Jh. Qi et L. Claesson-welsh, VEGF-induced activation of phosphoinositide 3-kinase is dependent on focaladhesion kinase, EXP CELL RE, 263(1), 2001, pp. 173-182
Vascular endothelial growth factor (VEGF)-A stimulates formation of new blo
od vessels (angiogenesis). This process includes migration of endothelial c
ells from the preexisting vessel toward the source of the growth factor. We
show that VEGF-A-induced migration of porcine aortic endothelial cells exp
ressing VEGF receptor-2 (VEGFR-2) is dependent on activation of phosphoinos
itide 3-kinase (PI3-kinase). There is no direct interaction between VEGF re
ceptor-2 and PI3-kinase; instead PI3-kinase is activated downstream of foca
l adhesion kinase (FAK) in VEGF-A-stimulated cells. Thus, VEGF-A stimulatio
n leads to complex formation between FAK and PI3-kinase and overexpression
of dominant-negative FAK decreases VEGF-A-induced PI3-kinase activation. FA
K activation by VEGF-A increases with increasing concentration of growth fa
ctor, without apparent collapse of the cytoskeleton, in contrast to the eff
ect 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 cell
s expressing mutant VEGFR-2 correlates with loss of migration capacity. The
se 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 di
rect interaction with the receptor. (C) 2001 Academic Press.