{"gene":"IL11RA","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1997,"finding":"IL11Ra is the functional receptor component required for IL-11 signaling in hematopoietic cells; null mutation of IL11Ra abolishes bone marrow cell response to IL-11 in hematopoietic assays, but IL-11 receptor signaling is dispensable for adult hematopoiesis under normal and stress conditions.","method":"Gene targeting (null mutation) in mice; hematopoietic colony assays; Northern blot and RT-PCR confirmation of null mutation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple hematopoietic readouts, confirmed absence of compensatory IL11Ra2 expression","pmids":["9310465"],"is_preprint":false},{"year":1996,"finding":"IL-11Rα forms a high-affinity receptor for IL-11 as a heterodimer with gp130; the IL11RA gene encodes a protein sharing homology with CNTF and IL-6 receptor alpha chains, with conserved domain structure consistent with the hematopoietic cytokine receptor family.","method":"Molecular cloning, genomic sequencing, exon-intron boundary determination, protein sequence alignment","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — structural/sequence analysis replicated across two independent cloning papers; receptor heterodimer identity inferred from homology and prior biochemical data cited in abstracts","pmids":["8808281","8786120"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in IL11RA (splice-site, missense p.Pro200Thr, p.Arg237Pro, nonsense p.Tyr232*, p.Arg292*) dramatically reduce IL-11-mediated STAT3 phosphorylation, establishing IL11RA as required for downstream STAT3 signaling; IL11RA protein is expressed in cranial mesenchyme localized around coronal and lambdoidal suture tips.","method":"Transient coexpression in HEK293T and COS7 cells with STAT3 phosphorylation assay; immunofluorescence of mouse Il11ra; in situ hybridization in zebrafish; in vitro exon trapping","journal":"Molecular genetics & genomic medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (functional STAT3 assay, localization by immunofluorescence and ISH, splice analysis) in a single rigorous study","pmids":["24498618"],"is_preprint":false},{"year":2022,"finding":"Xenopus il11ra.L is a functional IL-11 receptor component: knockout of il11ra.L abolishes nuclear localization of phosphorylated STAT3 induced by IL-11 in cultured cells, and knockdown of il11ra.L impairs tadpole tail regeneration.","method":"CRISPR knockout in Xenopus culture cells (pSTAT3 nuclear localization assay); morpholino knockdown in Xenopus tadpoles (tail regeneration assay)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two orthogonal loss-of-function approaches (KO + knockdown) with defined molecular and phenotypic readouts in a single study","pmids":["35115663"],"is_preprint":false},{"year":2024,"finding":"IL11RA promotes melanoma cell migration and invasion, and its loss reduces hepatic melanoma metastasis in vivo; mechanistically, IL11RA correlates positively with STAT3 activation, and IL11RA knockdown suppresses the STAT3 pathway in SKCM cells and mouse liver tissue; Il11ra knockout decreases Mmp2 expression in liver tissue.","method":"siRNA knockdown in human melanoma cell lines (wound healing and Transwell invasion assays); Il11ra knockout mice injected with B16-F10 cells (hepatic metastasis model); Western blotting and RT-qPCR for STAT3 pathway and MMP2/MMP9","journal":"Skin research and technology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with pathway (STAT3) and molecular (MMP2) readouts, single lab","pmids":["38468436"],"is_preprint":false},{"year":2025,"finding":"Missense variants in IL11RA (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for the tertiary structure of the IL-11 receptor alpha subunit, significantly reducing ligand-binding affinity to both IL-11 and gp130, as modeled by 3D protein structure modeling and molecular docking simulations.","method":"3D protein structure modeling and molecular docking simulations (in silico); whole-exome sequencing with Sanger validation","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational (molecular docking/modeling), no experimental validation of binding affinity","pmids":["40353334"],"is_preprint":false},{"year":2024,"finding":"Cell-cell interactions mediated by the IL11-IL11RA axis between Igfbp5+ chondrocytes, Cd36+Gpnmb+Il1b- macrophages, and Fmod+ fibroblasts form a pro-fibrotic community that limits tissue regeneration in murine wound healing models.","method":"Spatial transcriptomics deconvolution; cell-cell interaction analysis in murine wound healing models (C57BL/6 vs. MRL/MpJ strains)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, computational/spatial transcriptomics inference of cell-cell interaction, no direct experimental perturbation of IL11RA in this context","pmids":[],"is_preprint":true}],"current_model":"IL11RA encodes the ligand-binding alpha subunit of the IL-11 receptor, which forms a signaling complex with gp130; ligand binding activates STAT3 phosphorylation, and loss-of-function mutations in IL11RA abolish IL-11-mediated STAT3 signaling, disrupt cranial suture development causing craniosynostosis, and impair tissue regeneration, while IL11RA also promotes tumor cell migration and invasion via the STAT3/MMP2 axis."},"narrative":{"mechanistic_narrative":"IL11RA encodes the ligand-binding alpha subunit of the IL-11 receptor, which forms a high-affinity receptor complex with gp130 and transduces IL-11 signals to STAT3 [PMID:8808281, PMID:8786120, PMID:24498618]. It is the obligate receptor component for IL-11 responses: null mutation abolishes the hematopoietic response to IL-11, although IL-11 receptor signaling is dispensable for adult hematopoiesis under steady-state and stress conditions [PMID:9310465]. Loss-of-function mutations in IL11RA dramatically reduce IL-11-mediated STAT3 phosphorylation, and the protein is expressed in cranial mesenchyme around the coronal and lambdoidal suture tips, linking IL11RA to suture development [PMID:24498618]. Its role as a functional IL-11 receptor and the requirement of STAT3 nuclear translocation for downstream activity are conserved in Xenopus, where il11ra is also required for tadpole tail regeneration [PMID:35115663]. Beyond development and regeneration, IL11RA drives tumor cell behavior: it promotes melanoma cell migration and invasion and supports hepatic metastasis through STAT3 activation and downstream MMP2 expression [PMID:38468436].","teleology":[{"year":1996,"claim":"Establishing the molecular identity of the IL-11 receptor: cloning showed IL-11Rα is a hematopoietic cytokine receptor family member that pairs with gp130 to form a high-affinity IL-11 receptor.","evidence":"Molecular cloning, genomic sequencing, and protein sequence alignment against CNTF and IL-6 receptor alpha chains","pmids":["8808281","8786120"],"confidence":"Medium","gaps":["Heterodimer with gp130 inferred from homology rather than direct binding assay","No structural determination of the ligand-receptor complex"]},{"year":1997,"claim":"Testing whether IL11RA is functionally required for IL-11 responses in vivo: gene targeting showed it is essential for the hematopoietic response to IL-11 but dispensable for adult hematopoiesis.","evidence":"Null mutation in mice with hematopoietic colony assays and confirmation of absent compensatory expression","pmids":["9310465"],"confidence":"High","gaps":["Did not address non-hematopoietic roles","Downstream signaling effectors not dissected"]},{"year":2013,"claim":"Connecting IL11RA to human disease and signaling: patient mutations were shown to impair IL-11-driven STAT3 phosphorylation, and the receptor was localized to cranial suture mesenchyme, mechanistically linking IL11RA to craniosynostosis.","evidence":"Coexpression STAT3 phosphorylation assays in HEK293T/COS7, immunofluorescence, zebrafish in situ hybridization, exon trapping","pmids":["24498618"],"confidence":"High","gaps":["Quantitative receptor-ligand binding not measured for each variant","Mechanism linking STAT3 loss to suture fusion not resolved"]},{"year":2022,"claim":"Defining the requirement for STAT3 nuclear translocation and a regeneration role: il11ra loss abolished IL-11-induced nuclear pSTAT3 and impaired tail regeneration, demonstrating conserved receptor function in regeneration.","evidence":"CRISPR knockout and morpholino knockdown in Xenopus cells and tadpoles with pSTAT3 nuclear localization and tail regeneration readouts","pmids":["35115663"],"confidence":"High","gaps":["Conservation to mammalian regeneration not established","Downstream regeneration effectors of STAT3 not identified"]},{"year":2024,"claim":"Extending IL11RA to cancer: knockdown and knockout reduced melanoma migration, invasion, and hepatic metastasis through STAT3 activation and MMP2 induction, defining a pro-metastatic STAT3/MMP2 axis.","evidence":"siRNA knockdown in human melanoma lines, Il11ra knockout mice in a B16-F10 hepatic metastasis model, Western blot and RT-qPCR","pmids":["38468436"],"confidence":"Medium","gaps":["Single-lab study","Direct causal link between MMP2 and metastasis not isolated"]},{"year":2025,"claim":"Attempting to explain variant pathogenicity structurally: in silico modeling indicated missense variants disrupt hydrogen-bond networks and reduce binding to IL-11 and gp130.","evidence":"3D protein structure modeling and molecular docking with whole-exome sequencing and Sanger validation","pmids":["40353334"],"confidence":"Low","gaps":["Purely computational with no experimental validation of binding affinity","Predicted affinity changes not tested in cells"]},{"year":null,"claim":"How IL11RA-mediated signaling integrates into multicellular fibrotic and regenerative communities remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["Cell-cell interaction roles inferred only from spatial transcriptomics without direct IL11RA perturbation","Mechanism linking pro-fibrotic niche to STAT3 signaling unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]}],"complexes":["IL-11 receptor complex (IL-11Rα/gp130)"],"partners":["IL11","IL6ST"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14626","full_name":"Interleukin-11 receptor subunit alpha","aliases":[],"length_aa":422,"mass_kda":45.2,"function":"Receptor for interleukin-11 (IL11). The receptor systems for IL6, LIF, OSM, CNTF, IL11 and CT1 can utilize IL6ST for initiating signal transmission. The IL11/IL11RA/IL6ST complex may be involved in the control of proliferation and/or differentiation of skeletogenic progenitor or other mesenchymal cells (Probable). Essential for the normal development of craniofacial bones and teeth. Restricts suture fusion and tooth number Soluble form of IL11 receptor (sIL11RA) that acts as an agonist of IL11 activity (PubMed:26876177, PubMed:30279168). The IL11:sIL11RA complex binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL11RA in a process called IL11 trans-signaling (PubMed:26876177, PubMed:30279168) Soluble form of IL11 receptor (sIL11RA) that acts as an agonist of IL11 activity (PubMed:26876177, PubMed:30279168). The IL11:sIL11RA complex binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL11RA in a process called IL11 trans-signaling (PubMed:26876177, PubMed:30279168)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q14626/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL11RA","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL11RA","total_profiled":1310},"omim":[{"mim_id":"616821","title":"THROMBOSPONDIN TYPE 1 DOMAIN-CONTAINING PROTEIN 1; THSD1","url":"https://www.omim.org/entry/616821"},{"mim_id":"614188","title":"CRANIOSYNOSTOSIS AND DENTAL ANOMALIES; CRSDA","url":"https://www.omim.org/entry/614188"},{"mim_id":"606999","title":"GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE; GALT","url":"https://www.omim.org/entry/606999"},{"mim_id":"606255","title":"STATURE AS A QUANTITATIVE TRAIT","url":"https://www.omim.org/entry/606255"},{"mim_id":"604833","title":"CHEMOKINE, CC MOTIF, LIGAND 27; CCL27","url":"https://www.omim.org/entry/604833"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":36.3}],"url":"https://www.proteinatlas.org/search/IL11RA"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q14626","domains":[{"cath_id":"2.60.40.10","chopping":"34-108","consensus_level":"high","plddt":92.1927,"start":34,"end":108},{"cath_id":"2.60.40.10","chopping":"116-154_164-214","consensus_level":"high","plddt":93.5494,"start":116,"end":214},{"cath_id":"2.60.40.10","chopping":"221-312","consensus_level":"high","plddt":96.6021,"start":221,"end":312}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14626","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14626-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14626-F1-predicted_aligned_error_v6.png","plddt_mean":81.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL11RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL11RA"},"sequence":{"accession":"Q14626","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14626.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14626/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14626"}},"corpus_meta":[{"pmid":"9310465","id":"PMC_9310465","title":"Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis.","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9310465","citation_count":115,"is_preprint":false},{"pmid":"24498618","id":"PMC_24498618","title":"Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis.","date":"2013","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24498618","citation_count":63,"is_preprint":false},{"pmid":"29926465","id":"PMC_29926465","title":"IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29926465","citation_count":28,"is_preprint":false},{"pmid":"8808281","id":"PMC_8808281","title":"Molecular cloning and characterization of the human interleukin-11 receptor alpha-chain gene, IL11RA, located on chromosome 9p13.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8808281","citation_count":23,"is_preprint":false},{"pmid":"27920471","id":"PMC_27920471","title":"Identification of IL11RA and MELK amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines.","date":"2016","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/27920471","citation_count":17,"is_preprint":false},{"pmid":"38718659","id":"PMC_38718659","title":"Enhancing antitumor immunity and achieving tumor eradication with IL11RA mRNA immunotherapy.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38718659","citation_count":14,"is_preprint":false},{"pmid":"30811827","id":"PMC_30811827","title":"Evolution of the phenotype of craniosynostosis with dental anomalies syndrome and report of IL11RA variant population frequencies in a Crouzon-like autosomal recessive syndrome.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30811827","citation_count":14,"is_preprint":false},{"pmid":"24002815","id":"PMC_24002815","title":"A Novel Large Deletion Encompassing the Whole of the Galactose-1-Phosphate Uridyltransferase (GALT) Gene and Extending into the Adjacent Interleukin 11 Receptor Alpha (IL11RA) Gene Causes Classic Galactosemia Associated with Additional Phenotypic Abnormalities.","date":"2013","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/24002815","citation_count":13,"is_preprint":false},{"pmid":"23631681","id":"PMC_23631681","title":"IL-11/IL11RA receptor mediated signaling: a web accessible knowledgebase.","date":"2013","source":"Cell communication & adhesion","url":"https://pubmed.ncbi.nlm.nih.gov/23631681","citation_count":11,"is_preprint":false},{"pmid":"8786120","id":"PMC_8786120","title":"The human interleukin-11 receptor alpha gene (IL11RA): genomic organization and chromosome mapping.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8786120","citation_count":8,"is_preprint":false},{"pmid":"28143986","id":"PMC_28143986","title":"Expression of Biomarkers CXCR4, IL11-RA, TFF1, MLF1P in Advanced Breast Cancer Patients with Bone Metastatic: a Diagnostic Study.","date":"2016","source":"Acta medica Indonesiana","url":"https://pubmed.ncbi.nlm.nih.gov/28143986","citation_count":8,"is_preprint":false},{"pmid":"35115663","id":"PMC_35115663","title":"Xenopus laevis il11ra.L is an experimentally proven interleukin-11 receptor component that is required for tadpole tail regeneration.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35115663","citation_count":6,"is_preprint":false},{"pmid":"35331937","id":"PMC_35331937","title":"The outcome of targeted NGS screening in patients with syndromic forms of sagittal and pansynostosis - IL11RA is an emerging core-gene for pansynostosis.","date":"2022","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35331937","citation_count":4,"is_preprint":false},{"pmid":"38468436","id":"PMC_38468436","title":"Inhibiting IL11RA to mitigate hepatic metastasis in skin cutaneous melanoma: Comprehensive insights from in vitro and in vivo investigations.","date":"2024","source":"Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)","url":"https://pubmed.ncbi.nlm.nih.gov/38468436","citation_count":2,"is_preprint":false},{"pmid":"40353334","id":"PMC_40353334","title":"Genetic Insights Into Craniosynostosis: Identification of Novel IL11RA Variants in Chinese Pediatric Patients.","date":"2025","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40353334","citation_count":1,"is_preprint":false},{"pmid":"41289788","id":"PMC_41289788","title":"Identification of SARS2, PKN1, and IL11RA as causally-associated genes for patients with gastric cancer via immune cell activity: A multi-omics Mendelian randomization study integrating GWAS, eQTL, and pQTL data.","date":"2025","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41289788","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.01.646733","title":"Non-linear Age-related Change in Human Interleukin-11 and the receptor subunit alpha DNA Methylation","date":"2025-04-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.01.646733","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.05.602200","title":"Ultra-precision deconvolution of spatial transcriptomics decodes immune heterogeneity and fate-defining programs in tissues","date":"2024-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.05.602200","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11226,"output_tokens":1841,"usd":0.030647,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8727,"output_tokens":2211,"usd":0.049455,"stage2_stop_reason":"end_turn"},"total_usd":0.080102,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"IL11Ra is the functional receptor component required for IL-11 signaling in hematopoietic cells; null mutation of IL11Ra abolishes bone marrow cell response to IL-11 in hematopoietic assays, but IL-11 receptor signaling is dispensable for adult hematopoiesis under normal and stress conditions.\",\n      \"method\": \"Gene targeting (null mutation) in mice; hematopoietic colony assays; Northern blot and RT-PCR confirmation of null mutation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple hematopoietic readouts, confirmed absence of compensatory IL11Ra2 expression\",\n      \"pmids\": [\"9310465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IL-11Rα forms a high-affinity receptor for IL-11 as a heterodimer with gp130; the IL11RA gene encodes a protein sharing homology with CNTF and IL-6 receptor alpha chains, with conserved domain structure consistent with the hematopoietic cytokine receptor family.\",\n      \"method\": \"Molecular cloning, genomic sequencing, exon-intron boundary determination, protein sequence alignment\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — structural/sequence analysis replicated across two independent cloning papers; receptor heterodimer identity inferred from homology and prior biochemical data cited in abstracts\",\n      \"pmids\": [\"8808281\", \"8786120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in IL11RA (splice-site, missense p.Pro200Thr, p.Arg237Pro, nonsense p.Tyr232*, p.Arg292*) dramatically reduce IL-11-mediated STAT3 phosphorylation, establishing IL11RA as required for downstream STAT3 signaling; IL11RA protein is expressed in cranial mesenchyme localized around coronal and lambdoidal suture tips.\",\n      \"method\": \"Transient coexpression in HEK293T and COS7 cells with STAT3 phosphorylation assay; immunofluorescence of mouse Il11ra; in situ hybridization in zebrafish; in vitro exon trapping\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (functional STAT3 assay, localization by immunofluorescence and ISH, splice analysis) in a single rigorous study\",\n      \"pmids\": [\"24498618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Xenopus il11ra.L is a functional IL-11 receptor component: knockout of il11ra.L abolishes nuclear localization of phosphorylated STAT3 induced by IL-11 in cultured cells, and knockdown of il11ra.L impairs tadpole tail regeneration.\",\n      \"method\": \"CRISPR knockout in Xenopus culture cells (pSTAT3 nuclear localization assay); morpholino knockdown in Xenopus tadpoles (tail regeneration assay)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal loss-of-function approaches (KO + knockdown) with defined molecular and phenotypic readouts in a single study\",\n      \"pmids\": [\"35115663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL11RA promotes melanoma cell migration and invasion, and its loss reduces hepatic melanoma metastasis in vivo; mechanistically, IL11RA correlates positively with STAT3 activation, and IL11RA knockdown suppresses the STAT3 pathway in SKCM cells and mouse liver tissue; Il11ra knockout decreases Mmp2 expression in liver tissue.\",\n      \"method\": \"siRNA knockdown in human melanoma cell lines (wound healing and Transwell invasion assays); Il11ra knockout mice injected with B16-F10 cells (hepatic metastasis model); Western blotting and RT-qPCR for STAT3 pathway and MMP2/MMP9\",\n      \"journal\": \"Skin research and technology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with pathway (STAT3) and molecular (MMP2) readouts, single lab\",\n      \"pmids\": [\"38468436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Missense variants in IL11RA (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for the tertiary structure of the IL-11 receptor alpha subunit, significantly reducing ligand-binding affinity to both IL-11 and gp130, as modeled by 3D protein structure modeling and molecular docking simulations.\",\n      \"method\": \"3D protein structure modeling and molecular docking simulations (in silico); whole-exome sequencing with Sanger validation\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational (molecular docking/modeling), no experimental validation of binding affinity\",\n      \"pmids\": [\"40353334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cell-cell interactions mediated by the IL11-IL11RA axis between Igfbp5+ chondrocytes, Cd36+Gpnmb+Il1b- macrophages, and Fmod+ fibroblasts form a pro-fibrotic community that limits tissue regeneration in murine wound healing models.\",\n      \"method\": \"Spatial transcriptomics deconvolution; cell-cell interaction analysis in murine wound healing models (C57BL/6 vs. MRL/MpJ strains)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, computational/spatial transcriptomics inference of cell-cell interaction, no direct experimental perturbation of IL11RA in this context\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL11RA encodes the ligand-binding alpha subunit of the IL-11 receptor, which forms a signaling complex with gp130; ligand binding activates STAT3 phosphorylation, and loss-of-function mutations in IL11RA abolish IL-11-mediated STAT3 signaling, disrupt cranial suture development causing craniosynostosis, and impair tissue regeneration, while IL11RA also promotes tumor cell migration and invasion via the STAT3/MMP2 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL11RA encodes the ligand-binding alpha subunit of the IL-11 receptor, which forms a high-affinity receptor complex with gp130 and transduces IL-11 signals to STAT3 [#1, #2]. It is the obligate receptor component for IL-11 responses: null mutation abolishes the hematopoietic response to IL-11, although IL-11 receptor signaling is dispensable for adult hematopoiesis under steady-state and stress conditions [#0]. Loss-of-function mutations in IL11RA dramatically reduce IL-11-mediated STAT3 phosphorylation, and the protein is expressed in cranial mesenchyme around the coronal and lambdoidal suture tips, linking IL11RA to suture development [#2]. Its role as a functional IL-11 receptor and the requirement of STAT3 nuclear translocation for downstream activity are conserved in Xenopus, where il11ra is also required for tadpole tail regeneration [#3]. Beyond development and regeneration, IL11RA drives tumor cell behavior: it promotes melanoma cell migration and invasion and supports hepatic metastasis through STAT3 activation and downstream MMP2 expression [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the molecular identity of the IL-11 receptor: cloning showed IL-11Rα is a hematopoietic cytokine receptor family member that pairs with gp130 to form a high-affinity IL-11 receptor.\",\n      \"evidence\": \"Molecular cloning, genomic sequencing, and protein sequence alignment against CNTF and IL-6 receptor alpha chains\",\n      \"pmids\": [\"8808281\", \"8786120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterodimer with gp130 inferred from homology rather than direct binding assay\", \"No structural determination of the ligand-receptor complex\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Testing whether IL11RA is functionally required for IL-11 responses in vivo: gene targeting showed it is essential for the hematopoietic response to IL-11 but dispensable for adult hematopoiesis.\",\n      \"evidence\": \"Null mutation in mice with hematopoietic colony assays and confirmation of absent compensatory expression\",\n      \"pmids\": [\"9310465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address non-hematopoietic roles\", \"Downstream signaling effectors not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connecting IL11RA to human disease and signaling: patient mutations were shown to impair IL-11-driven STAT3 phosphorylation, and the receptor was localized to cranial suture mesenchyme, mechanistically linking IL11RA to craniosynostosis.\",\n      \"evidence\": \"Coexpression STAT3 phosphorylation assays in HEK293T/COS7, immunofluorescence, zebrafish in situ hybridization, exon trapping\",\n      \"pmids\": [\"24498618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative receptor-ligand binding not measured for each variant\", \"Mechanism linking STAT3 loss to suture fusion not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining the requirement for STAT3 nuclear translocation and a regeneration role: il11ra loss abolished IL-11-induced nuclear pSTAT3 and impaired tail regeneration, demonstrating conserved receptor function in regeneration.\",\n      \"evidence\": \"CRISPR knockout and morpholino knockdown in Xenopus cells and tadpoles with pSTAT3 nuclear localization and tail regeneration readouts\",\n      \"pmids\": [\"35115663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation to mammalian regeneration not established\", \"Downstream regeneration effectors of STAT3 not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending IL11RA to cancer: knockdown and knockout reduced melanoma migration, invasion, and hepatic metastasis through STAT3 activation and MMP2 induction, defining a pro-metastatic STAT3/MMP2 axis.\",\n      \"evidence\": \"siRNA knockdown in human melanoma lines, Il11ra knockout mice in a B16-F10 hepatic metastasis model, Western blot and RT-qPCR\",\n      \"pmids\": [\"38468436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct causal link between MMP2 and metastasis not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Attempting to explain variant pathogenicity structurally: in silico modeling indicated missense variants disrupt hydrogen-bond networks and reduce binding to IL-11 and gp130.\",\n      \"evidence\": \"3D protein structure modeling and molecular docking with whole-exome sequencing and Sanger validation\",\n      \"pmids\": [\"40353334\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational with no experimental validation of binding affinity\", \"Predicted affinity changes not tested in cells\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL11RA-mediated signaling integrates into multicellular fibrotic and regenerative communities remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cell-cell interaction roles inferred only from spatial transcriptomics without direct IL11RA perturbation\", \"Mechanism linking pro-fibrotic niche to STAT3 signaling unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [\"IL-11 receptor complex (IL-11Rα/gp130)\"],\n    \"partners\": [\"IL11\", \"IL6ST\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}