TNF-alpha employs a protein-tyrosine phosphatase to inhibit activation of hepatocyte growth factor receptor and hepatocyte growth factor-induced endothelial cell proliferation

Masahiro Sugano, Yoshiko Iwasaki, Masako Abe, Toyoki Maeda, Keiko Tsuchida, Naoki Makino

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

TNF-alpha impairs endothelial cell growth and angiogenesis. The anti-angiogenic effects of TNF-alpha have mainly been explained by its modulating vascular endothelial growth factor (VEGF)-specific angiogenic pathway. Hepatocyte growth factor (HGF) also promotes the growth of vascular endothelial cells and the development of new blood vessels through interaction with its specific receptor, c-met. However, it is little known whether TNF-alpha interacts with the HGF system or not. In this study, we examined the effect of TNF-alpha on HGF receptor function. In human umbilical venous endothelial cells (HUVEC), TNF-alpha acutely inhibited the phosphorylation and activation of c-met induced by HGF. The ability of TNF-alpha to inhibit HGF-induced c-met activity was impaired by sodium orthovanadate, suggesting that the inhibitory effect of TNF-alpha was mediated by a protein-tyrosine phosphatase. Treatment of HUVEC with TNF-alpha impairs the ability of HGF to activate MAPK and Akt, and this effect was blocked by SOV. HGF-induced c-met responses specifically associated with endothelial cell proliferation and mitogen-activated protein kinase activation were also inhibited by TNF-alpha, and these were reversed by sodium orthovanadate. HGF-induced SHP-1 (a cytoplasmic protein-tyrosine phosphatase) and pretreatment of HUVEC with TNF-alpha prior to HGF treatment resulted in substantial increase in the amount of SHP-1. These data suggest that TNF-alpha employs a protein-tyrosine phosphatase and may exert its anti-angiogenic function in part by modulating the HGF-specific angiogenic pathway in pathological settings.

Original languageEnglish
Pages (from-to)113-117
Number of pages5
JournalMolecular and cellular biochemistry
Volume322
Issue number1-2
DOIs
Publication statusPublished - 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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