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J. Biol. Chem., Vol. 282, Issue 33, 24049-24056, August 17, 2007

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Neuropilin-1 Binds to VEGF₁₂₁ and Regulates Endothelial Cell Migration and Sprouting^*

Qi Pan, Yvan Chathery¹, Yan Wu, Nisha Rathore^¶, Raymond K. Tong^||, Franklin Peale^¶, Anil Bagri, Marc Tessier-Lavigne^**, Alexander W. Koch^||2, and Ryan J. Watts³

From the Departments of Tumor Biology and Angiogenesis, Antibody Engineering, ^¶Pathology, ^||Protein Chemistry, and ^**Research Drug Discovery, Genentech, Inc., South San Francisco, California 94080

Neuropilin-1 (NRP1) was first described as a receptor for the axon guidance molecule, Semaphorin3A, regulating the development of the nervous system. It was later shown that NRP1 is an isoform-specific receptor for vascular endothelial growth factor (VEGF), specifically VEGF₁₆₅. Much interest has been placed on the role of the various VEGF isoforms in vascular biology. Here we report that blocking NRP1 function, using a recently described antibody that inhibits VEGF₁₆₅ binding to NRP1, surprisingly reduces VEGF₁₂₁-induced migration and sprout formation of endothelial cells. Intrigued by this observation, direct binding studies of NRP1 to various VEGF isoforms were performed. We show that VEGF₁₂₁ binds directly to NRP1; however, unlike VEGF₁₆₅, VEGF₁₂₁ is not sufficient to bridge the NRP1·VEGFR2 complex. Additionally, we show that VEGFR2 enhances VEGF₁₆₅, but not VEGF₁₂₁ binding to NRP1. We propose a new model for NRP1 interactions with various VEGF isoforms.

Received for publication, April 30, 2007 , and in revised form, June 11, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Biomedical Sciences Graduate Program, University of California, 533 Parnassus Ave., San Francisco, CA 94143.

² To whom correspondence may be addressed: Dept. of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080. Tel.: 650-467-7432; Fax: 650-225-5945; E-mail: akoch{at}gene.com. ³ To whom correspondence may be addressed: Dept. of Tumor Biology and Angiogenesis, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080. Tel.: 650-467-8197; Fax: 650-467-3562; E-mail: rwatts{at}gene.com.

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