Molecular and Cellular Biochemistry

, Volume 322, Issue 1, 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

DOI: 10.1007/s11010-008-9946-7

Cite this article as:
Sugano, M., Iwasaki, Y., Abe, M. et al. Mol Cell Biochem (2009) 322: 113. doi:10.1007/s11010-008-9946-7

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-alphaHepatocyte growth factor receptorProtein tyrosine phosphataseEndothelial 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