Affinage

GFRA1

GDNF family receptor alpha-1 · UniProt P56159

Length
465 aa
Mass
51.5 kDa
Annotated
2026-06-10
69 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GFRA1 is a GPI-anchored cell-surface co-receptor that binds GDNF with high selectivity and presents it to the RET receptor tyrosine kinase, nucleating a stepwise GDNF–GFRA1–RET complex that triggers RET autophosphorylation and downstream signaling (PMID:8674117, PMID:15709767). Ligand recognition occurs through an extended surface formed by the cadherin-like domains CLD1–CLD3 of RET that engages the GDNF–GFRA1 complex (PMID:14514671), and GFRA1 discriminates strongly for GDNF over the related ligand artemin (PMID:15709767). GFRA1 can act in trans: a soluble form released by GPI-specific phospholipase C cleavage presents GDNF to RET-expressing cells lacking membrane GFRA1 (PMID:8674117, PMID:9108413), and the receptor undergoes ligand-dependent endocytosis through both RET-dependent and RET-independent routes (PMID:12701883). Beyond enabling ligand binding, GFRA1 biases the quality of RET output toward AKT versus ERK activation (PMID:32245892). GFRA1 function also operates independently of RET kinase: it drives autophagy and cisplatin resistance in osteosarcoma via SRC/AMPK signaling (PMID:27754745) and, through a GDNF-dependent interaction with the lysosomal calcium channel MCOLN1, activates Ca2+–TFEB signaling to upregulate lysosomal biogenesis and autophagic flux that protects gastrointestinal tumor cells from stress-induced apoptosis (PMID:35288241, PMID:36808605). In spermatogonial stem cells GFRA1 maintains self-renewal upstream of RET phosphorylation, acting downstream of a PTN→SDC2→GFRA1 axis (PMID:17625109, PMID:39285301), and its expression is controlled by activating histone H3 methylation/acetylation and by ASH2L-dependent H3K4 trimethylation (PMID:20856864, PMID:36758123). GFRA1 is required for development: it functions on the Wolffian duct for ureteric bud outgrowth, and biallelic loss-of-function variants cause autosomal recessive bilateral renal agenesis in humans (PMID:33020172), while in the enteric nervous system GFRA1 acts upstream of RET through a pathway not bypassed by constitutively active RET, with hypomorphic reduction producing Hirschsprung's disease with enterocolitis in mice (PMID:11779046, PMID:30594740).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established the founding mechanism: how the secreted factor GDNF activates the RET kinase, which lacks direct high-affinity GDNF binding.

    Evidence Expression cloning with ligand binding, RET autophosphorylation, and soluble trans-activation/Ret-Fc competition in Neuro-2a cells

    PMID:8674117

    Open questions at the time
    • Structural basis of the ternary complex not resolved
    • Stoichiometry of GDNF:GFRA1:RET not defined
  2. 1997 Medium

    Extended GFRA1 to physiology by linking GDNF/GFRA1/RET co-induction to injury responses and demonstrating soluble GFRA1 trans-signaling in a hematopoietic context.

    Evidence In situ hybridization/RNase protection after sciatic nerve lesion; PI-PLC release of soluble GDNFR-alpha presenting GDNF to RET+ AML blasts with clonogenic and differentiation readouts

    PMID:9108413 PMID:9240402

    Open questions at the time
    • Nerve regeneration role inferred from expression, not direct GFRA1 manipulation
    • Physiological source of soluble GFRA1 in vivo unclear
  3. 2000 Medium

    Showed GFRA1 expression is dynamically regulated by neuronal activity, switching ligand responsiveness from neurturin toward GDNF.

    Evidence Competitive RT-PCR and survival assays in autonomic/sensory neurons under depolarization with L-type Ca2+ channel antagonists

    PMID:10704393

    Open questions at the time
    • Transcriptional effectors downstream of Ca2+ not identified
    • Relevance to mature neuronal circuits not tested
  4. 2001 Medium

    Defined GFRA1's position relative to RET in enteric neurogenesis using epistasis, showing it contributes beyond merely enabling RET kinase activity.

    Evidence RET(Men2B) constitutively active transgene crossed into gfra1-null mice; histopathology of intestinal aganglionosis

    PMID:11779046

    Open questions at the time
    • Nature of the RET-kinase-independent requirement not defined
    • Molecular intermediates unidentified
  5. 2003 High

    Mapped the molecular interface by which RET recognizes the GDNF–GFRA1 complex and characterized GFRA1's RET-independent endocytic behavior.

    Evidence Homologue-scanning mutagenesis of RET cadherin-like domains with binding assays; quantitative ligand-dependent internalization in RET-null and kinase-inactive-RET cells

    PMID:12701883 PMID:14514671

    Open questions at the time
    • No co-crystal structure of the full complex
    • Fate and signaling consequences of internalized GFRA1 unresolved
  6. 2005 High

    Quantified GFRA1's ligand selectivity, establishing GDNF as its physiological ligand over artemin.

    Evidence Cell-free binding, radioligand competition, RET/ERK/AKT phosphorylation, and DRG survival with blocking antibody

    PMID:15709767

    Open questions at the time
    • Selectivity determinants on GFRA1 not mapped at residue level
  7. 2007 Medium

    Defined GFRA1 as a self-renewal factor in spermatogonial stem cells acting upstream of RET, and as a tumor-promoting receptor in breast cancer linked to the inflammatory microenvironment.

    Evidence siRNA knockdown of Gfra1 in type A spermatogonia with differentiation/RET-phospho readouts; GDNF stimulation of RET+/GFRA1+ MCF7 cells with cytokine treatment and xenografts

    PMID:17625109 PMID:18089803

    Open questions at the time
    • Downstream self-renewal transcriptional program incomplete
    • Causal contribution of GFRA1 to tumor growth in vivo not isolated from RET
  8. 2010 Medium

    Identified epigenetic control of GFRA1 expression through chromatin modification rather than DNA methylation.

    Evidence ChIP-qPCR for H3 methylation/acetylation at the Gfra1 promoter with HDAC and KDM1 inhibitors in GC-1 germ cells

    PMID:20856864

    Open questions at the time
    • Specific writers/erasers acting at the locus not all identified
    • Connection to physiological self-renewal signals unclear
  9. 2016 Medium

    Revealed a RET-independent oncogenic function: GFRA1 drives chemoresistance through autophagy.

    Evidence GFRA1 gain/loss with SRC/AMPK signaling and autophagy/apoptosis assays plus xenografts in osteosarcoma; cisplatin-induced GFRA1 via NF-κB

    PMID:27754745

    Open questions at the time
    • Mechanism coupling GPI-anchored GFRA1 to SRC activation unresolved
    • Single tumor type
  10. 2018 Medium

    Showed GFRA1 activity is tuned by post-translational sialylation and modeled disease arising from reduced GFRA1 dosage.

    Evidence ST3GAL1 knockdown with RET/AKT/ERa phosphorylation and proliferation in ER+ breast cancer; Gfra1 hypomorphic mice with Hirschsprung/enterocolitis pathology

    PMID:30040982 PMID:30594740

    Open questions at the time
    • Sialylation sites on GFRA1 not mapped
    • Cellular trigger initiating enterocolitis pathology not defined
  11. 2020 Medium

    Established GFRA1 as a determinant of RET signal bias and demonstrated a causative human developmental disease role.

    Evidence Small-molecule RET agonists bypassing GFRA1 with AKT/ERK bias readouts in retinal cultures; exome sequencing identifying biallelic loss-of-function GFRA1 variants in bilateral renal agenesis

    PMID:32245892 PMID:33020172

    Open questions at the time
    • Structural basis of signal bias unknown
    • Renal phenotype not reconstituted in vitro
  12. 2022 Medium

    Identified a novel RET-independent effector mechanism through direct GFRA1–MCOLN1 coupling to lysosomal Ca2+/TFEB signaling.

    Evidence Co-IP of GFRA1–MCOLN1, Ca2+/TFEB activation, autophagy flux, and in vivo rescue in GIST

    PMID:35288241

    Open questions at the time
    • GFRA1–MCOLN1 interaction from single Co-IP without reciprocal/structural validation
    • How a cell-surface GPI protein reaches the lysosomal channel unclear
  13. 2023 Medium

    Generalized the RET-independent lysosomal/autophagy survival mechanism to gastric cancer metastasis driven by macrophage-derived GDNF.

    Evidence Gain/loss studies in vitro and in vivo with lysosomal/autophagy/Ca2+ readouts and rescue

    PMID:36808605

    Open questions at the time
    • Whether MCOLN1 mediates this gastric-cancer effect not directly tested
    • Source-cell specificity of GDNF not isolated
  14. 2024 Medium

    Placed GFRA1 within an upstream PTN→SDC2 axis for human stem-cell self-renewal and confirmed a treatment-resistance role in glioblastoma.

    Evidence Co-IP, knockdown, and PTN rescue in human spermatogonial stem cells; CRISPR/Cas9 KO of GFRA1/GDNF with chemo/radiotherapy sensitivity and GDNF rescue in patient-derived glioblastoma spheroids

    PMID:39085346 PMID:39285301

    Open questions at the time
    • Direct molecular link between SDC2 signaling and Gfra1 transcription unresolved
    • RET-dependence of glioblastoma resistance not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GFRA1 toggles between canonical RET co-receptor signaling and RET-independent effector programs (SRC/AMPK, MCOLN1/Ca2+/TFEB) within a single cell, and the structural basis of its signal-bias control, remain unresolved.
  • No structure of the GDNF–GFRA1–RET ternary complex
  • Mechanism switching GFRA1 between RET-dependent and RET-independent outputs unknown
  • How GPI-anchored GFRA1 engages intracellular/lysosomal partners not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 2
Partners
GDNFMCOLN1RETSDC2SRCST3GAL1
Complex memberships
GDNF–GFRA1–RET receptor complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 GFRA1 (GDNFR-alpha) is a GPI-linked cell surface receptor that binds GDNF specifically and mediates activation of the RET protein-tyrosine kinase (PTK). Treatment of GFRA1-expressing Neuro-2a cells with GDNF rapidly stimulates RET autophosphorylation. Soluble GFRA1 can also present GDNF to RET in trans (in cells lacking GFRA1), and this effect is blocked by a soluble Ret-Fc fusion protein, establishing a stepwise GDNF–GFRA1–RET signaling complex. Expression cloning, ligand binding assays, RET autophosphorylation assays in Neuro-2a cells, soluble receptor trans-activation experiments, Ret-Fc competition Cell High 8674117
2003 The first cadherin-like domain (CLD1) of RET, together with CLD2 and CLD3, forms an extended binding surface for the GDNF–GFRA1 complex. Homologue-scanning mutagenesis identified three small subsets of residues on the same face of CLD1 that are required for interaction with the GDNF–GFRA1 complex. N-linked glycosylation of the RET ectodomain is not required for ligand binding. Homologue-scanning mutagenesis (Xenopus/human chimeras), loss-of-function mutagenesis, binding assays with GDNF–GFRA1 complex, N-glycosylation experiments The Journal of biological chemistry High 14514671
2003 GPI-anchored GFRA1 undergoes efficient endocytosis (~30–40% of surface-bound ligand internalized within 2 min) in cells lacking RET. The Ret coreceptor tyrosine kinase slows GFRA1 internalization at early time points, indicating distinct Ret-dependent and Ret-independent internalization mechanisms. Internalization of GFRA1 is ligand-dependent. Endocytosis assays in neuroblastoma and transfected fibroblast cell lines lacking Ret; primary hippocampal neurons from transgenic mice expressing kinase-inactive Ret; quantitative internalization measurements Cellular and molecular neurobiology Medium 12701883
2005 GFRA1 is highly selective for GDNF over artemin (ART): in cell-free binding studies, GFRA1-Ig binds GDNF strongly but only weakly to ART in the presence of soluble RET. In GFRα1-transfected NB41A3 cells, ART shows no detectable competition against 125I-GDNF binding and is >10,000-fold less potent than GDNF in stimulating RET phosphorylation. Anti-GFRA1 antibody blocks GDNF- but not ART-promoted survival of DRG neurons. Cell-free binding assays, radioligand competition assay, ERK/AKT phosphorylation assays, RET phosphorylation assays, DRG neuronal survival assay with blocking antibody Biochemistry High 15709767
2007 RNA interference knockdown of Gfra1 in mouse type A spermatogonia induces their differentiation, evidenced by elevated KIT expression and decreased POU5F1 and PCNA. Gfra1 silencing also decreases RET phosphorylation, placing GFRA1 upstream of RET kinase activity in spermatogonial stem cell self-renewal. siRNA knockdown, Western blot for GFRA1, RET phosphorylation, KIT, POU5F1, PCNA; colony-forming assay in culture Biology of reproduction Medium 17625109
2007 GDNF stimulation of RET+/GFRα1+ MCF7 breast cancer cells via the RET–GFRα1 receptor complex enhances cell proliferation, survival, and cell scattering in vitro. Inflammatory cytokines TNF-α and IL-1β synergistically upregulate GDNF expression in fibroblasts and tumor cells, linking the inflammatory microenvironment to GDNF/GFRA1/RET signaling in breast cancer. In vitro proliferation and survival assays, cell scattering assay, cytokine treatment of fibroblasts and tumor cells, tumor xenografts Cancer research Medium 18089803
2016 GFRA1 promotes cisplatin resistance in osteosarcoma by inducing autophagy via SRC phosphorylation and AMPK-dependent signaling, independent of RET kinase. Cisplatin treatment induces GFRA1 expression through NF-κB, and GFRA1 expression reduces cisplatin-induced apoptosis while increasing cell survival. Autophagy inhibition in GFRA1-expressing xenograft models reduced tumor growth. GFRA1 overexpression/knockdown, Western blot for SRC phosphorylation and AMPK pathway, apoptosis assays, autophagy assays, mouse xenograft models Autophagy Medium 27754745
2018 GFRA1 is a substrate for ST3GAL1-mediated O-linked sialylation, which is required for GDNF-induced signaling in ER-positive breast cancer cells. ST3GAL1 silencing reduces GDNF-induced phosphorylation of RET, AKT, and ERα, as well as GDNF-mediated proliferation. GDNF induces transcription of ST3GAL1, revealing a positive feedback loop regulating ST3GAL1 and GDNF/GFRA1/RET signaling. ST3GAL1 knockdown, phosphorylation assays (RET, AKT, ERα), proliferation assays, transcription analysis Cancer letters Medium 30040982
2000 Depolarization (elevated KCl) causes a marked increase in GFRα-1 mRNA and a corresponding decrease in GFRα-2 mRNA in sympathetic, parasympathetic, and sensory neurons, accompanied by increased responsiveness to GDNF and decreased responsiveness to neurturin. These changes are inhibited by L-type Ca2+ channel antagonists, indicating they are mediated by elevated intracellular Ca2+. Competitive RT-PCR for GFRα-1 and GFRα-2 mRNAs, neuronal survival assays with GDNF and neurturin, L-type Ca2+ channel antagonist treatment Development (Cambridge, England) Medium 10704393
2020 Biallelic loss-of-function variants in GFRA1 (nonsense and frameshift) cause autosomal recessive bilateral renal agenesis in humans, establishing that GFRA1 function on the Wolffian duct is required for ureteric bud outgrowth and renal development. Genome/exome sequencing, homozygosity mapping, identification of loss-of-function GFRA1 variants in two unrelated patients with isolated bilateral renal agenesis Journal of the American Society of Nephrology : JASN Medium 33020172
2018 Reduction of GFRa1 expression by ~70–80% in mice (hypomorphic allele) results in Hirschsprung's disease and HSCR-associated enterocolitis (HAEC), with disease progression from goblet cell dysplasia and abnormal mucin production to epithelial damage. Microbial enterocyte adherence is a late event, not the primary cause of HAEC. Gene targeting in mouse embryonic stem cells to generate GFRa1 hypomorphic mice; histopathology, disease progression analysis Cellular and molecular gastroenterology and hepatology Medium 30594740
1997 GFRA1 (GDNFR-alpha) and RET mRNAs are both upregulated in spinal cord motor neurons after sciatic nerve crush or resection in adult mice, with GDNFR-alpha also upregulated in the distal nerve. A similar expression pattern is seen during embryonic development, suggesting GDNF/GFRA1/RET signaling is involved in nerve regeneration. RNase protection assay, in situ hybridization in muscle, nerve, and spinal cord after sciatic nerve lesion; GDNF administration and nerve pinch test The European journal of neuroscience Low 9240402
1997 Soluble GDNFR-alpha released from bone marrow stromal cells by PI-specific phospholipase C cleavage can present GDNF to RET-expressing AML blasts in trans, reducing their clonogenic growth and triggering monocytic maturation, demonstrating a paracrine/trans-signaling mechanism for soluble GFRA1. PI-specific phospholipase C treatment of stromal cells, GDNF binding to RET-expressing AML blasts, clonogenic growth assay, differentiation assay Blood Medium 9108413
2020 Small-molecule RET agonists (Q compounds) that bypass GFRa1 activate RET irrespective of GFRa1 expression. When GFRa1 is present, it modulates RET-mediated signaling by biasing AKT or ERK activation, demonstrating that GFRa1 influences the quality/bias of RET downstream signals beyond simply enabling ligand binding. Biochemical signaling assays (AKT, ERK phosphorylation), TUNEL staining, immunohistochemistry in murine cells/tissues, retinal organotypic cultures, genetic mutant model The Journal of biological chemistry Medium 32245892
2022 GFRA1 interacts with the lysosomal calcium channel MCOLN1 in a GDNF-dependent manner, activating Ca2+-dependent TFEB signaling independent of RET. Activated TFEB transcriptionally upregulates intracellular lysosome levels and autophagic flux, protecting GIST cells from apoptosis under stress and promoting tumor dormancy and imatinib resistance. Loss- and gain-of-function studies, co-immunoprecipitation (GFRA1-MCOLN1 interaction), calcium signaling assays, TFEB localization/activation assays, autophagy flux measurement, in vitro and in vivo rescue experiments Cancer letters Medium 35288241
2023 In gastric cancer, GFRA1 protects tumor cells from apoptosis under metabolic stress via regulation of lysosomal functions and autophagy flux through Ca2+ signaling, in a RET-independent, non-canonical manner. TAM-derived GDNF activates GFRA1 in this context to promote liver metastasis formation. Loss- and gain-of-function studies in vitro and in vivo, lysosomal function assays, autophagy flux measurement, Ca2+ signaling analysis, rescue experiments Cellular oncology (Dordrecht, Netherlands) Medium 36808605
2010 Histone H3 methylation and acetylation regulate Gfra1 promoter activity in spermatogonial cells. Inhibition of HDAC (by trichostatin A) or histone demethylase KDM1 (by tranylcypromine) specifically induces Gfra1 expression in the GC-1 germ cell line, associated with increased activating histone marks (H3 methylation and acetylation) at the Gfra1 promoter, without changes in CpG DNA methylation. Chromatin immunoprecipitation (ChIP)-qPCR for histone H3 methylation and acetylation at Gfra1 promoter, pharmacological histone modification, qPCR for gene expression PloS one Medium 20856864
2024 CRISPR/Cas9 knockout of GFRA1 in patient-derived glioblastoma spheroid cultures sensitizes cells to chemotherapy (temozolomide and lomustine) and radiotherapy. Upregulation of GDNF and GFRA1 is consistently observed after all three treatment modalities (TMZ, CCNU, irradiation) by qPCR. Sensitivity conferred by GDNF KO is reversed by exogenous GDNF, confirming that the GDNF/GFRA1 axis mediates chemo- and radioresistance. CRISPR/Cas9 KO of GDNF and GFRA1 in patient-derived glioblastoma spheroids, qPCR for expression changes, GDNF rescue experiment, cell viability assays Scientific reports Medium 39085346
1999 GFR alpha-1 protein is localized at the neuromuscular junction (NMJ) and myelinated peripheral nerves in human skeletal muscle by immunoreactivity, while GFR alpha-1 mRNA is detected in the ventral horn of spinal cord but not in skeletal muscle itself, suggesting that GFR alpha-1 protein is transported to the NMJ and may mediate uptake and retrograde transport of GDNF at the human NMJ. Immunohistochemistry (GFR alpha-1 localization at NMJ and nerves), RT-PCR (mRNA in spinal cord vs. muscle) Neuroscience letters Low 10821644
2001 RET(Men2B), a constitutively active RET mutant, does not prevent intestinal aganglionosis in gfr alpha-1 null mice, demonstrating that GFRA1 deficiency causes pan-intestinal aganglionosis through a mechanism that cannot be bypassed by constitutively active RET signaling alone (epistasis: GFRA1 acts upstream of RET in enteric neurogenesis through a pathway beyond kinase activation). Genetic epistasis in mice: RET(Men2B) transgene crossed into gfr alpha-1(-/-) background; histopathological analysis Pediatric and developmental pathology Medium 11779046
2008 In E12.5 and E18.5 mice lacking GFRalpha1 or GDNF, the development of B-FABP immunoreactive satellite cells in sympathetic ganglia is normal, establishing that neither GDNF nor GFRalpha1 is essential for the development of satellite glia in sympathetic ganglia (negative result for this specific function). Immunohistochemistry in GFRalpha1 and GDNF knockout mice; satellite glial cell markers (B-FABP, Sox10) Glia Medium 18551627
2024 PTN (pleiotrophin) from Leydig cells activates SDC2 (syndecan-2) in human spermatogonial stem cells; SDC2 knockdown downregulates GFRA1 expression and inhibits SSC proliferation and self-renewal. Exogenous PTN rescues GFRA1 expression and proliferation in SDC2 knockdown SSCs, placing SDC2 upstream of GFRA1 in a PTN→SDC2→GFRA1 axis regulating human SSC self-renewal. Single-cell sequencing data analysis, immunofluorescence, co-immunoprecipitation (PTN–SDC2 interaction), siRNA knockdown, transcriptome analysis, proliferation/DNA synthesis assays, exogenous PTN rescue Biological research Medium 39285301
2023 ASH2L-dependent H3K4 trimethylation in the ureteric bud lineage is required for expression of Ret, Gfra1, and Wnt11. Inactivation of Ash2l in the ureteric bud caused CAKUT-like phenotypes with downregulation of RET/GFRA1 signaling components, establishing ASH2L-mediated H3K4 methylation as an upstream epigenetic regulator of Gfra1 expression in ureteric bud morphogenesis. UB-specific Ash2l conditional knockout in mice, RNA-seq, CUT&TAG sequencing, histopathology, H3K4me3 ChIP analysis Journal of the American Society of Nephrology : JASN Medium 36758123

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 1027 8674117
2017 circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a. Journal of experimental & clinical cancer research : CR 286 29037220
1997 Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR alpha after sciatic nerve lesion in the mouse. The European journal of neuroscience 219 9240402
1997 Neurturin and glial cell line-derived neurotrophic factor receptor-beta (GDNFR-beta), novel proteins related to GDNF and GDNFR-alpha with specific cellular patterns of expression suggesting roles in the developing and adult nervous system and in peripheral organs. The Journal of neuroscience : the official journal of the Society for Neuroscience 218 9334423
2007 Gfra1 silencing in mouse spermatogonial stem cells results in their differentiation via the inactivation of RET tyrosine kinase. Biology of reproduction 145 17625109
2016 GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy. Autophagy 133 27754745
2007 A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer research 122 18089803
1996 De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Human molecular genetics 119 8968758
2011 Distribution of GFRA1-expressing spermatogonia in adult mouse testis. Reproduction (Cambridge, England) 90 22143971
2000 Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta neuropathologica 81 10672319
1997 Cloning, mRNA distribution and chromosomal localisation of the gene for glial cell line-derived neurotrophic factor receptor beta, a homologue to GDNFR-alpha. Human molecular genetics 81 9259272
1998 Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2. Cancer research 59 9605760
2016 A long non-coding RNA interacts with Gfra1 and maintains survival of mouse spermatogonial stem cells. Cell death & disease 58 26962690
1998 Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics 46 9545641
2003 Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET. The Journal of biological chemistry 44 14514671
1997 Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. Blood 43 9108413
2018 GFRA1: A Novel Molecular Target for the Prevention of Osteosarcoma Chemoresistance. International journal of molecular sciences 41 29617307
2018 Reciprocal feedback regulation of ST3GAL1 and GFRA1 signaling in breast cancer cells. Cancer letters 39 30040982
1999 Expression of GDNF and GDNFR-alpha mRNAs in muscles of patients with motor neuron diseases. Neurochemical research 36 10447463
2009 Efficient enrichment of undifferentiated GFR alpha 1+ spermatogonia from immature rat testis by magnetic activated cell sorting. Cell and tissue research 34 19434428
2005 Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-1 (GFR alpha 1) is highly selective for GDNF versus artemin. Biochemistry 34 15709767
1998 Up-regulation of GDNFR-alpha and c-ret mRNA in facial motor neurons following facial nerve injury in the rat. Brain research. Molecular brain research 33 9582449
2002 Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A. International journal of cancer 32 11979448
2009 Magnetic activated cell sorting allows isolation of spermatogonia from adult primate testes and reveals distinct GFRa1-positive subpopulations in men. Journal of medical primatology 31 20015158
1999 Investigation of germline GFR alpha-1 mutations in Hirschsprung disease. Journal of medical genetics 29 10204848
2014 Gdnf-Gfra1 pathway is expressed in a spermatogenetic-dependent manner and is regulated by Fsh in a fish testis. Biology of reproduction 28 25165121
1999 Expression of GDNF receptor (RET and GDNFR-alpha) mRNAs in the spinal cord of patients with amyotrophic lateral sclerosis. Brain research 28 10023033
2023 Tumor-associated macrophage-derived GDNF promotes gastric cancer liver metastasis via a GFRA1-modulated autophagy flux. Cellular oncology (Dordrecht, Netherlands) 25 36808605
2021 CircRNA GFRA1 promotes hepatocellular carcinoma progression by modulating the miR-498/NAP1L3 axis. Scientific reports 25 33431945
2018 Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice. Cellular and molecular gastroenterology and hepatology 25 30594740
2017 An Anti-GDNF Family Receptor Alpha 1 (GFRA1) Antibody-Drug Conjugate for the Treatment of Hormone Receptor-Positive Breast Cancer. Molecular cancer therapeutics 25 29282299
1998 Molecular cloning and expression analysis of GFR alpha-3, a novel cDNA related to GDNFR alpha and NTNR alpha. Biochemical and biophysical research communications 24 9535755
2020 LncRNA SNHG15 contributes to doxorubicin resistance of osteosarcoma cells through targeting the miR-381-3p/GFRA1 axis. Open life sciences 23 33817274
2025 Molecular mechanisms of GDNF/GFRA1/RET and PI3K/AKT/ERK signaling interplay in neuroprotection: Therapeutic strategies for treating neurological disorders. Neuropeptides 22 40101330
2008 Development of satellite glia in mouse sympathetic ganglia: GDNF and GFR alpha 1 are not essential. Glia 22 18551627
1998 Mutational analysis of the GDNF/RET-GDNFR alpha signaling complex in a kindred with vesicoureteral reflux. Human genetics 22 9600247
2010 Epigenetic mechanisms regulate stem cell expressed genes Pou5f1 and Gfra1 in a male germ cell line. PloS one 20 20856864
1998 Expression of glial cell line-derived neurotrophic factor and GDNFR-alpha mRNAs in human peripheral neuropathies. Brain research 20 9853108
2022 The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux. Cancer letters 18 35288241
2004 Expression of GDNF and GFR alpha 1 in mouse taste bud cells. The Journal of comparative neurology 18 15389609
2020 Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors. The Journal of biological chemistry 17 32245892
2020 Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis. Journal of the American Society of Nephrology : JASN 17 33020172
2001 Responsiveness to neurturin of subpopulations of embryonic rat spinal motoneuron does not correlate with expression of GFR alpha 1 or GFR alpha 2. Developmental dynamics : an official publication of the American Association of Anatomists 17 11241828
2000 GFR alpha-1 is expressed in parvalbumin GABAergic neurons in the hippocampus. Brain research 17 10986340
1999 Expression of human GFR alpha-1 (GDNF receptor) at the neuromuscular junction and myelinated nerves. Neuroscience letters 16 10821644
2010 GFR α-1 receptor expression in the aging nigrostriatal and mesoaccumbens pathways. Journal of neurochemistry 15 20731758
2018 Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer. Oncotarget 14 29796165
2003 Internalization of glial cell-derived neurotrophic factor receptor GFR alpha 1 in the absence of the ret tyrosine kinase coreceptor. Cellular and molecular neurobiology 14 12701883
2002 Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer. Thyroid : official journal of the American Thyroid Association 14 12490080
2022 LMX1B Activated Circular RNA GFRA1 Modulates the Tumorigenic Properties and Immune Escape of Prostate Cancer. Journal of immunology research 13 35832649
2020 LncRNA LINC00210 regulated radiosensitivity of osteosarcoma cells via miR-342-3p/GFRA1 axis. Journal of clinical laboratory analysis 11 32841458
2000 Depolarisation causes reciprocal changes in GFR(alpha)-1 and GFR(alpha)-2 receptor expression and shifts responsiveness to GDNF and neurturin in developing neurons. Development (Cambridge, England) 11 10704393
1998 Genomic structure and chromosomal localization of the human GDNFR-alpha gene. Oncogene 11 9482105
2023 ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model. Journal of the American Society of Nephrology : JASN 8 36758123
2021 Biallelic loss-of-function variants of GFRA1 cause lethal bilateral renal agenesis. European journal of medical genetics 7 34737117
2006 [RET and GFRA1 germline polymorphisms in medullary thyroid cancer patients]. Molekuliarnaia biologiia 7 16813162
2024 PTN from Leydig cells activates SDC2 and modulates human spermatogonial stem cell proliferation and survival via GFRA1. Biological research 6 39285301
2001 RET(Men2B)-transgene produces sympathoadrenal tumors but does not prevent intestinal aganglionosis in gdnf-/- or gfr alpha-1(-/-) mice. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 6 11779046
1999 Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours. British journal of cancer 6 10408842
2024 GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma. Scientific reports 5 39085346
2024 WTAP-mediated m6A modification of circ_0032463 promotes osteosarcoma progression by sponging miR-145-5p and regulating GFRA1 expression. Journal of biochemical and molecular toxicology 5 39243199
2003 [Expressions of GDNF, GDNFR alpha and Ret proteins in the brain of rats with seizures induced by pilocarpine]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 5 12914250
2022 Missense Variants in GFRA1 and NPNT Are Associated with Congenital Anomalies of the Kidney and Urinary Tract. Genes 4 36292572
2000 Expression of GFR alpha-1, GFR alpha-2, and c-Ret mRNAs in rat adrenal gland. Journal of neurocytology 4 11428050
2016 Association Between RET (rs1800860) and GFRA1 (rs45568534, rs8192663, rs181595401, rs7090693, and rs2694770) Variants and Kidney Size in Healthy Newborns. Genetic testing and molecular biomarkers 3 27533506
2000 [The expression of glial cell derived neurotrophic factor and its receptor GDNFR-alpha and GDNFR-beta mRNA in spinal cord, brainstem and frontal cortex during morphine withdrawal in rats]. Zhonghua yi xue za zhi 3 11798749
1997 Assignment of mouse Gfra1, the homologue of a new human HSCR candidate gene, to the telomeric region of mouse chromosome 19. Cytogenetics and cell genetics 2 9465906
2025 Epigenetic Regulation of GFRA1 by Extracellular Vesicle lncRNA SOX9-AS1 Facilitates Breast Cancer Metastasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 40526376
2003 [Expression and significance of GFR alpha 1 gene in the recovery spermatogenesis of mice]. Zhonghua nan ke xue = National journal of andrology 0 14727347

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