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J. Biol. Chem., Vol. 278, Issue 15, 13453-13461, April 11, 2003
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From the Division of Genetics, Institute of Medical Science,
University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku,
Tokyo 108-8639, Japan
The vascular endothelial growth factor
(VEGF) family plays important roles in angiogenesis and vascular
permeability. Novel members of the VEGF family encoded in the Orf virus
genome, VEGF-E, function as potent angiogenic factors by specifically
binding and activating VEGFR-2 (KDR). VEGF-E is about 45% homologous
to VEGF-A at amino acid levels, however, the amino acid residues in
VEGF-A crucial for the VEGFR-2-binding are not conserved in VEGF-E. To
understand the molecular basis of the biological activity of VEGF-E, we
have functionally mapped residues important for interaction of VEGF-E
with VEGFR-2 by exchanging the domains between VEGF-ENZ-7 and PlGF, which binds only to VEGFR-1
(Flt-1). Exchange on the amino- and carboxyl-terminal regions had no
suppressive effect on biological activity. However, exchange on either
the loop-1 or -3 region of VEGF-ENZ-7 significantly reduced
activities. On the other hand, introduction of the loop-1 and -3 of
VEGF-ENZ-7 to placenta growth factor rescued the biological
activities. The chimera between VEGF-A and VEGF-ENZ-7 gave
essentially the same results. These findings strongly suggest that a
common rule exists for VEGFR-2 ligands (VEGF-ENZ-7 and
VEGF-A) that they build up the binding structure for VEGFR-2 through
the appropriate interaction between loop-1 and -3 regions.
A Set of Loop-1 and -3 Structures in the
Novel Vascular Endothelial Growth Factor (VEGF) Family Member,
VEGF-ENZ-7, Is Essential for the Activation of VEGFR-2
Signaling*
*
This work was supported by Special Project Research on
Cancer-Bioscience Grant-in-aid 12215024 from the Ministry of Education, Culture, Sports, Science and Technology in Japan and the program "Research for the Future" of Japan Society for Promotion of
Science.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. Tel.: 81-3-5449-5550;
Fax: 81-3-5449-5425; E-mail: shibuya@ims.u-tokyo.ac.jp.
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