Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation

Li Wha Wu, Lindsey Mayo, James D. Dunbar, Kelly M. Kessler, Melinda R. Baerwald, Eric A. Jaffe, Dongfang Wang, Robert S. Warren, David B. Donner

Research output: Contribution to journalArticle

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Abstract

This study was initiated to identify signaling proteins used by the receptors for vascular endothelial cell growth factor KDR/Flk1, and Flt1. Two-hybrid cloning and immunoprecipitation from human umbilical vein endothelial cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase Cγ (PLCγ). Neither placental growth factor, which activates Flt1, epidermal growth factor (EGF), or fibroblast growth factor (FGF) induced tyrosine phosphorylation of PLCγ, indicating that KDR is uniquely important to PLCγ activation in HUVEC. By signaling through KDR, VEGF promoted the tyrosine phosphorylation of focal adhesion kinase, induced activation of Akt, protein kinase Cε (PKCε), mitogen- activated protein kinase (MAPK), and promoted thymidine incorporation into DNA. VEGF activates PLCγ, PKCε, and phosphatidylinositol 3-kinase independently of one another. MEK, PLCγ, and to a lesser extent PKC, are in the pathway through which KDR activates MAPK. PLCγ or PKC inhibitors did not affect FGF- or EGF-mediated MAPK activation. MAPK/ERK kinase inhibition diminished VEGF., FGF-, and EGF-promoted thymidine incorporation into DNA. However, blockade of PKC diminished thymidine incorporation into DNA induced by VEGF but not FGF or EGF. Signaling through KDR/Flk1 activates signaling pathways not utilized by other mitogens to induce proliferation of HUVEC.

Original languageEnglish
Pages (from-to)5096-5103
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number7
DOIs
StatePublished - Feb 18 2000

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Vascular Endothelial Growth Factor Receptor
Endothelial cells
Cell proliferation
Type C Phospholipases
Mitogens
Fibroblast Growth Factors
Endothelial Cells
Protein Kinase C
Cell Proliferation
Mitogen-Activated Protein Kinases
Epidermal Growth Factor
Vascular Endothelial Growth Factor A
Phosphorylation
Human Umbilical Vein Endothelial Cells
Thymidine
Tyrosine
Chemical activation
Mitogen-Activated Protein Kinase Kinases
DNA
Phosphatidylinositol 3-Kinase

ASJC Scopus subject areas

  • Biochemistry

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Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. / Wu, Li Wha; Mayo, Lindsey; Dunbar, James D.; Kessler, Kelly M.; Baerwald, Melinda R.; Jaffe, Eric A.; Wang, Dongfang; Warren, Robert S.; Donner, David B.

In: Journal of Biological Chemistry, Vol. 275, No. 7, 18.02.2000, p. 5096-5103.

Research output: Contribution to journalArticle

Wu, Li Wha ; Mayo, Lindsey ; Dunbar, James D. ; Kessler, Kelly M. ; Baerwald, Melinda R. ; Jaffe, Eric A. ; Wang, Dongfang ; Warren, Robert S. ; Donner, David B. / Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 7. pp. 5096-5103.
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