title: A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
abstract: Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-alpha) that is structurally related to GDNFR-alpha. We further demonstrate that NTNR-alpha binds NTN (K[d] approximately 10 pM) but not GDNF with high affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-alpha. Finally, we show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-alpha as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Klein
authors.forename: D
authors.initials: D
authors.lastname: Sherman
authors.forename: W H
authors.initials: WH
authors.lastname: Ho
authors.forename: D
authors.initials: D
authors.lastname: Stone
authors.forename: G L
authors.initials: GL
authors.lastname: Bennett
authors.forename: B
authors.initials: B
authors.lastname: Moffat
authors.forename: R
authors.initials: R
authors.lastname: Vandlen
authors.forename: L
authors.initials: L
authors.lastname: Simmons
authors.forename: Q
authors.initials: Q
authors.lastname: Gu
authors.forename: J A
authors.initials: JA
authors.lastname: Hongo
authors.forename: B
authors.initials: B
authors.lastname: Devaux
authors.forename: K
authors.initials: K
authors.lastname: Poulsen
authors.forename: M
authors.initials: M
authors.lastname: Armanini
authors.forename: C
authors.initials: C
authors.lastname: Nozaki
authors.forename: N
authors.initials: N
authors.lastname: Asai
authors.forename: A
authors.initials: A
authors.lastname: Goddard
authors.forename: H
authors.initials: H
authors.lastname: Phillips
authors.forename: C E
authors.initials: CE
authors.lastname: Henderson
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Rosenthal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051101:Neurturin; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: 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; D008024:Ligands; C495053:NRTN protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; C495056:Nrtn protein, mouse; C495057:Nrtn protein, rat; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat