The role of phosphatidylinositol 3-kinase in vascular endothelial growth factor signaling

J Biol Chem. 1999 Apr 9;274(15):10002-7. doi: 10.1074/jbc.274.15.10002.


Vascular endothelial growth factor (VEGF) receptor Flk-1/KDR in endothelial cells is activated during vasculogenesis and angiogenesis upon ligand-receptor interaction. Activated Flk-1/KDR has been shown to recruit Src homology 2 domain-containing signaling molecules that are known to serve as links to the activation of the mitogen-activated protein (MAP) kinase signaling pathway. To define the functional significance of phosphatidylinositol (PI) 3-kinase in VEGF signaling, we have examined its role in human umbilical vein endothelial cell (HUVEC) cycle progression. We show herein that p85, the regulatory subunit of PI 3-kinase, is constitutively associated with Flk-1/KDR. The treatment of HUVECs with VEGF promoted tyrosine autophosphorylation of Flk-1/KDR and also induced phosphorylation of p85. This was followed by an increase in the PI 3-kinase activity, which was sensitive to wortmannin, a potent PI 3-kinase inhibitor. VEGF also induced a striking activation of MAP kinase in a time-dependent manner. Inhibition studies with both a dominant-negative p85 mutant and the PI 3-kinase inhibitor, wortmannin, were employed to show for the first time that VEGF-stimulated PI 3-kinase modulates MAP kinase activation and nuclear events such as transcription from c-fos promoter and entry into the synthesis (S)-phase. Our data demonstrate the importance of PI 3-kinase as a necessary signaling component of VEGF-mediated cell cycle progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • Endothelial Growth Factors / physiology*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Lymphokines / physiology*
  • Nuclear Proteins / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Serum Response Factor
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcriptional Activation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Wortmannin


  • Androstadienes
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Flavonoids
  • Lymphokines
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Growth Factor
  • Serum Response Factor
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Wortmannin