Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation

Dan Qun Guo, Li Wha Wu, James D. Dunbar, Osman Nidai Ozes, Lindsey D. Mayo, Kelly M. Kessler, Jason A. Gustin, Melinda R. Baerwald, Eric A. Jaffe, Robert S. Warren, David B. Donner

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Vascular endothelial cell growth factor (VEGF) binds to and promotes the activation of one of its receptors, KDR. Once activated, KDR induces the tyrosine phosphorylation of cytoplasmic signaling proteins that are important to endothelial cell proliferation. In human umbilical vein endothelial cells (HUVECs), tumor necrosis factor (TNF) inhibits the phosphorylation and activation of KDR. The ability of TNF to diminish VEGF-stimulated KDR activity was impaired by sodium orthovanadate, suggesting that the inhibitory activity of TNF was mediated by a protein-tyrosine phosphatase. KDR-initiated responses specifically associated with endothelial cell proliferation, mitogen-activated protein kinase activation and DNA synthesis, were also inhibited by TNF, and this was reversed by sodium orthovanadate. Stimulation of HUVECs with TNF induced association of the SHP-1 protein-tyrosine phosphatase with KDR, identifying this phosphatase as a candidate negative regulator of VEGF signal transduction. Heterologous receptor inactivation mediated by a protein-tyrosine phosphatase provides insight into how TNF may inhibit endothelial cell proliferative responses and modulate angiogenesis in pathological settings.

Original languageEnglish (US)
Pages (from-to)11216-11221
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number15
DOIs
StatePublished - Apr 14 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Guo, D. Q., Wu, L. W., Dunbar, J. D., Ozes, O. N., Mayo, L. D., Kessler, K. M., Gustin, J. A., Baerwald, M. R., Jaffe, E. A., Warren, R. S., & Donner, D. B. (2000). Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. Journal of Biological Chemistry, 275(15), 11216-11221. https://doi.org/10.1074/jbc.275.15.11216