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