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

103 Citations (Scopus)

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

Fingerprint

Protein Tyrosine Phosphatases
Endothelial cells
Cell proliferation
Cell growth
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Endothelial Cells
Tumor Necrosis Factor-alpha
Chemical activation
Cell Proliferation
Vanadates
Human Umbilical Vein Endothelial Cells
Phosphorylation
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Sodium
Pathologic Neovascularization
Mitogen-Activated Protein Kinases
Phosphoric Monoester Hydrolases
Signal transduction
Tyrosine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. / Guo, Dan Qun; Wu, Li Wha; Dunbar, James D.; Ozes, Osman Nidai; Mayo, Lindsey D.; Kessler, Kelly M.; Gustin, Jason A.; Baerwald, Melinda R.; Jaffe, Eric A.; Warren, Robert S.; Donner, David B.

In: Journal of Biological Chemistry, Vol. 275, No. 15, 14.04.2000, p. 11216-11221.

Research output: Contribution to journalArticle

Guo, Dan Qun ; Wu, Li Wha ; Dunbar, James D. ; Ozes, Osman Nidai ; Mayo, Lindsey D. ; Kessler, Kelly M. ; Gustin, Jason A. ; Baerwald, Melinda R. ; Jaffe, Eric A. ; Warren, Robert S. ; Donner, David B. / Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 15. pp. 11216-11221.
@article{7f7440c8a36240078a759f209ef80872,
title = "Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation",
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.",
author = "Guo, {Dan Qun} and Wu, {Li Wha} and Dunbar, {James D.} and Ozes, {Osman Nidai} and Mayo, {Lindsey D.} and Kessler, {Kelly M.} and Gustin, {Jason A.} and Baerwald, {Melinda R.} and Jaffe, {Eric A.} and Warren, {Robert S.} and Donner, {David B.}",
year = "2000",
month = "4",
day = "14",
doi = "10.1074/jbc.275.15.11216",
language = "English (US)",
volume = "275",
pages = "11216--11221",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "15",

}

TY - JOUR

T1 - Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation

AU - Guo, Dan Qun

AU - Wu, Li Wha

AU - Dunbar, James D.

AU - Ozes, Osman Nidai

AU - Mayo, Lindsey D.

AU - Kessler, Kelly M.

AU - Gustin, Jason A.

AU - Baerwald, Melinda R.

AU - Jaffe, Eric A.

AU - Warren, Robert S.

AU - Donner, David B.

PY - 2000/4/14

Y1 - 2000/4/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0034646704&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034646704&partnerID=8YFLogxK

U2 - 10.1074/jbc.275.15.11216

DO - 10.1074/jbc.275.15.11216

M3 - Article

C2 - 10753929

AN - SCOPUS:0034646704

VL - 275

SP - 11216

EP - 11221

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 15

ER -