Vascular Endothelial Growth Factor Receptor-2 and Neuropilin-1 Form a Receptor Complex That Is Responsible for the Differential Signaling Potency of VEGF165 and VEGF121

• Published in: The Journal of biological chemistry Vol. 276; no. 27; pp. 25520 - 25531
• Main Authors: Whitaker, G. Brian, Limberg, Brian J., Rosenbaum, Jan S.
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 06.07.2001
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M102315200

The two most abundant secreted isoforms of vascular endothelial growth factor A (VEGF 165 and VEGF 121 ) are formed as a result of differential splicing of the VEGF-A gene. VEGF 165 and VEGF 121 share similar affinities at the isolated VEGF receptor (VEGFR)-2 but have been previously demonstrated to have differential ability to activate VEGFR-2-mediated effects on endothelial cells. Herein we investigate whether the recently described VEGF 165 isoform-specific receptor neuropilin-1 (Npn-1) is responsible for the difference in potency observed for these ligands. We demonstrate that although VEGFR-2 and Npn-1 form a complex, this complex does not result in an increase in VEGF 165 binding affinity. Therefore, the differential activity of VEGF 165 and VEGF 121 cannot be explained by a differential binding affinity for the complex. Using an antagonist that competes for VEGF 165 binding at the VEGFR-2·Npn-1 complex, we observe specific antagonism of VEGF 165 -meditated phosphorylation of VEGFR-2 without affecting the VEGF 121 response. These data indicate that the formation of the complex is responsible for the increased potency of VEGF 165 versus VEGF 121 . Taken together, these data suggest a receptor-clustering role for Npn-1, as opposed to Npn-1 behaving as an affinity-converting subunit.