproteinase-2, Vanadates, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2
Cell
Date: Jul. 25, 2003
PubMed ID: 12887919
View in: Pubmed Google Scholar
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