Abstract
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for central and peripheral neurons, and is essential for the development of kidneys and the enteric nervous system. Despite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We further demonstrate that GDNF promotes the formation of a physical complex between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the ligand-binding and signalling components, respectively.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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CHO Cells
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Cell Line
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Cloning, Molecular
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Cricetinae
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Cricetulus
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Cross-Linking Reagents
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Drosophila Proteins*
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Embryo, Mammalian / metabolism
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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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Humans
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Mesencephalon / metabolism
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Mice
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Molecular Sequence Data
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Motor Neurons / metabolism
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Nerve Growth Factors*
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Nerve Tissue Proteins / metabolism*
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Phosphatidylinositol Diacylglycerol-Lyase
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Phosphoric Diester Hydrolases
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Phosphorylation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ret
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Rats
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Signal Transduction
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Tissue Distribution
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Tumor Cells, Cultured
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Tyrosine / metabolism
Substances
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Cross-Linking Reagents
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Drosophila Proteins
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GDNF protein, human
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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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Nerve Growth Factors
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Nerve Tissue Proteins
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Proto-Oncogene 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
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Phosphoric Diester Hydrolases
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Phosphatidylinositol Diacylglycerol-Lyase