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J. Biol. Chem., Vol. 276, Issue 21, 17686-17692, May 25, 2001
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From the Departments of Activation of vascular endothelial growth factor
receptor-2 (VEGFR-2) plays a critical role in vasculogenesis and
angiogenesis. However, the mechanism by which VEGFR-2 activation
elicits these cellular events is not fully understood. We recently
constructed a chimeric receptor containing the extracellular domain of
human CSF-1R/c-fms, fused with the entire transmembrane and
cytoplasmic domains of murine VEGFR-2 (Rahimi, N., Dayanir, V., and
Lashkari, K. (2000) J. Biol. Chem. 275, 16986-16992).
In this study we used VEGFR-2 chimera (herein named CKR) to elucidate
the signal transduction relay of VEGFR-2 in porcine aortic endothelial
(PAE) cells. Mutation of tyrosines 799 and 1173 individually on CKR
resulted in partial loss of CKR's ability to stimulate cell growth.
Double mutation of these sites caused total loss of CKR's ability to
stimulate cell growth. Interestingly, mutation of these sites had no
effect on the ability of CKR to stimulate cell migration. Further
analysis revealed that tyrosines 799 and 1173 are docking sites for p85 of phosphatidylinositol 3-kinase (PI3K). Pretreatment of cells with wortmannin, an inhibitor of PI3K, and rapamycin, a potent inhibitor of S6 kinase, abrogated CKR-mediated cell growth. However, expression of a dominant negative form of ras (N17ras) and
inhibition of the mitogen-activated protein kinase (MAPK) pathway by
PD98059 did not attenuate CKR-stimulated cell growth. Altogether, these
results demonstrate that activation of VEGFR-2 results in activation of
PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is
responsible for VEGFR-2-mediated cell growth.
Identification of Tyrosine Residues in Vascular Endothelial
Growth Factor Receptor-2/FLK-1 Involved in Activation of
Phosphatidylinositol 3-Kinase and Cell Proliferation*
,
Ophthalmology and
Biochemistry, School of Medicine, Boston University,
Boston, Massachusetts 02118 and the § Department of
Ophthalmology, Schepens Eye Research Institute, Harvard Medical School,
Boston, Massachusetts 02114
*
This work was supported in part by departmental grants from
Research To Prevent Blindness, Inc., the Massachusetts Lions Eye Research Fund Inc., and the American Cancer Society, Massachusetts Division, Inc. (to N. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Funded by TUBITAK (the Scientific and Technical Research Council
of Turkey) NATO Science Scholarship and Turkish Education Foundation
Scholarship Programs.
To whom correspondence should be addressed: Depts. of
Ophthalmology and Biochemistry, School of Medicine, Boston University, 715 Albany St.. Rm. L921, Boston, MA 02118. Tel.: 617-638-5011; Fax:
617-638-5337; E-mail: nrahimi@bu.edu.
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