Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells.
The tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase activity required for cell migration/invasion associated with cancer progression and angiogenesis. TIMPs also modulate cell proliferation in vitro and angiogenesis in vivo independent of their matrix metalloproteinase inhibitory activity. Here, we show that TIMP-2 mediates G1 growth arrest in human endothelial ... cells through de novo synthesis of the cyclin-dependent kinase inhibitor p27Kip1. TIMP-2-mediated inhibition of Cdk4 and Cdk2 activity is associated with increased binding of p27Kip1 to these complexes in vivo. Protein-tyrosine phosphatase inhibitors or expression of a dominant negative Shp-1 mutant ablates TIMP-2 induction of p27Kip1. Finally, angiogenic responses to fibroblast growth factor-2 and vascular endothelial growth factor-A in "motheaten viable" Shp-1-deficient mice are resistant to TIMP-2 inhibition, demonstrating that Shp-1 is an important negative regulator of angiogenesis in vivo.
Mesh Terms:
Animals, Blotting, Northern, Blotting, Western, Cell Cycle, Cell Proliferation, Cells, Cultured, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p27, Endothelium, Vascular, G1 Phase, Gene Expression Regulation, Genes, Dominant, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Mice, Transgenic, Microcirculation, Microscopy, Fluorescence, Models, Biological, Mutation, Neovascularization, Physiologic, Phosphorylation, Polymerase Chain Reaction, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, RNA, Small Interfering, Subcellular Fractions, Tissue Inhibitor of Metalloproteinase-2, Transfection, Vascular Endothelial Growth Factor A
Animals, Blotting, Northern, Blotting, Western, Cell Cycle, Cell Proliferation, Cells, Cultured, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p27, Endothelium, Vascular, G1 Phase, Gene Expression Regulation, Genes, Dominant, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Mice, Transgenic, Microcirculation, Microscopy, Fluorescence, Models, Biological, Mutation, Neovascularization, Physiologic, Phosphorylation, Polymerase Chain Reaction, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, RNA, Small Interfering, Subcellular Fractions, Tissue Inhibitor of Metalloproteinase-2, Transfection, Vascular Endothelial Growth Factor A
J. Biol. Chem.
Date: Feb. 10, 2006
PubMed ID: 16326706
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