{"gene":"IL5RA","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1991,"finding":"The high-affinity human IL-5 receptor is a heterodimer composed of an IL-5-specific alpha chain (IL5RA) and a beta chain (βc) shared with the GM-CSF receptor; the major transcript in HL-60 eosinophilic cells and cord blood eosinophilic myelocytes encodes a secreted/soluble form of IL5RA that acts as an antagonist of IL-5 signaling.","method":"cDNA cloning, receptor binding assays, functional antagonism assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — original receptor reconstitution and cloning with functional validation, foundational study replicated extensively","pmids":["1833065"],"is_preprint":false},{"year":2002,"finding":"The signaling subunit βc is recruited sequentially to a preformed IL5:IL5Rα complex; βc binds with moderate affinity (~0.2–1 µM) and a fast off-rate directly to IL5:IL5Rα but not to IL5Rα or IL5 alone, supporting a model of ordered receptor assembly.","method":"Optical biosensor (surface plasmon resonance) binding kinetics using soluble βc ectodomain anchored via anti-His antibody","journal":"Analytical biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro reconstitution with kinetic dissection, single lab but multiple binding conditions tested","pmids":["12202242"],"is_preprint":false},{"year":1996,"finding":"IL5RA-deficient mice show absent IL-5-induced eosinophilopoiesis, severely reduced B-1 cell numbers, low serum IgM/IgG3, no IL-5-induced enhancement of B-cell responses to T-independent antigens, and impaired killing of Angiostrongylus cantonensis, establishing IL5RA as required for IL-5-dependent eosinophil and B-1 cell development.","method":"Gene targeting (knockout mouse), colony assays, flow cytometry, in vivo parasite challenge","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple orthogonal phenotypic readouts across cell lineages","pmids":["8630733"],"is_preprint":false},{"year":1996,"finding":"A unique cis-element (EOS1) in the IL-5Rα promoter acts as an enhancer and binds a nuclear factor that contacts DNA across two helical turns on one side of the helix, suggesting homodimeric binding; this element cooperates with a proximal AP-1 site to regulate eosinophil lineage-specific promoter activity.","method":"Promoter deletion/mutation analysis, electrophoretic mobility shift assay (EMSA), methylation interference","journal":"Current topics in microbiology and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional promoter mutagenesis and EMSA in a single study, EOS1 factor identity not yet determined","pmids":["8585949"],"is_preprint":false},{"year":1998,"finding":"An AP-1 site in the IL-5Rα promoter is necessary for promoter activity in eosinophilic HL-60 cells; it binds cJun, CREB, and CREM, and cooperates with the EOS1 site—mutation of either site alone reduces activity.","method":"Promoter reporter assays, EMSA, site-directed mutagenesis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutagenesis combined with protein-binding assays, single lab","pmids":["9742933"],"is_preprint":false},{"year":2006,"finding":"IL-5 is not required for differential splicing of transmembrane vs. soluble IL-5Rα isoforms in vivo; all three splice variants are expressed at equivalent ratios in IL-5 gene-deleted mice compared to wild-type, indicating the splicing decision is IL-5-independent.","method":"Quantitative RT-PCR in IL-5 gene-deleted vs. wild-type mice (BALB/c and C57BL/6) during Schistosoma mansoni infection","journal":"European journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic model (IL-5 KO) with quantitative isoform analysis in two genetic backgrounds; negative mechanistic finding","pmids":["16856933"],"is_preprint":false},{"year":2021,"finding":"IL-5Rα (CD125) is expressed on the surface of blood and lung neutrophils (not only eosinophils/basophils); lung neutrophil expression is higher than blood and increases in response to airway pathogens via translocation from intracellular stores; the receptor is functional as demonstrated by IL-5-induced down-regulation of surface CD62L and feed-forward up-regulation of receptor expression.","method":"Flow cytometry, immunohistochemistry, functional stimulation assays on purified neutrophils from blood and BAL","journal":"Annals of allergy, asthma & immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional signaling readouts, single lab with multiple orthogonal methods","pmids":["34391897"],"is_preprint":false},{"year":2021,"finding":"During human eosinophilopoiesis from CD34+ progenitors, two IL5RA promoters (P1 and P2) are differentially active: P1 is relatively constant throughout development while P2 peaks early and wanes; transcription factor binding sites for GATA-1, PU.1, and C/EBP family members regulate promoter activity; the soluble isoform mRNA peaks early while the transmembrane (signaling-competent) isoform peaks later.","method":"Promoter reporter assays in eosinophilic cell lines, ChIP in primary human eosinophil cultures, qRT-PCR for isoforms","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validation in primary cells combined with functional reporter assays, single lab","pmids":["34638583"],"is_preprint":false},{"year":2016,"finding":"In FIP1L1-PDGFRA (F/P)-positive chronic eosinophilic leukemia cells, Lyn kinase is activated by F/P, associates with and phosphorylates IL-5Rα, and participates in a FIP1L1-PDGFRA/JAK2/Lyn/Akt signaling complex; this complex is disrupted by dual JAK2 and Lyn inhibition, suppressing proliferation in both imatinib-sensitive and -resistant cells.","method":"Co-immunoprecipitation, phosphorylation assays, pharmacological inhibition, cell viability/apoptosis assays, EOL-1 cell line and imatinib-resistant cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating complex membership plus functional rescue experiments, single lab","pmids":["29029406"],"is_preprint":false},{"year":2024,"finding":"In pulmonary fibrosis models, epithelial IL5RA expression is upregulated and promotes epithelial-mesenchymal transition (EMT) and ECM production via JAK2/STAT3 signaling cascades; inhibiting IL5RA deactivates JAK2/STAT3 and suppresses downstream EMT.","method":"Single-cell analysis, in vitro cell assays, in vivo mouse model, IL5RA knockdown/overexpression, pathway inhibition","journal":"Pulmonary pharmacology & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined pathway readout (JAK2/STAT3/EMT), single lab","pmids":["38191068"],"is_preprint":false},{"year":2022,"finding":"JMJD2C (a histone demethylase) removes H3K9me3 from the MDM2 promoter to upregulate MDM2; MDM2 then promotes ubiquitination and degradation of p53, which leads to upregulation of IL5RA expression and consequent cisplatin resistance in uveal melanoma cells; knockdown of IL5RA reversed CDDP resistance.","method":"ChIP assay, co-IP (p53/ubiquitin), RT-qPCR, Western blot, CCK-8, flow cytometry, in vivo xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including ChIP and Co-IP establishing pathway order, single lab","pmids":["35468881"],"is_preprint":false},{"year":2007,"finding":"IL-5Rα protein expression levels on peripheral blood eosinophils are associated with a promoter polymorphism (IL5RA c.-5091G>A): the A allele is associated with higher IL-5Rα surface expression as measured by flow cytometry.","method":"Flow cytometry of eosinophil surface IL-5Rα, SNP genotyping in asthmatic patients and controls","journal":"The Journal of allergy and clinical immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single flow cytometry method, genetic association study, no direct promoter functional assay","pmids":["17983872"],"is_preprint":false}],"current_model":"IL5RA encodes the IL-5-specific alpha subunit of the IL-5 receptor, which forms a high-affinity signaling complex by first binding IL-5 and then sequentially recruiting the shared βc subunit; the receptor gene is regulated by two promoters through combinatorial action of GATA-1, PU.1, C/EBP, and AP-1/EOS1 elements, producing both a signaling-competent transmembrane isoform and an antagonistic soluble isoform; IL5RA is required for IL-5-driven eosinophilopoiesis and B-1 cell development, is expressed and functional on neutrophils in addition to eosinophils/basophils, engages JAK2/Lyn/Akt signaling downstream of oncogenic FIP1L1-PDGFRA in eosinophilic leukemia, promotes EMT via JAK2/STAT3 in lung epithelial cells, and can be upregulated through an MDM2/p53 axis to confer chemotherapy resistance."},"narrative":{"mechanistic_narrative":"IL5RA encodes the IL-5-specific alpha subunit of the IL-5 receptor and is the central determinant of IL-5 responsiveness across hematopoietic and, more recently, epithelial cells [PMID:1833065, PMID:8630733]. The high-affinity receptor is a heterodimer in which the IL5RA alpha chain confers ligand specificity and the signaling beta chain (βc), shared with the GM-CSF receptor, is recruited in an ordered fashion: βc binds with moderate affinity and a fast off-rate to the preformed IL-5:IL5RA binary complex but not to either component alone [PMID:1833065, PMID:12202242]. The gene produces both a signaling-competent transmembrane isoform and a secreted/soluble isoform that antagonizes IL-5 signaling, with isoform output and overall expression controlled by two promoters (P1, P2) acting through GATA-1, PU.1, C/EBP, and cooperating EOS1/AP-1 elements during eosinophil development; the splicing decision itself is IL-5-independent [PMID:1833065, PMID:8585949, PMID:9742933, PMID:34638583, PMID:16856933]. Genetically, IL5RA is required for IL-5-driven eosinophilopoiesis and B-1 cell development, with loss eliminating IL-5-induced eosinophil production, depleting B-1 cells, lowering serum IgM/IgG3, and impairing antiparasite immunity [PMID:8630733]. The receptor is also expressed and functional on neutrophils, where airway pathogens drive its surface display from intracellular stores [PMID:34391897]. Beyond normal immunity, IL5RA participates in disease-associated signaling: it is phosphorylated by Lyn within a FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in eosinophilic leukemia [PMID:29029406], drives epithelial-mesenchymal transition via JAK2/STAT3 in pulmonary fibrosis [PMID:38191068], and is upregulated through an MDM2/p53 axis to confer chemotherapy resistance in uveal melanoma [PMID:35468881].","teleology":[{"year":1991,"claim":"Established the molecular identity of the IL-5 receptor, resolving that IL-5 specificity is conferred by a dedicated alpha chain partnered with a shared beta chain, and that an antagonistic soluble form exists.","evidence":"cDNA cloning, receptor binding and functional antagonism assays in eosinophilic cells","pmids":["1833065"],"confidence":"High","gaps":["Did not resolve the order or kinetics of subunit assembly","Regulation of soluble vs transmembrane isoform production not defined"]},{"year":1996,"claim":"Defined IL5RA as physiologically required for IL-5-dependent eosinophil and B-1 cell development, moving it from a biochemical receptor to an in vivo lineage determinant.","evidence":"Knockout mouse with colony assays, flow cytometry, and in vivo parasite challenge","pmids":["8630733"],"confidence":"High","gaps":["Does not address roles outside eosinophil/B-1 lineages","Downstream signaling effectors in vivo not dissected"]},{"year":1996,"claim":"Began mapping how lineage-restricted IL5RA transcription is achieved by identifying the EOS1 enhancer element and its cooperation with a proximal AP-1 site.","evidence":"Promoter mutagenesis, EMSA, and methylation interference","pmids":["8585949"],"confidence":"Medium","gaps":["Identity of the EOS1-binding factor not determined","Single-study promoter analysis"]},{"year":1998,"claim":"Identified the transcription factors binding the AP-1 site (cJun, CREB, CREM) and showed combinatorial dependence with EOS1 for eosinophil-specific promoter activity.","evidence":"Promoter reporter assays, EMSA, site-directed mutagenesis in HL-60 cells","pmids":["9742933"],"confidence":"Medium","gaps":["Endogenous chromatin occupancy not confirmed","Does not connect promoter activity to isoform choice"]},{"year":2002,"claim":"Resolved the assembly mechanism, showing βc is recruited sequentially with moderate affinity to a preformed IL-5:IL5RA complex, supporting an ordered receptor model.","evidence":"Surface plasmon resonance binding kinetics with soluble βc ectodomain","pmids":["12202242"],"confidence":"High","gaps":["Performed with soluble ectodomains, not full-length membrane receptors","Conformational basis of ordered binding not structurally resolved"]},{"year":2006,"claim":"Determined that the transmembrane-vs-soluble isoform splicing decision is IL-5-independent, ruling out ligand-driven feedback control of isoform ratios.","evidence":"Quantitative RT-PCR in IL-5 gene-deleted vs wild-type mice during Schistosoma infection","pmids":["16856933"],"confidence":"Medium","gaps":["Does not identify what does control the splicing decision","Negative finding limited to the infection model tested"]},{"year":2007,"claim":"Linked a promoter polymorphism (c.-5091G>A) to differential IL5RA surface expression on eosinophils, connecting genetic variation to receptor density.","evidence":"Eosinophil flow cytometry and SNP genotyping in asthmatic patients and controls","pmids":["17983872"],"confidence":"Low","gaps":["No direct promoter functional assay confirming causality","Single method (flow cytometry), association only"]},{"year":2016,"claim":"Placed IL5RA within an oncogenic signaling complex, showing Lyn associates with and phosphorylates it downstream of FIP1L1-PDGFRA in eosinophilic leukemia.","evidence":"Co-immunoprecipitation, phosphorylation assays, and dual JAK2/Lyn inhibition in EOL-1 and imatinib-resistant cells","pmids":["29029406"],"confidence":"Medium","gaps":["Direct vs indirect IL5RA-Lyn interaction not distinguished","Single lab, no reciprocal in vivo validation"]},{"year":2021,"claim":"Expanded IL5RA's cellular reach by demonstrating functional surface expression on neutrophils with pathogen-induced mobilization from intracellular stores.","evidence":"Flow cytometry, immunohistochemistry, and functional stimulation of blood and BAL neutrophils","pmids":["34391897"],"confidence":"Medium","gaps":["Physiological consequence of neutrophil IL-5 signaling in vivo unclear","Whether βc co-engages on neutrophils not shown"]},{"year":2021,"claim":"Defined the dual-promoter (P1/P2) program and transcription-factor inputs that time isoform expression across human eosinophilopoiesis, with soluble mRNA peaking early and transmembrane later.","evidence":"Promoter reporter assays, ChIP in primary eosinophil cultures, isoform qRT-PCR","pmids":["34638583"],"confidence":"Medium","gaps":["Causal contribution of each factor to isoform switching not isolated","Single-lab dataset"]},{"year":2024,"claim":"Extended IL5RA function to non-hematopoietic disease, showing epithelial IL5RA drives EMT and ECM production via JAK2/STAT3 in pulmonary fibrosis.","evidence":"Single-cell analysis, in vitro/in vivo loss- and gain-of-function, pathway inhibition","pmids":["38191068"],"confidence":"Medium","gaps":["Whether epithelial signaling requires βc and IL-5 ligand not defined","Single lab"]},{"year":2022,"claim":"Identified an upstream regulatory axis (JMJD2C/MDM2/p53) controlling IL5RA expression to confer cisplatin resistance, framing IL5RA as a chemoresistance effector.","evidence":"ChIP, p53/ubiquitin Co-IP, knockdown, and xenograft in uveal melanoma cells","pmids":["35468881"],"confidence":"Medium","gaps":["Mechanism by which IL5RA mediates resistance downstream not defined","Direct p53-IL5RA regulatory link not shown"]},{"year":null,"claim":"How IL5RA signaling specificity and isoform balance are coordinated across its diverse contexts (eosinophils, B-1 cells, neutrophils, epithelium, tumor cells) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the full-length signaling complex","Factors controlling the IL-5-independent splicing decision unidentified","Whether epithelial/tumor IL5RA functions require canonical βc/IL-5 engagement is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10]}],"complexes":["IL-5 receptor (IL5RA/βc heterodimer)","FIP1L1-PDGFRA/JAK2/Lyn/Akt signaling complex"],"partners":["CSF2RB","IL5","LYN","JAK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01344","full_name":"Interleukin-5 receptor subunit alpha","aliases":["CDw125"],"length_aa":420,"mass_kda":47.7,"function":"Cell surface receptor that plays an important role in the survival, differentiation, and chemotaxis of eosinophils (PubMed:9378992). Acts by forming a heterodimeric receptor with CSF2RB subunit and subsequently binding to interleukin-5 (PubMed:1495999, PubMed:22528658). In unstimulated conditions, interacts constitutively with JAK2. Heterodimeric receptor activation leads to JAK2 stimulation and subsequent activation of the JAK-STAT pathway (PubMed:9516124)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q01344/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL5RA","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/IL5RA","total_profiled":1310},"omim":[{"mim_id":"613936","title":"TRANSMEMBRANE PROTEIN 102; TMEM102","url":"https://www.omim.org/entry/613936"},{"mim_id":"604011","title":"UNC119 LIPID-BINDING CHAPERONE; UNC119","url":"https://www.omim.org/entry/604011"},{"mim_id":"602217","title":"SYNDECAN-BINDING PROTEIN; SDCBP","url":"https://www.omim.org/entry/602217"},{"mim_id":"308385","title":"INTERLEUKIN 3 RECEPTOR, ALPHA; IL3RA","url":"https://www.omim.org/entry/308385"},{"mim_id":"184430","title":"SRY-BOX 4; SOX4","url":"https://www.omim.org/entry/184430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":5.9},{"tissue":"fallopian tube","ntpm":10.1}],"url":"https://www.proteinatlas.org/search/IL5RA"},"hgnc":{"alias_symbol":["CDw125","CD125"],"prev_symbol":["IL5R"]},"alphafold":{"accession":"Q01344","domains":[{"cath_id":"2.60.40.10","chopping":"33-54_62-117","consensus_level":"high","plddt":94.4483,"start":33,"end":117},{"cath_id":"2.60.40.10","chopping":"129-234","consensus_level":"high","plddt":94.5482,"start":129,"end":234},{"cath_id":"2.60.40.10","chopping":"242-330","consensus_level":"high","plddt":95.7409,"start":242,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01344","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01344-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01344-F1-predicted_aligned_error_v6.png","plddt_mean":83.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL5RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL5RA"},"sequence":{"accession":"Q01344","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01344.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01344/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01344"}},"corpus_meta":[{"pmid":"1833065","id":"PMC_1833065","title":"A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1833065","citation_count":579,"is_preprint":false},{"pmid":"8630733","id":"PMC_8630733","title":"Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5R alpha-deficient mice.","date":"1996","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8630733","citation_count":180,"is_preprint":false},{"pmid":"28913336","id":"PMC_28913336","title":"Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma.","date":"2017","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28913336","citation_count":69,"is_preprint":false},{"pmid":"32445070","id":"PMC_32445070","title":"MiRNA-495-3p Attenuates TNF-α Induced Apoptosis and Inflammation in Human 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haematology","url":"https://pubmed.ncbi.nlm.nih.gov/16856933","citation_count":5,"is_preprint":false},{"pmid":"34638583","id":"PMC_34638583","title":"Transcriptional Regulation of the Human IL5RA Gene through Alternative Promoter Usage during Eosinophil Development.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34638583","citation_count":4,"is_preprint":false},{"pmid":"37905709","id":"PMC_37905709","title":"The Study of the Influence of IL5RA Variants on Chronic Obstructive Pulmonary Disease.","date":"2023","source":"COPD","url":"https://pubmed.ncbi.nlm.nih.gov/37905709","citation_count":2,"is_preprint":false},{"pmid":"20337967","id":"PMC_20337967","title":"Cord blood molecular biomarkers of eosinophilopoiesis: kinetic analysis of GATA-1, MBP1 and IL-5R alpha mRNA expression.","date":"2010","source":"Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20337967","citation_count":2,"is_preprint":false},{"pmid":"24332579","id":"PMC_24332579","title":"Case-control study of rhinoconjunctivitis associated with IL5RA polymorphisms in Japanese women: the Kyushu Okinawa Maternal and Child Health Study.","date":"2013","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/24332579","citation_count":1,"is_preprint":false},{"pmid":"41976339","id":"PMC_41976339","title":"Extracellular Vesicle IL5RA and BCMA in Serum Enable Non-Invasive Risk Stratification of Multiple Myeloma.","date":"2026","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/41976339","citation_count":0,"is_preprint":false},{"pmid":"41898298","id":"PMC_41898298","title":"Preliminary Effects of Benralizumab in an AML Cell Model with Promyelocytic Features Expressing IL-5R: An Exploratory Proof-of-Concept 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signaling.\",\n      \"method\": \"cDNA cloning, receptor binding assays, functional antagonism assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original receptor reconstitution and cloning with functional validation, foundational study replicated extensively\",\n      \"pmids\": [\"1833065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The signaling subunit βc is recruited sequentially to a preformed IL5:IL5Rα complex; βc binds with moderate affinity (~0.2–1 µM) and a fast off-rate directly to IL5:IL5Rα but not to IL5Rα or IL5 alone, supporting a model of ordered receptor assembly.\",\n      \"method\": \"Optical biosensor (surface plasmon resonance) binding kinetics using soluble βc ectodomain anchored via anti-His antibody\",\n      \"journal\": \"Analytical biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro reconstitution with kinetic dissection, single lab but multiple binding conditions tested\",\n      \"pmids\": [\"12202242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IL5RA-deficient mice show absent IL-5-induced eosinophilopoiesis, severely reduced B-1 cell numbers, low serum IgM/IgG3, no IL-5-induced enhancement of B-cell responses to T-independent antigens, and impaired killing of Angiostrongylus cantonensis, establishing IL5RA as required for IL-5-dependent eosinophil and B-1 cell development.\",\n      \"method\": \"Gene targeting (knockout mouse), colony assays, flow cytometry, in vivo parasite challenge\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple orthogonal phenotypic readouts across cell lineages\",\n      \"pmids\": [\"8630733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A unique cis-element (EOS1) in the IL-5Rα promoter acts as an enhancer and binds a nuclear factor that contacts DNA across two helical turns on one side of the helix, suggesting homodimeric binding; this element cooperates with a proximal AP-1 site to regulate eosinophil lineage-specific promoter activity.\",\n      \"method\": \"Promoter deletion/mutation analysis, electrophoretic mobility shift assay (EMSA), methylation interference\",\n      \"journal\": \"Current topics in microbiology and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional promoter mutagenesis and EMSA in a single study, EOS1 factor identity not yet determined\",\n      \"pmids\": [\"8585949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"An AP-1 site in the IL-5Rα promoter is necessary for promoter activity in eosinophilic HL-60 cells; it binds cJun, CREB, and CREM, and cooperates with the EOS1 site—mutation of either site alone reduces activity.\",\n      \"method\": \"Promoter reporter assays, EMSA, site-directed mutagenesis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutagenesis combined with protein-binding assays, single lab\",\n      \"pmids\": [\"9742933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-5 is not required for differential splicing of transmembrane vs. soluble IL-5Rα isoforms in vivo; all three splice variants are expressed at equivalent ratios in IL-5 gene-deleted mice compared to wild-type, indicating the splicing decision is IL-5-independent.\",\n      \"method\": \"Quantitative RT-PCR in IL-5 gene-deleted vs. wild-type mice (BALB/c and C57BL/6) during Schistosoma mansoni infection\",\n      \"journal\": \"European journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic model (IL-5 KO) with quantitative isoform analysis in two genetic backgrounds; negative mechanistic finding\",\n      \"pmids\": [\"16856933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-5Rα (CD125) is expressed on the surface of blood and lung neutrophils (not only eosinophils/basophils); lung neutrophil expression is higher than blood and increases in response to airway pathogens via translocation from intracellular stores; the receptor is functional as demonstrated by IL-5-induced down-regulation of surface CD62L and feed-forward up-regulation of receptor expression.\",\n      \"method\": \"Flow cytometry, immunohistochemistry, functional stimulation assays on purified neutrophils from blood and BAL\",\n      \"journal\": \"Annals of allergy, asthma & immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional signaling readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34391897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During human eosinophilopoiesis from CD34+ progenitors, two IL5RA promoters (P1 and P2) are differentially active: P1 is relatively constant throughout development while P2 peaks early and wanes; transcription factor binding sites for GATA-1, PU.1, and C/EBP family members regulate promoter activity; the soluble isoform mRNA peaks early while the transmembrane (signaling-competent) isoform peaks later.\",\n      \"method\": \"Promoter reporter assays in eosinophilic cell lines, ChIP in primary human eosinophil cultures, qRT-PCR for isoforms\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation in primary cells combined with functional reporter assays, single lab\",\n      \"pmids\": [\"34638583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In FIP1L1-PDGFRA (F/P)-positive chronic eosinophilic leukemia cells, Lyn kinase is activated by F/P, associates with and phosphorylates IL-5Rα, and participates in a FIP1L1-PDGFRA/JAK2/Lyn/Akt signaling complex; this complex is disrupted by dual JAK2 and Lyn inhibition, suppressing proliferation in both imatinib-sensitive and -resistant cells.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, pharmacological inhibition, cell viability/apoptosis assays, EOL-1 cell line and imatinib-resistant cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating complex membership plus functional rescue experiments, single lab\",\n      \"pmids\": [\"29029406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pulmonary fibrosis models, epithelial IL5RA expression is upregulated and promotes epithelial-mesenchymal transition (EMT) and ECM production via JAK2/STAT3 signaling cascades; inhibiting IL5RA deactivates JAK2/STAT3 and suppresses downstream EMT.\",\n      \"method\": \"Single-cell analysis, in vitro cell assays, in vivo mouse model, IL5RA knockdown/overexpression, pathway inhibition\",\n      \"journal\": \"Pulmonary pharmacology & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined pathway readout (JAK2/STAT3/EMT), single lab\",\n      \"pmids\": [\"38191068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD2C (a histone demethylase) removes H3K9me3 from the MDM2 promoter to upregulate MDM2; MDM2 then promotes ubiquitination and degradation of p53, which leads to upregulation of IL5RA expression and consequent cisplatin resistance in uveal melanoma cells; knockdown of IL5RA reversed CDDP resistance.\",\n      \"method\": \"ChIP assay, co-IP (p53/ubiquitin), RT-qPCR, Western blot, CCK-8, flow cytometry, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including ChIP and Co-IP establishing pathway order, single lab\",\n      \"pmids\": [\"35468881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-5Rα protein expression levels on peripheral blood eosinophils are associated with a promoter polymorphism (IL5RA c.-5091G>A): the A allele is associated with higher IL-5Rα surface expression as measured by flow cytometry.\",\n      \"method\": \"Flow cytometry of eosinophil surface IL-5Rα, SNP genotyping in asthmatic patients and controls\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single flow cytometry method, genetic association study, no direct promoter functional assay\",\n      \"pmids\": [\"17983872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL5RA encodes the IL-5-specific alpha subunit of the IL-5 receptor, which forms a high-affinity signaling complex by first binding IL-5 and then sequentially recruiting the shared βc subunit; the receptor gene is regulated by two promoters through combinatorial action of GATA-1, PU.1, C/EBP, and AP-1/EOS1 elements, producing both a signaling-competent transmembrane isoform and an antagonistic soluble isoform; IL5RA is required for IL-5-driven eosinophilopoiesis and B-1 cell development, is expressed and functional on neutrophils in addition to eosinophils/basophils, engages JAK2/Lyn/Akt signaling downstream of oncogenic FIP1L1-PDGFRA in eosinophilic leukemia, promotes EMT via JAK2/STAT3 in lung epithelial cells, and can be upregulated through an MDM2/p53 axis to confer chemotherapy resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL5RA encodes the IL-5-specific alpha subunit of the IL-5 receptor and is the central determinant of IL-5 responsiveness across hematopoietic and, more recently, epithelial cells [#0, #2]. The high-affinity receptor is a heterodimer in which the IL5RA alpha chain confers ligand specificity and the signaling beta chain (βc), shared with the GM-CSF receptor, is recruited in an ordered fashion: βc binds with moderate affinity and a fast off-rate to the preformed IL-5:IL5RA binary complex but not to either component alone [#0, #1]. The gene produces both a signaling-competent transmembrane isoform and a secreted/soluble isoform that antagonizes IL-5 signaling, with isoform output and overall expression controlled by two promoters (P1, P2) acting through GATA-1, PU.1, C/EBP, and cooperating EOS1/AP-1 elements during eosinophil development; the splicing decision itself is IL-5-independent [#0, #3, #4, #7, #5]. Genetically, IL5RA is required for IL-5-driven eosinophilopoiesis and B-1 cell development, with loss eliminating IL-5-induced eosinophil production, depleting B-1 cells, lowering serum IgM/IgG3, and impairing antiparasite immunity [#2]. The receptor is also expressed and functional on neutrophils, where airway pathogens drive its surface display from intracellular stores [#6]. Beyond normal immunity, IL5RA participates in disease-associated signaling: it is phosphorylated by Lyn within a FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in eosinophilic leukemia [#8], drives epithelial-mesenchymal transition via JAK2/STAT3 in pulmonary fibrosis [#9], and is upregulated through an MDM2/p53 axis to confer chemotherapy resistance in uveal melanoma [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the molecular identity of the IL-5 receptor, resolving that IL-5 specificity is conferred by a dedicated alpha chain partnered with a shared beta chain, and that an antagonistic soluble form exists.\",\n      \"evidence\": \"cDNA cloning, receptor binding and functional antagonism assays in eosinophilic cells\",\n      \"pmids\": [\"1833065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the order or kinetics of subunit assembly\", \"Regulation of soluble vs transmembrane isoform production not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined IL5RA as physiologically required for IL-5-dependent eosinophil and B-1 cell development, moving it from a biochemical receptor to an in vivo lineage determinant.\",\n      \"evidence\": \"Knockout mouse with colony assays, flow cytometry, and in vivo parasite challenge\",\n      \"pmids\": [\"8630733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address roles outside eosinophil/B-1 lineages\", \"Downstream signaling effectors in vivo not dissected\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Began mapping how lineage-restricted IL5RA transcription is achieved by identifying the EOS1 enhancer element and its cooperation with a proximal AP-1 site.\",\n      \"evidence\": \"Promoter mutagenesis, EMSA, and methylation interference\",\n      \"pmids\": [\"8585949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the EOS1-binding factor not determined\", \"Single-study promoter analysis\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified the transcription factors binding the AP-1 site (cJun, CREB, CREM) and showed combinatorial dependence with EOS1 for eosinophil-specific promoter activity.\",\n      \"evidence\": \"Promoter reporter assays, EMSA, site-directed mutagenesis in HL-60 cells\",\n      \"pmids\": [\"9742933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous chromatin occupancy not confirmed\", \"Does not connect promoter activity to isoform choice\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the assembly mechanism, showing βc is recruited sequentially with moderate affinity to a preformed IL-5:IL5RA complex, supporting an ordered receptor model.\",\n      \"evidence\": \"Surface plasmon resonance binding kinetics with soluble βc ectodomain\",\n      \"pmids\": [\"12202242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed with soluble ectodomains, not full-length membrane receptors\", \"Conformational basis of ordered binding not structurally resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Determined that the transmembrane-vs-soluble isoform splicing decision is IL-5-independent, ruling out ligand-driven feedback control of isoform ratios.\",\n      \"evidence\": \"Quantitative RT-PCR in IL-5 gene-deleted vs wild-type mice during Schistosoma infection\",\n      \"pmids\": [\"16856933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify what does control the splicing decision\", \"Negative finding limited to the infection model tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked a promoter polymorphism (c.-5091G>A) to differential IL5RA surface expression on eosinophils, connecting genetic variation to receptor density.\",\n      \"evidence\": \"Eosinophil flow cytometry and SNP genotyping in asthmatic patients and controls\",\n      \"pmids\": [\"17983872\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct promoter functional assay confirming causality\", \"Single method (flow cytometry), association only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed IL5RA within an oncogenic signaling complex, showing Lyn associates with and phosphorylates it downstream of FIP1L1-PDGFRA in eosinophilic leukemia.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphorylation assays, and dual JAK2/Lyn inhibition in EOL-1 and imatinib-resistant cells\",\n      \"pmids\": [\"29029406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect IL5RA-Lyn interaction not distinguished\", \"Single lab, no reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded IL5RA's cellular reach by demonstrating functional surface expression on neutrophils with pathogen-induced mobilization from intracellular stores.\",\n      \"evidence\": \"Flow cytometry, immunohistochemistry, and functional stimulation of blood and BAL neutrophils\",\n      \"pmids\": [\"34391897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of neutrophil IL-5 signaling in vivo unclear\", \"Whether βc co-engages on neutrophils not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the dual-promoter (P1/P2) program and transcription-factor inputs that time isoform expression across human eosinophilopoiesis, with soluble mRNA peaking early and transmembrane later.\",\n      \"evidence\": \"Promoter reporter assays, ChIP in primary eosinophil cultures, isoform qRT-PCR\",\n      \"pmids\": [\"34638583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of each factor to isoform switching not isolated\", \"Single-lab dataset\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended IL5RA function to non-hematopoietic disease, showing epithelial IL5RA drives EMT and ECM production via JAK2/STAT3 in pulmonary fibrosis.\",\n      \"evidence\": \"Single-cell analysis, in vitro/in vivo loss- and gain-of-function, pathway inhibition\",\n      \"pmids\": [\"38191068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether epithelial signaling requires βc and IL-5 ligand not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an upstream regulatory axis (JMJD2C/MDM2/p53) controlling IL5RA expression to confer cisplatin resistance, framing IL5RA as a chemoresistance effector.\",\n      \"evidence\": \"ChIP, p53/ubiquitin Co-IP, knockdown, and xenograft in uveal melanoma cells\",\n      \"pmids\": [\"35468881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IL5RA mediates resistance downstream not defined\", \"Direct p53-IL5RA regulatory link not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL5RA signaling specificity and isoform balance are coordinated across its diverse contexts (eosinophils, B-1 cells, neutrophils, epithelium, tumor cells) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the full-length signaling complex\", \"Factors controlling the IL-5-independent splicing decision unidentified\", \"Whether epithelial/tumor IL5RA functions require canonical βc/IL-5 engagement is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\"IL-5 receptor (IL5RA/βc heterodimer)\", \"FIP1L1-PDGFRA/JAK2/Lyn/Akt signaling complex\"],\n    \"partners\": [\"CSF2RB\", \"IL5\", \"LYN\", \"JAK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}