title: Characterization of a multicomponent receptor for GDNF.
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.
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Treanor
authors.forename: L
authors.initials: L
authors.lastname: Goodman
authors.forename: F
authors.initials: F
authors.lastname: de Sauvage
authors.forename: D M
authors.initials: DM
authors.lastname: Stone
authors.forename: K T
authors.initials: KT
authors.lastname: Poulsen
authors.forename: C D
authors.initials: CD
authors.lastname: Beck
authors.forename: C
authors.initials: C
authors.lastname: Gray
authors.forename: M P
authors.initials: MP
authors.lastname: Armanini
authors.forename: R A
authors.initials: RA
authors.lastname: Pollock
authors.forename: F
authors.initials: F
authors.lastname: Hefti
authors.forename: H S
authors.initials: HS
authors.lastname: Phillips
authors.forename: A
authors.initials: A
authors.lastname: Goddard
authors.forename: M W
authors.initials: MW
authors.lastname: Moore
authors.forename: A
authors.initials: A
authors.lastname: Buj-Bello
authors.forename: A M
authors.initials: AM
authors.lastname: Davies
authors.forename: N
authors.initials: N
authors.lastname: Asai
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: R
authors.initials: R
authors.lastname: Vandlen
authors.forename: C E
authors.initials: CE
authors.lastname: Henderson
authors.forename: A
authors.initials: A
authors.lastname: Rosenthal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents; D029721:Drosophila Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D029721:Drosophila Proteins; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat; D010727:Phosphoric Diester Hydrolases; D043265:Phosphatidylinositol Diacylglycerol-Lyase