Molecular and Cellular Biochemistry

, Volume 322, Issue 1–2, pp 113–117

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
Article

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.

Keywords

TNF-alpha Hepatocyte growth factor receptor Protein tyrosine phosphatase Endothelial cells 

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Masahiro Sugano
    • 1
  • Yoshiko Iwasaki
    • 1
  • Masako Abe
    • 1
  • Toyoki Maeda
    • 2
  • Keiko Tsuchida
    • 2
  • Naoki Makino
    • 2
  1. 1.Human Biology, Department of Health ScienceOita University of Nursing and Health ScienceOitaJapan
  2. 2.Department of Molecular and Cellular Biology, Division of Molecular and Clinical GerontologyMedical Institute of Bioregulation, Kyushu UniversityBeppuJapan

Personalised recommendations