Document Detail

Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells.
MedLine Citation:
PMID:  16326706     Owner:  NLM     Status:  MEDLINE    
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.
Dong-Wan Seo; Hongmei Li; Cheng-Kui Qu; Junseo Oh; Young-Sik Kim; Tere Diaz; Beiyang Wei; Jeung-Whan Han; William G Stetler-Stevenson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2005-12-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-07     Completed Date:  2006-04-11     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3711-21     Citation Subset:  IM    
Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-1500, USA.
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MeSH Terms
Blotting, Northern
Blotting, Western
Cell Cycle
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase 2 / metabolism
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Endothelium, Vascular / cytology*
G1 Phase
Gene Expression Regulation*
Genes, Dominant
Intracellular Signaling Peptides and Proteins / metabolism,  physiology*
Mice, Transgenic
Microcirculation / enzymology*
Microscopy, Fluorescence
Models, Biological
Neovascularization, Physiologic*
Polymerase Chain Reaction
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases / metabolism,  physiology*
RNA, Small Interfering / metabolism
Subcellular Fractions / metabolism
Tissue Inhibitor of Metalloproteinase-2 / biosynthesis*
Vascular Endothelial Growth Factor A / metabolism
Grant Support
Z01 SC009179-17/SC/NCI NIH HHS
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/RNA, Small Interfering; 0/Vascular Endothelial Growth Factor A; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC Kinase 2; EC Kinase 4; EC protein, human; EC Tyrosine Phosphatase, Non-Receptor Type 6; EC Tyrosine Phosphatases; EC protein, mouse

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