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J. Biol. Chem., Vol. 275, Issue 22, 16986-16992, June 2, 2000
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From the Boston University, School of Medicine, Departments of
Ophthalmology & Biochemistry, Boston, Massachusetts 02118 and
¶ Schepens Eye Research Institute, Harvard Medical School,
Boston, Massachusetts 02114
Vascular endothelial growth factor (VEGF)
provokes angiogenesis in vivo and stimulates growth and
differentiation of endothelial cells in vitro. Although
VEGF receptor-1 (VEGFR-1) and VEGFR-2 are known to be high affinity
receptors for VEGF, it is not clear which of the VEGFRs are responsible
for the transmission of the diverse biological responses of VEGF. For
this purpose we have constructed a chimeric receptor for VEGFR-1 (CTR)
and VEGFR-2 (CKR) in which the extracellular domain of each receptor
was replaced with the extracellular domain of human colony-stimulating
factor-1 receptor (CSF-1R), and these receptors were expressed in pig
aortic endothelial (PAE) cells. We show that CKR individually expressed in PAE cells is readily tyrosine-phosphorylated in vivo,
autophosphorylated in vitro, and stimulates cell
proliferation in a CSF-1-dependent manner. In contrast, CTR
individually expressed in PAE cells showed no significant in
vivo, in vitro tyrosine phosphorylation and cell
growth in response to CSF-1 stimulation. The kinase activity of CKR was
essential for its biological activity, since mutation of lysine 866 to
arginine abolished its in vivo, in vitro
tyrosine phosphorylation and mitogenic signals. Remarkably, activation of CTR repressed CKR-mediated mitogen-activate protein kinase activation and cell proliferation. Similar effects were observed for
VEGFR-2 co-expressed with VEGFR-1. Collectively, these findings demonstrate that VEGFR-2 activation plays a positive role in
angiogenesis by promoting endothelial cell proliferation. In contrast,
activation of VEGFR-1 plays a stationary role in angiogenesis by
antagonizing VEGFR-2 responses.
Receptor Chimeras Indicate That the Vascular Endothelial Growth
Factor Receptor-1 (VEGFR-1) Modulates Mitogenic Activity of VEGFR-2 in
Endothelial Cells*
,
*
This work was supported in part by departmental grants from
Research To Prevent Blindness, Inc. and the Massachusetts Lions Eye
Research Fund, Inc.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.
To whom correspondence should be addressed: Boston University,
School of Medicine, 715 Albany St. Room 921L, Boston, MA 02118. Tel.:
617-638-5011; Fax: 617-638-5337; E-mail: nrahimi@bu.edu.
§
Funded by TUBITAK (The Scientific and Technical Research Council of
Turkey) NATO Science Scholarship Program.
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