title: Broad specificity of GDNF family receptors GFRalpha1 and GFRalpha2 for GDNF and NTN in neurons and transfected cells.
abstract: The glial cell line-derived neurotrophic factor (GDNF) family of ligands binds to lipid anchored proteins termed GDNF family receptor (GFR)alphas, and then activates the RET receptor tyrosine kinase, by ligand GFRalpha. The binding of soluble GFRalphas to transfected cells suggested that different GFRalphas were dedicated to particular ligands, with GDNF acting primarily or entirely through GFRalpha1, and neurturin (NTN), through GFRalpha2. More recent evidence has suggested the possibility of cross-talk between these ligands and the two receptors. We examined here whether crosstalk between the GDNF ligands and the GFRalphas is biologically relevant, using midbrain dopaminergic, and parasympathetic, submandibular gland neurons. By biochemical and genetic addition and/or deletion of GFRalpha1 and 2, we show that in both neuronal cell types, robust biological activities of GDNF or NTN can be mediated by either GFRalpha1 or GFRalpha2, although GDNF is slightly more potent in dopaminergic (DA) neurons which normally express GFRalpha1, and NTN in submandibular neurons which normally express GFRalpha2. Throughout the body, GDNF and NTN are likely to have important biological actions on both GFRalpha1- and GFRalpha2-expressing cells.
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Shih
authors.forename: J
authors.initials: J
authors.lastname: Hongo
authors.forename: B
authors.initials: B
authors.lastname: Devaux
authors.forename: M
authors.initials: M
authors.lastname: Hynes
mesh_terms: D000818:Animals; D019556:COS Cells; D002470:Cell Survival / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins; D005724:Ganglia / Q000166:cytology; D015870:Gene Expression / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D051101:Neurturin; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; C494988:Gfra1 protein, mouse; C494991:Gfra2 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; C495056:Nrtn protein, mouse; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D004298:Dopamine