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Originally published In Press as doi:10.1074/jbc.M210931200 on January 27, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13453-13461, April 11, 2003
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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*

Atsushi Kiba, Naoyuki Yabana, and Masabumi ShibuyaDagger

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.


* 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.

Dagger To whom correspondence should be addressed. Tel.: 81-3-5449-5550; Fax: 81-3-5449-5425; E-mail: shibuya@ims.u-tokyo.ac.jp.


Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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