Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cell

Dong Wan Seo, Hongmei Li, Cheng Kui Qu, Junseo Oh, Young Sik Kim, Tere Diaz, Beiyang Wei, Jeung Whan Han, William G. Stetler-Stevenson

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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 p27 Kip1 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.

Original languageEnglish
Pages (from-to)3711-3721
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number6
DOIs
Publication statusPublished - 2006 Feb 10

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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