Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1

J Biol Chem. 2008 Sep 12;283(37):25110-25114. doi: 10.1074/jbc.C800137200. Epub 2008 Jul 15.

Abstract

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. VEGF(165) 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 VEGF(165) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Animals
  • Carrier Proteins / chemistry
  • Cytoplasm / metabolism
  • Humans
  • Mice
  • Models, Biological
  • Neuropeptides / chemistry
  • Neuropilin-1 / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Signal Transduction
  • Swine
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GIPC1 protein, human
  • Gipc1 protein, mouse
  • Neuropeptides
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1
  • Vascular Endothelial Growth Factor Receptor-2