GFR alpha-4 and the tyrosine kinase Ret form a functional receptor complex for persephin.
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.
Enokido
Y
Y
School of Biomedical Sciences, University of St. Andrews, Scotland.
de Sauvage
F
F
Hongo
J A
JA
Ninkina
N
N
Rosenthal
A
A
Buchman
V L
VL
Davies
A M
AM
D001667:Binding, Competitive; D002460:Cell Line; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007668:Kidney; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D051101:Neurturin; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020239:Receptor Cross-Talk; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; C494990:GFRA2 protein, human; C494993:GFRA3 protein, human; C491860:GFRA4 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008562:Membrane Glycoproteins; C495053:NRTN protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; C110758:persephin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila