title: 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.
abstract: 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.
authors.affiliation: Departments of Biotechnology and High-Throughput Screening and of Biochemical Pharmacology, Janssen Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium. smasure@janbe.jnj.com
authors.forename: S
authors.initials: S
authors.lastname: Masure
authors.forename: M
authors.initials: M
authors.lastname: Cik
authors.forename: E
authors.initials: E
authors.lastname: Hoefnagel
authors.forename: C A
authors.initials: CA
authors.lastname: Nosrat
authors.forename: I
authors.initials: I
authors.lastname: Van der Linden
authors.forename: R
authors.initials: R
authors.lastname: Scott
authors.forename: P
authors.initials: P
authors.lastname: Van Gompel
authors.forename: A S
authors.initials: AS
authors.lastname: Lesage
authors.forename: P
authors.initials: P
authors.lastname: Verhasselt
authors.forename: C F
authors.initials: CF
authors.lastname: Ibáñez
authors.forename: R D
authors.initials: RD
authors.lastname: Gordon
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002645:Chickens; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D006224:Cricetinae; D003545:Cysteine / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D029721:Drosophila Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017403:In Situ Hybridization; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D030161:Avian Proteins; D018076:DNA, Complementary; D029721:Drosophila Proteins; C113146:GFR receptor alpha 4, Gallus gallus; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; C494988:Gfra1 protein, mouse; C494989:Gfra1 protein, rat; C494992:Gfra2 protein, rat; C494994:Gfra3 protein, mouse; C494995:Gfra3 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; C110758:persephin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D003545:Cysteine