GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF

Cell. 1996 Jun 28;85(7):1113-24. doi: 10.1016/s0092-8674(00)81311-2.

Abstract

We report the expression cloning and characterization of GDNFR-alpha, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line-derived neurotrophic factor (GDNF). GDNFR-alpha binds GDNF specifically and mediates activation of the Ret protein-tyrosine kinase (PTK). Treatment of Neuro-2a cells expressing GDNFR-alpha with GDNF rapidly stimulates Ret autophosphorylation. Ret is also activated by treatment with a combination of GDNF and soluble GDNFR-alpha in cells lacking GDNFR-alpha, and this effect is blocked by a soluble Ret-Fc fusion protein. Ret activation by GDNF was also observed in cultured embryonic rat spinal cord motor neurons, a cell type that responds to GDNF in vivo. A model for the stepwise formation of a GDNF signal-transducing complex including GDNF, GDNFR-alpha, and the Ret PTK is proposed.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cells, Cultured / drug effects
  • Cloning, Molecular
  • Dose-Response Relationship, Drug
  • Drosophila Proteins*
  • Fetus / cytology
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Glycosylphosphatidylinositols / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Motor Neurons / metabolism
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / pharmacology
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptors, Nerve Growth Factor / genetics*
  • Recombinant Proteins / metabolism
  • Retina / cytology
  • Spinal Cord / cytology
  • Tyrosine / metabolism

Substances

  • Drosophila Proteins
  • Gdnf protein, mouse
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Glycosylphosphatidylinositols
  • Membrane Proteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Receptors, Nerve Growth Factor
  • Recombinant Proteins
  • Tyrosine
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse
  • Ret protein, rat

Associated data

  • GENBANK/U59486