Neuropilin-2 and Neuropilin-1 Are Receptors for the 165-Amino Acid Form of Vascular Endothelial Growth Factor (VEGF) and of Placenta Growth Factor-2, but Only Neuropilin-2 Functions as a Receptor for the 145-Amino Acid Form of VEGF*

  1. Gera Neufeld§
  1. From the Department of Biology, Technion, Israel Institute of Technology, Haifa 32000, Israel

Abstract

Neuropilin-1 (np-1) and neuropilin-2 (np-2) are receptors for axon guidance factors belonging to the class 3 semaphorins. np-1 also binds to the 165-amino acid heparin-binding form of VEGF (VEGF165) but not to the shorter VEGF121 form, which lacks a heparin binding ability. We report that human umbilical vein-derived endothelial cells express the a17 and a22 splice forms of the np-2 receptor. Both np-2 forms bind VEGF165 with high affinity in the presence of heparin (KD 1.3 × 10 10 m) but not VEGF121. np-2 also binds the heparin-binding form of placenta growth factor. These binding characteristics resemble those of np-1. VEGF145 is a secreted heparin binding VEGF form that contains the peptide encoded by exon 6 of VEGF but not the peptide encoded by exon 7, which is present in VEGF165. VEGF145 binds to np-2 with high affinity (KD 7 × 10 10 m). Surprisingly, VEGF145 did not bind to np-1. Indeed, VEGF145does not bind to MDA-MB-231 breast cancer cells, which predominantly express np-1. By contrast, VEGF145 binds to human umbilical vein-derived endothelial cells, which express both np-1 and np-2. The binding of VEGF165 to porcine aortic endothelial cells expressing recombinant np-2 did not affect the proliferation or migration of the cells. Nevertheless, it is possible that VEGF-induced np-2-mediated signaling will take place only in the presence of other VEGF receptors such as VEGF receptor-1 or VEGF receptor-2.

  • Abbreviations:
    VEGF
    vascular endothelial growth factor
    BS3
    bis(sulfosuccinimidyl) suberate
    HUVEC
    human umbilical vein-derived endothelial cell
    PAE
    porcine aortic endothelial
    np-1
    neuropilin-1
    np-2
    neuropilin-2
    PAGE
    polyacrylamide gel electrophoresis
    VEGF165
    165-amino acid form of vascular endothelial growth factor
    VEGF121
    121-amino acid form of vascular endothelial growth factor
    VEGF145
    145-amino acid form of vascular endothelial growth factor
    VEGFR-1
    tyrosine kinase vascular endothelial growth factor receptor-1 (flt-1)
    VEGFR-2
    tyrosine-kinase vascular endothelial growth factor receptor-2 (KDR/flk-1)
    PCR
    polymerase chain reaction
    PlGF
    placenta growth factor
    • Received November 15, 1999.
    • Revision received February 8, 2000.
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