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10 sources retrieved · Most recent: April 2026 · Index updated 15 days ago
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GFRA2
GDNF family receptor alpha 2
Chromosome 8 · 8p21.3
NCBI Gene: 2675Ensembl: ENSG00000168546.12HGNC: HGNC:4244UniProt: O00451
39PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
FUNCTIONAL ROLE
Receptor
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
glial cell-derived neurotrophic factor receptor activityheparan sulfate bindingglial cell-derived neurotrophic factor receptor signaling pathwayplasma membranepoisoningdevice complicationesophageal ulcerVitiligo
✦AI Summary

GFRA2 (GDNF family receptor alpha 2) is a glycosylphosphatidylinositol (GPI)-anchored cell surface receptor that functions as a co-receptor in neurotrophic signaling pathways 1. The protein mediates neurturin (NRTN)-induced signaling by forming complexes that activate downstream receptor tyrosine kinases, particularly RET 23. GFRA2 has nine coding exons with structural similarity to other GFRA family members and contains heparan sulfate-binding sites that facilitate signaling complex assembly 12. The receptor plays crucial roles in nervous system development, particularly in myenteric nerve plexus formation 1. GFRA2 also functions as a cardiac progenitor cell marker and mediates cardiomyocyte differentiation through RET-independent pathways 4. In disease contexts, GFRA2 serves as a genetic modifier in frontotemporal lobar degeneration with GRN mutations, where decreased GFRA2 expression is associated with increased disease risk 5. The receptor is also implicated in pancreatic cancer progression, where neurturin-GFRA2-RET signaling enhances glycolysis by phosphorylating hexokinase 2 3. Additionally, GFRA2 expression is upregulated in degenerative disc disease and may contribute to discogenic pain pathogenesis 6.

Sources cited
1
GFRA2 is a GPI-anchored receptor with nine coding exons, required for myenteric nerve plexus development
PMID: 11409869
2
GFRA2 forms complexes with neurturin and contains heparan sulfate-binding sites for signaling
PMID: 29414779
3
GFRA2-RET signaling phosphorylates hexokinase 2 and promotes pancreatic cancer glycolysis
PMID: 39988080
4
GFRA2 variants modify disease risk in frontotemporal lobar degeneration with GRN mutations
PMID: 29724592
5
GFRA2 marks cardiac progenitors and mediates cardiomyocyte differentiation via RET-independent pathways
PMID: 27396331
6
GFRA2 is upregulated in degenerative disc disease and may contribute to discogenic pain
PMID: 37958856
Disease Associationsⓘ20
poisoningOpen Targets
0.32Weak
device complicationOpen Targets
0.30Weak
esophageal ulcerOpen Targets
0.30Weak
VitiligoOpen Targets
0.29Weak
temporomandibular joint disorderOpen Targets
0.28Weak
neurodegenerative diseaseOpen Targets
0.25Weak
injuryOpen Targets
0.24Weak
connective tissue diseaseOpen Targets
0.21Weak
tooth diseaseOpen Targets
0.21Weak
response to selective serotonin reuptake inhibitorOpen Targets
0.20Weak
ShockOpen Targets
0.20Weak
ankylosing spondylitisOpen Targets
0.19Weak
crush injuryOpen Targets
0.19Weak
mouth neoplasmOpen Targets
0.19Weak
Hodgkins lymphomaOpen Targets
0.17Weak
Abruptio PlacentaeOpen Targets
0.13Weak
alcohol drinkingOpen Targets
0.12Weak
response to xenobiotic stimulusOpen Targets
0.12Weak
Abnormality of limbsOpen Targets
0.11Weak
placental retentionOpen Targets
0.10Weak
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
GDNFProtein interaction100%NCAM1Protein interaction82%NTRK1Protein interaction77%PSPNProtein interaction75%RETProtein interaction69%NRTNProtein interaction68%
Tissue Expression6 tissues
Brain
100%
Heart
54%
Bone Marrow
35%
Lung
14%
Ovary
12%
Liver
11%
Gene Interaction Network
Click a node to explore
GFRA2GDNFNCAM1NTRK1PSPNRETNRTN
PROTEIN STRUCTURE
Preparing viewer…
PDB5MR5 · 2.00 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.69LoF Tolerant
pLIⓘ
0.10Tolerant
Observed/Expected LoF0.44 [0.29–0.69]
RankingsWhere GFRA2 stands among ~20K protein-coding genes
  • #10,327of 20,598
    Most Researched39
  • #5,264of 17,882
    Most Constrained (LOEUF)0.69
Genes detectedGFRA2
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Cloning and characterization of the human GFRA2 locus and investigation of the gene in Hirschsprung disease.
PMID: 11409869
Hum Genet · 2001
1.00
2
Structure and biophysical characterization of the human full-length neurturin-GFRa2 complex: A role for heparan sulfate in signaling.
PMID: 29414779
J Biol Chem · 2018
0.90
3
Neurturin-induced activation of GFRA2-RET axis potentiates pancreatic cancer glycolysis via phosphorylated hexokinase 2.
PMID: 39988080
Cancer Lett · 2025
0.80
4
Single-cell transcriptome analysis of the in vivo response to viral infection in the cave nectar bat Eonycteris spelaea.
PMID: 36351376
Immunity · 2022
0.70
5
Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.
PMID: 29724592
Lancet Neurol · 2018
0.60