1. GDNF–Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF
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Jean-Claude Louis, Duanzhi Wen, Gary M. Fox, Zheng Hu, Rod Cupples, Paige Holst, Sylvia Hu, Laarni Antonio, Mei Fang, Shuqian Jing, Rami Tamir, Yanbin Yu, Yi Luo, and Bruce W. Altrock
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endocrine system ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,endocrine system diseases ,Glycosylphosphatidylinositols ,Neurturin ,animal diseases ,Persephin ,Molecular Sequence Data ,Artemin ,Nerve Tissue Proteins ,Receptors, Nerve Growth Factor ,General Biochemistry, Genetics and Molecular Biology ,Retina ,Rats, Sprague-Dawley ,Mice ,Fetus ,Neurotrophic factors ,Proto-Oncogene Proteins ,Glial cell line-derived neurotrophic factor ,Animals ,Drosophila Proteins ,Amino Acid Sequence ,Glial Cell Line-Derived Neurotrophic Factor ,Nerve Growth Factors ,Cloning, Molecular ,Phosphorylation ,Cells, Cultured ,Motor Neurons ,biology ,Base Sequence ,Dose-Response Relationship, Drug ,Biochemistry, Genetics and Molecular Biology(all) ,urogenital system ,Proto-Oncogene Proteins c-ret ,Membrane Proteins ,Receptor Protein-Tyrosine Kinases ,Molecular biology ,Recombinant Proteins ,Rats ,Mice, Inbred C57BL ,Spinal Cord ,nervous system ,biology.protein ,Tyrosine ,GDNF family of ligands ,Tyrosine kinase - 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.
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