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Neuropilin-1 and neuropilin-2 enhance VEGF₁₂₁ stimulated signal transduction by the VEGFR-2 receptor

Niva Shraga-Heled^*, Ofra Kessler^*, Claudia Prahst, Jens Kroll, Hellmut Augustin and Gera Neufeld^*,1

^* Cancer and Vascular Biology Research Center, Rappaport Research Institute in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel; and

Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Freiburg, Germany

¹Correspondence: Cancer and Vascular Biology Research Center, Rappaport Research Institute in the Medical Sciences, Bruce Rappoport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa 31096, Israel. E-mail: gera{at}tx.technion.ac.il

The neuropilin-1 (np1) receptor binds the 165 amino-acid form of vascular endothelial growth factor₁₆₅ (VEGF₁₆₅) and functions as an enhancer that potentiates VEGF₁₆₅ signaling via the VEGFR-2 tyrosine-kinase receptor. To study the mechanism by which neuropilins potentiate VEGF activity we produced a VEGF₁₆₅ mutant (VEGF_165KF) that binds to neuropilins but displays a much lower affinity toward VEGFR-1 and VEGFR-2. VEGF_165KF failed to induce VEGFR-2 phosphorylation in cells lacking neuropilins. However, in the presence of np1, VEGF_165KF bound weakly to VEGFR-2, induced VEGFR-2 phosphorylation, and activated ERK1/2. Interestingly, VEGF_165KF did not promote formation of VEGFR-2/np1 complexes nor did high concentrations of VEGF_165KF inhibit VEGF₁₆₅ induced formation of such complexes, suggesting that VEGF₁₆₅ does not stabilize VEGFR-2/np1 complexes by forming bridges spanning VEGFR-2 and np1. VEGF₁₂₁ is a VEGF form that does not bind to neuropilins. Surprisingly, both np1 and neuropilin-2 (np2) enhanced VEGF₁₂₁-induced phosphorylation of VEGFR-2 and VEGF₁₂₁-induced proliferation of endothelial cells. The enhancement of VEGF₁₂₁ activity by np1 was accompanied by a 10-fold increase in binding affinity to VEGFR-2 and was not associated with the formation of new VEGFR-2/np1 complexes. These observations suggest that neuropilins enhance the activity of VEGF forms that do not bind to neuropilins, indicate that np2 is a functional VEGF receptor, and imply that spontaneously formed VEGFR-2/np1 complexes suffice for efficient neuropilin mediated enhancement of VEGF activity.—Shraga-Heled, N., Kessler, O., Prahst, C., Kroll, J., Augustin, H., Neufeld, G. Neuropilin-1 and neuropilin-2 enhance VEGF₁₂₁ stimulated signal transduction by the VEGFR-2 receptor.

Key Words: angiogenesis • semaphorin • endothelial cells • vascular endothelial growth factor

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