VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase.
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.
Qi
J H
JH
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, S-751 85, Sweden.
Claesson-Welsh
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology; D002465:Cell Movement; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008222:Lymphokines / Q000494:pharmacology*; D008969:Molecular Sequence Data; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D051419:Paxillin; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases