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J. Biol. Chem., Vol. 283, Issue 37, 25110-25114, September 12, 2008

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Neuropilin-1-VEGFR-2 Complexing Requires the PDZ-binding Domain of Neuropilin-1^*

Claudia Prahst, Mélanie Héroult, Anthony A. Lanahan, Noa Uziel^¶, Ofra Kessler^¶, Niva Shraga-Heled^¶, Michael Simons, Gera Neufeld^¶, and Hellmut G. Augustin¹

From the Joint Research Division Vascular Biology of the Medical Faculty Mannheim (CBTM), University of Heidelberg, and the German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany, the Angiogenesis Research Center and Section of Cardiology, Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756, and the ^¶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 31096, Israel

Vascular endothelial growth factor (VEGF) acts as a hierarchically high switch of the angiogenic cascade by interacting with its high affinity VEGF receptors and with neuropilin co-receptors. VEGF₁₆₅ binds to both Neuropilin-1 (NP-1) and VEGFR-2, and it is believed that ligand binding forms an extracellular bridge between both molecules. This leads to complex formation, thereby enhancing VEGFR-2 phosphorylation and subsequent signaling. We found that inhibition of VEGF receptor (VEGFR) phosphorylation reduced complex formation between NP-1 and VEGFR-2, suggesting a functional role of the cytoplasmic domain of VEGFR-2 for complex formation. Correspondingly, deleting the PDZ-binding domain of NP-1 decreased complex formation, indicating that extracellular VEGF₁₆₅ binding is not sufficient for VEGFR-2-NP-1 interaction. Synectin is an NP-1 PDZ-binding domain-interacting molecule. Experiments in Synectin-deficient endothelial cells revealed reduced VEGFR-2-NP-1 complex formation, suggesting a role for Synectin in VEGFR-2-NP-1 signaling. Taken together, the experiments have identified a novel mechanism of NP-1 interaction with VEGFR-2, which involves the cytoplasmic domain of NP-1.

Received for publication, July 8, 2008

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SPP1190 (Au83/9-1; to H. G. A.), the German-Israel-Foundation (to G. N. and H. G. A.), and National Institutes of Health Grant HL084619 (to M. S.). 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 Supported by an endowed chair from the Aventis Foundation. To whom correspondence should be addressed: Joint Research Division Vascular Biology, Medical Faculty Mannheim (CBTM), University of Heidelberg, and the German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany. Fax: 49-6221-421515; E-mail: augustin{at}angiogenese.de.

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