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VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding

Authors

  • Shay Soker,

    Corresponding author
    1. Department of Urology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
    • Children's Hospital, Department of Urology, 300 Longwood Avenue, Boston, MA 02115.
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  • Hua-Quan Miao,

    1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
    Current affiliation:
    1. ImClone Systems, New York, NY 10014, USA.
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  • Masashi Nomi,

    1. Department of Urology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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  • Seiji Takashima,

    1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
    Current affiliation:
    1. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita Osaka 565-0871, Japan.
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  • Michael Klagsbrun

    1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
    2. Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Abstract

Co-expression of NRP1 and (VEGFR-2) KDR on the surface of endothelial cells (EC) enhances VEGF165 binding to KDR and EC chemotaxis in response to VEGF165. Overexpression of NRP1 by prostate tumor cells in vivo results in increased tumor angiogenesis and growth. We investigated the molecular mechanisms underlying NRP1-mediated angiogenesis by analyzing the association of NRP1 and KDR. An intracellular complex containing NRP1 and KDR was immunoprecipitated from EC by anti-NRP1 antibodies only in the presence of VEGF165. In contrast, VEGF121, which does not bind to NRP1, did not support complex formation. Complexes containing VEGF165, NRP1, and KDR were also formed in an intercellular fashion by co-culture of EC expressing KDR only, with cells expressing NRP1 only, for example, breast carcinoma cells. VEGF165 also mediated the binding of a soluble NRP1 dimer to cells expressing KDR only, confirming the formation of such complexes. Furthermore, the formation of complexes containing KDR and NRP1 markedly increased 125I-VEGF165 binding to KDR. Our results suggest that formation of a ternary complex of VEGF165, KDR, and NRP1 potentiates VEGF165 binding to KDR. These complexes are formed on the surface of EC and in a juxtacrine manner via association of tumor cell NRP1 and EC KDR. J. Cell. Biochem. 85: 357–368, 2002. © 2002 Wiley-Liss, Inc.

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