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Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain.

Neuroplin-1 (NRP1), a receptor for vascular endothelial growth factor (VEGF) family members, has three distinct extracellular domains, a1a2, b1b2, and c. To determine the VEGF(165) and placenta growth factor 2 (PlGF-2)-binding sites of NRP1, recombinant NRP1 domains were expressed in mammalian cells as Myc-tagged, soluble proteins, and used in co-precipitation experiments with 125I-VEGF165 and 125I-PlGF-2. Anti-Myc antibodies immunoprecipitated 125I-VEGF165 and 125I-PlGF-2 in the presence of the b1b2 but not of the a1a2 and c domains. Neither b1 nor b2 alone was capable of binding 125I-VEGF165. In competition experiments, VEGF165 competed PlGF-2 binding to the NRP1 b1b2 domain, suggesting that the binding sites of VEGF165 and PlGF-2 overlap. The presence of the a1a2 domain greatly enhanced VEGF165, but not PlGF-2 binding to b1b2. Heparin enhanced the binding of both 125I-VEGF165 and 125I-PlGF-2 to the b1b2 domain by 20- and 4-fold, respectively. A heparin chain of at least 20-24 monosaccharides was necessary for binding. In addition, the b1b2 domain of NRP1 could bind heparin directly, requiring heparin oligomers of at least 8 monosaccharide units. It was concluded that an intact b1b2 domain serves as the VEGF165-, PlGF-2-, and heparin-binding sites in NRP1, and that heparin is a critical component for regulating VEGF165 and PlGF-2 interactions with NRP1 by physically interacting with both receptor and ligands.

Pubmed ID: 11986311

Authors

  • Mamluk R
  • Gechtman Z
  • Kutcher ME
  • Gasiunas N
  • Gallagher J
  • Klagsbrun M

Journal

The Journal of biological chemistry

Publication Data

July 5, 2002

Associated Grants

None

Mesh Terms

  • Angiogenesis Inducing Agents
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms
  • Cells, Cultured
  • Cloning, Molecular
  • DNA Primers
  • Endothelial Growth Factors
  • Endothelium, Vascular
  • Heparin
  • Humans
  • Kinetics
  • Lymphokines
  • Nerve Tissue Proteins
  • Neuropilin-1
  • Pregnancy Proteins
  • Recombinant Proteins
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors