{"gene":"GFRA2","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":1997,"finding":"TrnR2 (GFRA2) is a GPI-linked cell surface receptor that mediates both neurturin (NTN) and GDNF signaling through the RET tyrosine kinase; fibroblasts co-expressing TrnR2 and RET are ~30-fold more sensitive to NTN than to GDNF, establishing TrnR2-RET as a preferential receptor complex for NTN.","method":"In vitro signaling assays in fibroblasts expressing TrnR2 and RET; GPI-linkage characterization; comparison with TrnR1-expressing cells","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — functional reconstitution in defined cell system with quantitative ligand sensitivity measurements, foundational paper with 305 citations","pmids":["9182803"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of NRTN alone and in complex with GFRα2 (first structure of a GFRα with all three domains) revealed that domain 1 of GFRα2 does not directly contact NRTN but exposes a conserved surface that may interact with RET and/or NCAM; a heparan sulfate-binding site was identified on NRTN and a putative binding site on GFRα2, implicating heparan sulfate in assembly of the signaling complex; cell-surface GFRα2 concentration affects functional affinity of NRTN through avidity effects.","method":"X-ray crystallography of NRTN and NRTN-GFRα2 complex; biophysical binding assays; cell-based functional assays with heparan sulfate-binding mutants of NRTN","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis and biophysical validation in single study","pmids":["29414779"],"is_preprint":false},{"year":2016,"finding":"GFRA2 marks cardiac progenitor cells and mediates cardiomyocyte differentiation through a RET-independent signaling pathway distinct from the canonical GDNF/neurturin-RET axis; Gfra2 loss-of-function mutants show defects in cardiomyocyte differentiation both in vitro and in vivo.","method":"FACS isolation of GFRA2+ cardiac progenitors from mouse and human pluripotent stem cells; Gfra2 knockout mouse analysis; in vitro differentiation assays; genetic epistasis placing GFRA2 upstream of cardiomyocyte differentiation in a RET-independent pathway","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype and pathway placement, but RET-independence inferred rather than biochemically reconstituted","pmids":["27396331"],"is_preprint":false},{"year":2025,"finding":"Neurturin binding to GFRA2 on pancreatic cancer cells induces RET kinase recruitment and GFRA2-RET heterodimer assembly; this receptor tyrosine kinase complex phosphorylates hexokinase 2 (HK2) at Ser122, augmenting hexokinase activity and driving aerobic glycolysis to fuel pancreatic cancer growth.","method":"Integrated metabolomics; co-receptor binding/recruitment assays; phosphorylation site mapping of HK2 (Ser122); in vivo xenograft models with neurturin blockade and RET inhibitor combination","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — defined substrate (HK2 Ser122 phosphorylation) with in vivo corroboration, but single lab with limited independent replication","pmids":["39988080"],"is_preprint":false}],"current_model":"GFRA2 is a GPI-anchored co-receptor that preferentially binds neurturin (and, with lower affinity, GDNF) and recruits RET to form a signaling complex — as resolved by crystal structure — through which it activates downstream kinase cascades including direct phosphorylation of HK2 at Ser122 to drive glycolysis; additionally, GFRA2 can signal through a RET-independent pathway to promote cardiomyocyte differentiation from cardiac progenitor cells, and heparan sulfate participates in assembly of the full NRTN-GFRα2-RET signaling complex."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing the identity of GFRA2 as a GPI-linked co-receptor that pairs with RET to transduce neurturin signaling with ~30-fold preference over GDNF answered the fundamental question of how NTN signals at the cell surface and defined the ligand–co-receptor–kinase paradigm for this family.","evidence":"Reconstitution in fibroblasts co-expressing TrnR2/GFRA2 and RET with quantitative ligand sensitivity measurements","pmids":["9182803"],"confidence":"High","gaps":["No structural basis for ligand selectivity or RET recruitment","Whether GFRA2 can signal independently of RET was untested","Downstream signaling targets beyond RET autophosphorylation were uncharacterized"]},{"year":2016,"claim":"Discovery that GFRA2 marks cardiac progenitor cells and drives cardiomyocyte differentiation through a RET-independent pathway expanded the receptor's functional repertoire beyond the nervous system and demonstrated a non-canonical signaling mode.","evidence":"FACS isolation of GFRA2+ cardiac progenitors from mouse/human pluripotent stem cells; Gfra2 knockout mouse with cardiomyocyte differentiation defects","pmids":["27396331"],"confidence":"Medium","gaps":["RET-independence inferred genetically but not biochemically reconstituted","Downstream effectors of the RET-independent pathway remain unidentified","Ligand for GFRA2 in cardiac progenitor context not definitively established"]},{"year":2018,"claim":"The crystal structure of NRTN–GFRα2 resolved how the co-receptor engages its ligand and revealed that domain 1 is free to interact with RET or NCAM, while identifying heparan sulfate–binding sites on both NRTN and GFRα2 that participate in complex assembly.","evidence":"X-ray crystallography of NRTN alone and NRTN–GFRα2 complex; mutagenesis of heparan sulfate–binding residues; cell-based functional assays","pmids":["29414779"],"confidence":"High","gaps":["No structure of the ternary NRTN–GFRα2–RET complex","Functional significance of the putative NCAM interaction surface not validated","Heparan sulfate contribution quantified only through NRTN mutants, not GFRα2 mutants"]},{"year":2025,"claim":"Identification of HK2 Ser122 as a direct phosphorylation target downstream of the NRTN–GFRA2–RET complex linked co-receptor signaling to metabolic reprogramming (aerobic glycolysis) in pancreatic cancer, providing the first specific kinase substrate for this pathway in a cancer context.","evidence":"Phosphorylation site mapping of HK2; metabolomics; in vivo xenograft models with neurturin blockade and RET inhibitor combination","pmids":["39988080"],"confidence":"Medium","gaps":["Single-lab finding; independent replication of HK2 Ser122 phosphorylation by GFRA2-RET pending","Whether RET directly phosphorylates HK2 or acts through an intermediate kinase is unresolved","Generalizability of this metabolic mechanism to other GFRA2-expressing cancers untested"]},{"year":null,"claim":"A ternary NRTN–GFRα2–RET structure, the identity of the downstream effectors in RET-independent cardiac signaling, and the breadth of GFRA2-driven metabolic rewiring across tissues remain open questions.","evidence":"","pmids":[],"confidence":"High","gaps":["No ternary complex structure resolved","RET-independent signaling pathway effectors unidentified","Scope of HK2/glycolysis regulation by GFRA2-RET beyond pancreatic cancer unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]}],"complexes":[],"partners":["RET","NRTN","GDNF","HK2"],"other_free_text":[]},"mechanistic_narrative":"GFRA2 is a GPI-anchored co-receptor that preferentially binds neurturin (NRTN) and, with lower affinity, GDNF, recruiting the RET receptor tyrosine kinase to form a signaling complex that activates downstream kinase cascades [PMID:9182803]. The crystal structure of the NRTN–GFRα2 complex reveals that domain 1 of GFRα2 does not contact NRTN but presents a conserved surface for RET and/or NCAM interaction, and heparan sulfate participates in signaling-complex assembly through binding sites on both NRTN and GFRα2 [PMID:29414779]. In pancreatic cancer cells, NRTN-induced GFRA2–RET signaling phosphorylates hexokinase 2 (HK2) at Ser122, augmenting glycolysis and tumor growth [PMID:39988080]. GFRA2 also functions in a RET-independent pathway in cardiac progenitor cells, where it is required for cardiomyocyte differentiation [PMID:27396331]."},"prefetch_data":{"uniprot":{"accession":"O00451","full_name":"GDNF family receptor alpha-2","aliases":["GDNF receptor beta","GDNFR-beta","Neurturin receptor alpha","NRTNR-alpha","NTNR-alpha","RET ligand 2","TGF-beta-related neurotrophic factor receptor 2"],"length_aa":464,"mass_kda":51.5,"function":"Receptor for neurturin (NRTN), a growth factor that supports the survival of sympathetic neurons (PubMed:10829012, PubMed:29414779, PubMed:31535977, PubMed:9182803). NRTN-binding leads to autophosphorylation and activation of the RET receptor (PubMed:31535977). Also able to mediate GDNF signaling through the RET tyrosine kinase receptor (PubMed:9182803) Participates in NRTN-induced 'Ser-727' phosphorylation of STAT3","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O00451/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GFRA2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GFRA2","total_profiled":1310},"omim":[{"mim_id":"605710","title":"GDNF FAMILY RECEPTOR ALPHA-3; GFRA3","url":"https://www.omim.org/entry/605710"},{"mim_id":"601956","title":"GDNF FAMILY RECEPTOR ALPHA-2; GFRA2","url":"https://www.omim.org/entry/601956"},{"mim_id":"601496","title":"GDNF FAMILY RECEPTOR ALPHA-1; GFRA1","url":"https://www.omim.org/entry/601496"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":9.0},{"tissue":"thyroid gland","ntpm":8.2}],"url":"https://www.proteinatlas.org/search/GFRA2"},"hgnc":{"alias_symbol":["RETL2","GDNFRB","NTNRA","TRNR2"],"prev_symbol":[]},"alphafold":{"accession":"O00451","domains":[{"cath_id":"-","chopping":"41-118","consensus_level":"high","plddt":88.8301,"start":41,"end":118},{"cath_id":"1.10.220.110","chopping":"136-140_159-358","consensus_level":"medium","plddt":94.9121,"start":136,"end":358}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00451","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00451-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00451-F1-predicted_aligned_error_v6.png","plddt_mean":75.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GFRA2","jax_strain_url":"https://www.jax.org/strain/search?query=GFRA2"},"sequence":{"accession":"O00451","fasta_url":"https://rest.uniprot.org/uniprotkb/O00451.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00451/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00451"}},"corpus_meta":[{"pmid":"9182803","id":"PMC_9182803","title":"TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret.","date":"1997","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/9182803","citation_count":305,"is_preprint":false},{"pmid":"30250203","id":"PMC_30250203","title":"GWAS and eQTL analysis identifies a SNP associated with both residual feed intake and GFRA2 expression in beef cattle.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30250203","citation_count":46,"is_preprint":false},{"pmid":"29414779","id":"PMC_29414779","title":"Structure and biophysical characterization of the human full-length neurturin-GFRa2 complex: A role for heparan sulfate in signaling.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29414779","citation_count":29,"is_preprint":false},{"pmid":"27396331","id":"PMC_27396331","title":"GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27396331","citation_count":23,"is_preprint":false},{"pmid":"11409869","id":"PMC_11409869","title":"Cloning and characterization of the human GFRA2 locus and investigation of the gene in Hirschsprung disease.","date":"2001","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11409869","citation_count":15,"is_preprint":false},{"pmid":"16140423","id":"PMC_16140423","title":"Age-related alteration of neurturin receptor GFRa2 and nNOS in pelvic ganglia.","date":"2005","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/16140423","citation_count":14,"is_preprint":false},{"pmid":"12490080","id":"PMC_12490080","title":"Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.","date":"2002","source":"Thyroid : official journal of the American Thyroid Association","url":"https://pubmed.ncbi.nlm.nih.gov/12490080","citation_count":14,"is_preprint":false},{"pmid":"20369355","id":"PMC_20369355","title":"Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRA2) gene is associated with tardive dyskinesia.","date":"2010","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20369355","citation_count":7,"is_preprint":false},{"pmid":"39988080","id":"PMC_39988080","title":"Neurturin-induced activation of GFRA2-RET axis potentiates pancreatic cancer glycolysis via phosphorylated hexokinase 2.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39988080","citation_count":2,"is_preprint":false},{"pmid":"41622043","id":"PMC_41622043","title":"Exploratory genome-wide analysis suggests potential associations of PPP1R12B, FSTL5, G5K3B, and GFRA2 loci with a derived HDL functionality score.","date":"2026","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/41622043","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6225,"output_tokens":1236,"usd":0.018607},"stage2":{"model":"claude-opus-4-6","input_tokens":4467,"output_tokens":1678,"usd":0.096427},"total_usd":0.115034,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"TrnR2 (GFRA2) is a GPI-linked cell surface receptor that mediates both neurturin (NTN) and GDNF signaling through the RET tyrosine kinase; fibroblasts co-expressing TrnR2 and RET are ~30-fold more sensitive to NTN than to GDNF, establishing TrnR2-RET as a preferential receptor complex for NTN.\",\n      \"method\": \"In vitro signaling assays in fibroblasts expressing TrnR2 and RET; GPI-linkage characterization; comparison with TrnR1-expressing cells\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional reconstitution in defined cell system with quantitative ligand sensitivity measurements, foundational paper with 305 citations\",\n      \"pmids\": [\"9182803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of NRTN alone and in complex with GFRα2 (first structure of a GFRα with all three domains) revealed that domain 1 of GFRα2 does not directly contact NRTN but exposes a conserved surface that may interact with RET and/or NCAM; a heparan sulfate-binding site was identified on NRTN and a putative binding site on GFRα2, implicating heparan sulfate in assembly of the signaling complex; cell-surface GFRα2 concentration affects functional affinity of NRTN through avidity effects.\",\n      \"method\": \"X-ray crystallography of NRTN and NRTN-GFRα2 complex; biophysical binding assays; cell-based functional assays with heparan sulfate-binding mutants of NRTN\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis and biophysical validation in single study\",\n      \"pmids\": [\"29414779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GFRA2 marks cardiac progenitor cells and mediates cardiomyocyte differentiation through a RET-independent signaling pathway distinct from the canonical GDNF/neurturin-RET axis; Gfra2 loss-of-function mutants show defects in cardiomyocyte differentiation both in vitro and in vivo.\",\n      \"method\": \"FACS isolation of GFRA2+ cardiac progenitors from mouse and human pluripotent stem cells; Gfra2 knockout mouse analysis; in vitro differentiation assays; genetic epistasis placing GFRA2 upstream of cardiomyocyte differentiation in a RET-independent pathway\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and pathway placement, but RET-independence inferred rather than biochemically reconstituted\",\n      \"pmids\": [\"27396331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Neurturin binding to GFRA2 on pancreatic cancer cells induces RET kinase recruitment and GFRA2-RET heterodimer assembly; this receptor tyrosine kinase complex phosphorylates hexokinase 2 (HK2) at Ser122, augmenting hexokinase activity and driving aerobic glycolysis to fuel pancreatic cancer growth.\",\n      \"method\": \"Integrated metabolomics; co-receptor binding/recruitment assays; phosphorylation site mapping of HK2 (Ser122); in vivo xenograft models with neurturin blockade and RET inhibitor combination\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined substrate (HK2 Ser122 phosphorylation) with in vivo corroboration, but single lab with limited independent replication\",\n      \"pmids\": [\"39988080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GFRA2 is a GPI-anchored co-receptor that preferentially binds neurturin (and, with lower affinity, GDNF) and recruits RET to form a signaling complex — as resolved by crystal structure — through which it activates downstream kinase cascades including direct phosphorylation of HK2 at Ser122 to drive glycolysis; additionally, GFRA2 can signal through a RET-independent pathway to promote cardiomyocyte differentiation from cardiac progenitor cells, and heparan sulfate participates in assembly of the full NRTN-GFRα2-RET signaling complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GFRA2 is a GPI-anchored co-receptor that preferentially binds neurturin (NRTN) and, with lower affinity, GDNF, recruiting the RET receptor tyrosine kinase to form a signaling complex that activates downstream kinase cascades [PMID:9182803]. The crystal structure of the NRTN–GFRα2 complex reveals that domain 1 of GFRα2 does not contact NRTN but presents a conserved surface for RET and/or NCAM interaction, and heparan sulfate participates in signaling-complex assembly through binding sites on both NRTN and GFRα2 [PMID:29414779]. In pancreatic cancer cells, NRTN-induced GFRA2–RET signaling phosphorylates hexokinase 2 (HK2) at Ser122, augmenting glycolysis and tumor growth [PMID:39988080]. GFRA2 also functions in a RET-independent pathway in cardiac progenitor cells, where it is required for cardiomyocyte differentiation [PMID:27396331].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the identity of GFRA2 as a GPI-linked co-receptor that pairs with RET to transduce neurturin signaling with ~30-fold preference over GDNF answered the fundamental question of how NTN signals at the cell surface and defined the ligand–co-receptor–kinase paradigm for this family.\",\n      \"evidence\": \"Reconstitution in fibroblasts co-expressing TrnR2/GFRA2 and RET with quantitative ligand sensitivity measurements\",\n      \"pmids\": [\"9182803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural basis for ligand selectivity or RET recruitment\",\n        \"Whether GFRA2 can signal independently of RET was untested\",\n        \"Downstream signaling targets beyond RET autophosphorylation were uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that GFRA2 marks cardiac progenitor cells and drives cardiomyocyte differentiation through a RET-independent pathway expanded the receptor's functional repertoire beyond the nervous system and demonstrated a non-canonical signaling mode.\",\n      \"evidence\": \"FACS isolation of GFRA2+ cardiac progenitors from mouse/human pluripotent stem cells; Gfra2 knockout mouse with cardiomyocyte differentiation defects\",\n      \"pmids\": [\"27396331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"RET-independence inferred genetically but not biochemically reconstituted\",\n        \"Downstream effectors of the RET-independent pathway remain unidentified\",\n        \"Ligand for GFRA2 in cardiac progenitor context not definitively established\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The crystal structure of NRTN–GFRα2 resolved how the co-receptor engages its ligand and revealed that domain 1 is free to interact with RET or NCAM, while identifying heparan sulfate–binding sites on both NRTN and GFRα2 that participate in complex assembly.\",\n      \"evidence\": \"X-ray crystallography of NRTN alone and NRTN–GFRα2 complex; mutagenesis of heparan sulfate–binding residues; cell-based functional assays\",\n      \"pmids\": [\"29414779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the ternary NRTN–GFRα2–RET complex\",\n        \"Functional significance of the putative NCAM interaction surface not validated\",\n        \"Heparan sulfate contribution quantified only through NRTN mutants, not GFRα2 mutants\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of HK2 Ser122 as a direct phosphorylation target downstream of the NRTN–GFRA2–RET complex linked co-receptor signaling to metabolic reprogramming (aerobic glycolysis) in pancreatic cancer, providing the first specific kinase substrate for this pathway in a cancer context.\",\n      \"evidence\": \"Phosphorylation site mapping of HK2; metabolomics; in vivo xenograft models with neurturin blockade and RET inhibitor combination\",\n      \"pmids\": [\"39988080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication of HK2 Ser122 phosphorylation by GFRA2-RET pending\",\n        \"Whether RET directly phosphorylates HK2 or acts through an intermediate kinase is unresolved\",\n        \"Generalizability of this metabolic mechanism to other GFRA2-expressing cancers untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A ternary NRTN–GFRα2–RET structure, the identity of the downstream effectors in RET-independent cardiac signaling, and the breadth of GFRA2-driven metabolic rewiring across tissues remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No ternary complex structure resolved\",\n        \"RET-independent signaling pathway effectors unidentified\",\n        \"Scope of HK2/glycolysis regulation by GFRA2-RET beyond pancreatic cancer unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RET\",\n      \"NRTN\",\n      \"GDNF\",\n      \"HK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}