Direct activation of the high-affinity nerve growth factor receptor by a non-peptide symmetrical polyanion

J. S. Gill, A. J. Windebank

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The high-affinity nerve growth factor receptor (gp140(TrkA)) is a tyrosine kinase receptor. The dimeric ligand, nerve growth factor, activates the receptor by stabilizing homodimer formation, which initiates transautophosphorylation. Suramin is a symmetrical planar polyanionic molecule which is being used as a novel experimental anti-neoplastic agent. Proposed mechanisms of the drug's anti-proliferative activity include blocking mitogenic stimulatory growth factors or inhibition of tumor-specific cellular enzymes. In PC12 cells and in dorsal root ganglion neurons, suramin has been shown to act as a partial agonist for gp140(TrkA). We now demonstrate direct activation of gp140(TrkA) by suramin using in vitro protein kinase assays and receptor dimerization studies. Additionally, activation of phosphatidylinositol-3-kinase by suramin and nerve growth factor was observed with 10-min exposure. The addition of anti-nerve growth factor antibodies along with suramin did not reduce the level of gp140(TrkA) phosphorylation, excluding induction of an autocrine loop of nerve growth factor release and activation. This demonstrates that a small polyanion can directly activate gp140(TrkA) via receptor dimerization. Our study reveals a suramin-induced homodimerization of gp140(TrkA). This finding correlated with significant neurite outgrowth in naive PC12 cells exposed to the drug. Studies will be initiated to design structural analogs of suramin which possess neurotrophic properties with no associated neurotoxicity.

Original languageEnglish (US)
Pages (from-to)855-860
Number of pages6
JournalNeuroscience
Volume87
Issue number4
DOIs
StatePublished - Aug 18 1998

Keywords

  • Neurite outgrowth
  • PC12 cells
  • Receptor dimerization
  • Suramin
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

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