Mammalian GFRalpha -4, a divergent member of the GFRalpha family of coreceptors for glial cell line-derived neurotrophic factor family ligands, is a receptor for the neurotrophic factor persephin

• Published in: The Journal of biological chemistry 2000-12, Vol.275 (50), p.39427
• Main Authors: Masure, S, Cik, M, Hoefnagel, E, Nosrat, C A, Van der Linden, I, Scott, R, Van Gompel, P, Lesage, A S, Verhasselt, P, Ibáñez, C F, Gordon, R D
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Amino Acid Sequence; Animals; Avian Proteins; Blotting, Northern; Blotting, Western; Brain - metabolism; Chickens; CHO Cells; Chromosome Mapping; Cloning, Molecular; Cricetinae; Cysteine - chemistry; DNA, Complementary - metabolism; Drosophila Proteins; Embryo, Mammalian - metabolism; Embryo, Nonmammalian; Glial Cell Line-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor Receptors; In Situ Hybridization; Kinetics; Medicin och hälsovetenskap; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Mice; Molecular Sequence Data; Nerve Growth Factors - metabolism; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ret; Rats; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Receptors, Nerve Growth Factor; Recombinant Proteins - metabolism; RNA, Messenger - metabolism; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Signal Transduction; Tissue Distribution; Transfection
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M003867200

Four members of the glial cell line-derived neurotrophic factor family have been identified (GDNF, neurturin, persephin, and enovin/artemin). They bind to a specific membrane-anchored GDNF family receptor as follows: GFRalpha-1 for GDNF, GFRalpha-2 for neurturin, GFRalpha-3 for enovin/artemin, and (chicken) GFRalpha-4 for persephin. Subsequent signaling occurs through activation of a common transmembrane tyrosine kinase, cRET. GFRalpha-4, the coreceptor for persephin, was previously identified in chicken only. We describe the cloning and characterization of a mammalian persephin receptor GFRalpha-4. The novel GFRalpha receptor is substantially different in sequence from all known GFRalphas, including chicken GFRalpha-4, and lacks the first cysteine-rich domain present in all previously characterized GFRalphas. At least two different GFRalpha-4 splice variants exist in rat tissues, differing at their respective COOH termini. GFRalpha-4 mRNA is expressed at low levels in different brain areas in the adult as well as in some peripheral tissues including testis and heart. Recombinant rat GFRalpha-4 variants were expressed in mammalian cells and shown to be at least partially secreted from the cells. Persephin binds specifically and with high affinity (K(D) = 6 nm) to the rat GFRalpha-4 receptor, but no cRET activation could be demonstrated. Although the newly characterized mammalian GFRalpha-4 receptor is structurally divergent from previously characterized GFRalpha family members, we suggest that it is a mammalian orthologue of the chicken persephin receptor. This discovery will allow a more detailed investigation of the biological targets of persephin action and its potential involvement in diseases of the nervous system.