GFRα-2 and GFRα-3 Are Two New Receptors for Ligands of the GDNF Family
- Shuqian Jing‡§,
- Yanbin Yu‡,
- Mei Fang‡,
- Zheng Hu‡,
- Paige L. Holst‡,
- Thomas Boone¶,
- John Delaney¶,
- Henry Schultz‖,
- Renping Zhou** and
- Gary M. Fox‡
- From the Departments of ‡Molecular Genomics,¶Process Development, and ‖Computational Biology, Amgen, Inc., Thousand Oaks, California 91320-1789 and the **Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855
Abstract
The receptor for glial cell line-derived neurotrophic factor (GDNF) consists of GFRα-1 and Ret. Neurturin is a GDNF-related neurotrophin whose receptor is presently unknown. Here we report that neurturin can bind to either GFRα-1 or GFRα-2, a novel receptor related to GFRα-1. Both GFRα-1 and GFRα-2 mediate neurturin-induced Ret phosphorylation. GDNF can also bind to either GFRα-1 or GFRα-2, and activate Ret in the presence of either binding receptor. Although both ligands interact with both receptors, cells expressing GFRα-1 bind GDNF more efficiently than neurturin, while cells expressing GFRα-2 bind neurturin preferentially. Cross-linking and Ret activation data also suggest that while there is cross-talk, GFRα-1 is the primary receptor for GDNF and GFRα-2 exhibits a preference for neurturin. We have also cloned a cDNA that apparently codes for a third member of the GFRα receptor family. This putative receptor, designated GFRα-3, is closely related in amino acid sequence and is nearly identical in the spacing of its cysteine residues to both GFRα-1 and GFRα-2. Analysis of the tissue distribution of GFRα-1, GFRα-2, GFRα-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression. Consistent with a role in GDNF function, the GFRαs and Ret are expressed in many of the same tissues, suggesting that GFRαs mediate the action of GDNF family ligands in vivo.
Footnotes
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↵§ To whom correspondence should be addressed. Tel.: 805-447-8392; Fax: 805-499-2751; E-mail: sjing{at}amgen.com.
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* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are: GDNF, glial cell line-derived neurotropic factor; NTN, neurturin; PTK, protein tyrosine kinase; RT-PCR, reverse transcriptase-polymerase chain reaction; CM, conditioned medium; PAGE, polyacrylamide gel electrophoresis; EST, expressed sequence tag; kb, kilobase pairs(s).
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↵2 S. Jing, Y. Yu, M. Fang, Z. Hu, P. L. Holst, and G. M. Fox, unpublished data.
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↵3 L. Hillier, WashU-Merck EST Project, unpublished data.
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↵4 M. Marra, WashU-HHMI Mouse EST Project, unpublished data.
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- Received June 9, 1997.
- Revision received October 15, 1997.
