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 neurons1,2,3,4,5,6. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-α) and the transmembrane protein tyrosine kinase Ret7,8,9,10,11,12. 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-α) that is structurally related to GDNFR-α. We further demonstrate that NTNR-α binds NTN (Kd ∼ 10 pM) but not GDNF with high affinity; that GDNFR-α binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-α. Finally, we show that NTN, in the presence of NTNR-α, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-α and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-α 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.
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Acknowledgements
We thank J. Milbrandt and E. Johnson (who were supported by NIH grants) for providing unpublished information and reagents; W. Anstine for preparing the figures; E. Berry for help with the manuscript; A. Ryan for help with the in situ hybridization analysis; M. Vasser, P. Jhurani and P.Ng for synthetic oligonucleotides; M. Yang for the PIPLC enzyme; and V. Arce for help with motor neuron cultures. This work was supported in part by INSERM, Association Francaise contre les Myopathies (AFM) and Institut pour la Recherche sur la Moelle Epiniere (IRME) to C.E.H., and by grants-in-aid from scientific research from the Ministry of Education, Science and Culture of Japan to M.T.
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Klein, R., Sherman, D., Ho, WH. et al. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387, 717–721 (1997). https://doi.org/10.1038/42722
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DOI: https://doi.org/10.1038/42722
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