Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase.
Neurturin (NTN) is a recently identified homologue of glial-cell-line-derived neurotrophic factor (GDNF). Both factors promote the survival of a variety of neurons, and GDNF is required for the development of the enteric nervous system and kidney. GDNF signals through a receptor complex consisting of the receptor tyrosine kinase Ret and a glycosyl-phosphatidylinositol (GPI)-linked receptor termed GDNFR-alpha. Here we report the cloning of a new GPI-linked receptor termed NTNR-alpha that is homologous with GDNFR-alpha and is widely expressed in the nervous system and other tissues. By using microinjection to introduce expression plasmids into neurons, we show that coexpression of NTNR-alpha with Ret confers a survival response to neurturin but not GDNF, and that coexpression of GDNFR-alpha with Ret confers a survival response to GDNF but not neurturin. Our findings indicate that GDNF and neurturin promote neuronal survival by signalling through similar multicomponent receptors that consist of a common receptor tyrosine kinase and a member of a GPI-linked family of receptors that determines ligand specificity.
Buj-Bello
A
A
School of Biological and Medical Sciences, University of St Andrews, Fife, UK.
Adu
J
J
Piñón
L G
LG
Horton
A
A
Thompson
J
J
Rosenthal
A
A
Chinchetru
M
M
Buchman
V L
VL
Davies
A M
AM
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051101:Neurturin; D009620:Nodose Ganglion / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; C495056:Nrtn protein, mouse; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D010738:Type C Phospholipases