VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase

Exp Cell Res. 2001 Feb 1;263(1):173-82. doi: 10.1006/excr.2000.5102.

Abstract

Vascular endothelial growth factor (VEGF)-A stimulates formation of new blood vessels (angiogenesis). This process includes migration of endothelial cells from the preexisting vessel toward the source of the growth factor. We show that VEGF-A-induced migration of porcine aortic endothelial cells expressing VEGF receptor-2 (VEGFR-2) is dependent on activation of phosphoinositide 3-kinase (PI3-kinase). There is no direct interaction between VEGF receptor-2 and PI3-kinase; instead PI3-kinase is activated downstream of focal adhesion kinase (FAK) in VEGF-A-stimulated cells. Thus, VEGF-A stimulation leads to complex formation between FAK and PI3-kinase and overexpression of dominant-negative FAK decreases VEGF-A-induced PI3-kinase activation. FAK activation by VEGF-A increases with increasing concentration of growth factor, without apparent collapse of the cytoskeleton, in contrast to the effect of platelet-derived growth factor. FAK activation is mediated via the C-terminal tail of VEGFR-2 and loss of VEGF-A-induced FAK activation in cells expressing mutant VEGFR-2 correlates with loss of migration capacity. These data show that VEGF-A-induced FAK and PI3-kinase activation are required for migration of cells expressing VEGFR-2, via a pathway independent of direct interaction with the receptor.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aorta / cytology
  • Cell Movement*
  • Cells, Cultured
  • Culture Media, Serum-Free
  • Cytoskeletal Proteins / metabolism
  • Endothelial Growth Factors / pharmacology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology
  • Enzyme Activation
  • Focal Adhesion Protein-Tyrosine Kinases
  • Lymphokines / pharmacology*
  • Molecular Sequence Data
  • Paxillin
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism
  • Precipitin Tests
  • Protein-Tyrosine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Signal Transduction / physiology*
  • Swine
  • Transfection
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Culture Media, Serum-Free
  • Cytoskeletal Proteins
  • Endothelial Growth Factors
  • Lymphokines
  • Paxillin
  • Phosphoproteins
  • Platelet-Derived Growth Factor
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptors, Vascular Endothelial Growth Factor
  • Focal Adhesion Protein-Tyrosine Kinases