GFR alpha-4 and the tyrosine kinase Ret form a functional receptor complex for persephin

Curr Biol. 1998 Sep 10;8(18):1019-22. doi: 10.1016/s0960-9822(07)00422-8.


Glial-cell-line-derived neurotrophic factor (GDNF), neurturin and persephin are structurally related, secreted proteins that are widely expressed in the nervous system and other tissues and promote the survival of a variety of neurons during development. GDNF and neurturin signal through multicomponent receptors that consist of the Ret receptor tyrosine kinase and one of two structurally related glycosyl-phosphatidylinositol (GPI)-linked ligand-binding subunits: GFR alpha-1 is the preferred ligand-binding subunit for GDNF, and GFR alpha-2 is the preferred ligand-binding subunit for neurturin. Two additional members of the GFR alpha family of GPI-linked proteins have recently been cloned: GFR alpha-3 and GFR alpha-4. We have shown that persephin binds efficiently only to GFR alpha-4, and labelled persephin is effectively displaced from cells expressing GFR alpha-4 by persephin but not by GDNF or neurturin. Using microinjection to introduce expression plasmids into cultured neurons, we have also shown that coexpression of Ret with GFR alpha-4, confers a marked survival response to persephin but not to GDNF or neurturin. These results demonstrate that GFR alpha-4 is the ligand-binding subunit for persephin and that persephin, like GDNF and neurturin, also requires Ret for signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Drosophila Proteins*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Humans
  • Kidney
  • Membrane Glycoproteins / metabolism*
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / pharmacology
  • Neurturin
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ret
  • Receptor Cross-Talk*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Nerve Growth Factor*
  • Recombinant Proteins / metabolism
  • Transfection


  • Drosophila Proteins
  • GDNF protein, human
  • GFRA1 protein, human
  • GFRA2 protein, human
  • GFRA3 protein, human
  • GFRA4 protein, human
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Membrane Glycoproteins
  • NRTN protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neurturin
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, Nerve Growth Factor
  • Recombinant Proteins
  • persephin
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila