HGNC Approved Gene Symbol: GFRA4
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:3,659,248-3,663,399 (from NCBI)
GFRA4 is a receptor for the neurotrophic factor persephin (PSPN; 602921) and is involved in cell survival and neurite outgrowth (Lindahl et al., 2001; Yang et al., 2004).
Masure et al. (2000) cloned 2 variants of rat Gfra4, which encode predicted proteins of 273 and 258 amino acids. Both variants contain a 29-amino acid N-terminal signal peptide but differ at their C termini. The longer isoform was predicted to be a glycosylphosphatidylinositol (GPI)-anchored membrane protein, whereas the smaller isoform was predicted to be soluble. Northern blot analysis detected Gfra4 transcripts at low levels in rat heart, brain, and testis and in mouse brain, testis, and embryo. In situ hybridization of adult mouse brain revealed Gfra4 transcripts in cortex, hippocampus, and substantia nigra. Recombinant expression of rat Gfra4 in CHO cells showed that the protein was likely secreted and present as multimers or aggregates.
Lindahl et al. (2001) cloned 3 variants of human GFRA4 from a thyroid cDNA library. The GFRA4A and GFRA4B isoforms contain 290 and 299 amino acids, respectively, and have identical N- and C-terminal ends. Both GFRA4A and GFRA4B were predicted to be GPI-anchored membrane proteins with N-terminal signal sequences. The 236-amino acid GFRA4C isoform was predicted to be soluble. RT-PCR analysis detected high expression of GFRA4 transcripts in adult thyroid gland and lower expression in fetal adrenal and thyroid glands.
Using a binding assay, Masure et al. (2000) showed that rat Gfra4 bound to persephin.
Using binding and cross-linking analyses, Lindahl et al. (2001) showed that human GFRA4 bound specifically to PSPN. PSPN also bound RET (164761) and activated the GFRA4-RET receptor complex, thereby activating a survival-promoting program in superior cervical ganglion neurons. RT-PCR and in situ hybridization analyses revealed that GFRA4 was selectively expressed in malignant C cells in medullary thyroid carcinoma samples.
Using Western blot analysis, Yang et al. (2004) confirmed that mouse Gfra4 was a GPI-anchored membrane glycoprotein. Immunoprecipitation analysis revealed that Gfra4 bound to Pspn and Ret and thereby mediated Pspn-induced phosphorylation of Ret. The Pspn-Gfra4 complex only weakly recruited Ret to lipid rafts upon ligand stimulation, but it was still able to support cell survival and mediate neurite outgrowth.
Lindahl et al. (2001) determined that the GFRA4 gene contains 6 exons.
Gross (2019) mapped the GFRA4 gene to chromosome 20p13 based on an alignment of the GFRA4 sequence (GenBank AF253318) with the genomic sequence (GRGh38).
Masure et al. (2000) mapped the mouse Gfra4 gene to chromosome 2.
Gross, M. B. Personal Communication. Baltimore, Md. 11/25/2019.
Lindahl, M., Poteryaev, D., Yu, L., Arumae, U., Timmusk, T., Bongarzone, I., Aiello, A., Pierotti, M. A., Airaksinen, M. S., Saarma, M. Human glial cell line-derived neurotrophic factor receptor alpha-4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. J. Biol. Chem. 276: 9344-9351, 2001. [PubMed: 11116144] [Full Text: https://doi.org/10.1074/jbc.M008279200]
Masure, S., Cik, M., Hoefnagel, E., Nosrat, C. A., Van der Linden, I., Scott, R., Van Gompel, P., Lesage, A. S. J., Verhasselt, P., Ibanez, C. F., Gordon, R. D. Mammalian GFR-alpha-4, a divergent member of the GFR-alpha family of coreceptors for glial cell line-derived neurotrophic factor family ligands, is a receptor for the neurotrophic factor persephin. J. Biol. Chem. 275: 39427-39434, 2000. [PubMed: 10958791] [Full Text: https://doi.org/10.1074/jbc.M003867200]
Yang, J., Lindahl, M., Lindholm, P., Virtanen, H., Coffey, E., Runeberg-Roos, P., Saarma, M. PSPN/GFR-alpha-4 has a significantly weaker capacity than GDNF/GFR-alpha-1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. FEBS Lett. 569: 267-271, 2004. [PubMed: 15225646] [Full Text: https://doi.org/10.1016/j.febslet.2004.06.007]