TNF-alpha employs a protein-tyrosine phosphatase to inhibit activation of hepatocyte growth factor receptor and hepatocyte growth factor-induced endothelial cell proliferation.
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.
Sugano
Masahiro
M
Human Biology, Department of Health Science, Oita University of Nursing and Health Science, 2944 Megusuno, Oita, 870-1201, Japan. sugano@oita-nhs.ac.jp
Iwasaki
Yoshiko
Y
Abe
Masako
M
Maeda
Toyoki
T
Tsuchida
Keiko
K
Makino
Naoki
N
D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D017027:Protein Tyrosine Phosphatases