{"gene":"IL11RA","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1997,"finding":"IL11Ra null mice generated by gene targeting display normal adult hematopoiesis, including normal megakaryocytes, platelets, and recovery from hematopoietic stress, demonstrating that IL-11 receptor signaling via IL11Ra is dispensable for adult hematopoiesis.","method":"Gene targeting (knockout mouse), hematopoietic colony assays, peripheral blood analysis, bone marrow analysis, stress hematopoiesis (5-FU, phenylhydrazine)","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — clean KO with multiple defined cellular phenotypic readouts, replicated across multiple hematopoietic assays","pmids":["9310465"],"is_preprint":false},{"year":1996,"finding":"The IL-11 high-affinity receptor is a heterodimer composed of the IL-11R alpha chain (IL11RA) and gp130; IL11RA shares structural and evolutionary homology with the alpha chains of CNTF and IL-6 receptors, with exon-intron organization conserved within the hematopoietic cytokine receptor family.","method":"Genomic cloning, exon-intron boundary determination, sequence analysis, FISH chromosomal mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1–2 — structural characterization with multiple orthogonal methods, replicated across two independent papers (PMID 8808281 and 8786120)","pmids":["8808281","8786120"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in IL11RA (splice-site, missense, nonsense) dramatically reduce IL-11-mediated STAT3 phosphorylation, establishing that IL11RA is required for IL-11/STAT3 signal transduction; IL11RA protein is specifically expressed in cranial mesenchyme around coronal and lambdoidal suture tips.","method":"Transient coexpression in HEK293T and COS7 cells with STAT3 phosphorylation assay, in vitro exon trapping, immunofluorescence, in situ hybridization","journal":"Molecular genetics & genomic medicine","confidence":"High","confidence_rationale":"Tier 1–2 — functional signaling assay with multiple mutations tested, combined with localization data","pmids":["24498618"],"is_preprint":false},{"year":2022,"finding":"In Xenopus laevis, il11ra.L encodes a component of the IL-11 receptor complex; knockout of il11ra.L abolishes IL-11-induced nuclear localization of phosphorylated STAT3, and knockdown impairs tadpole tail regeneration, demonstrating that IL11RA mediates IL-11/STAT3 signaling in a non-cell-autonomous manner to support tissue regeneration.","method":"CRISPR knockout cell assay (phospho-STAT3 nuclear localization), morpholino knockdown in Xenopus tadpoles (tail regeneration assay)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO abolishes downstream signaling with direct readout, combined with in vivo loss-of-function phenotype","pmids":["35115663"],"is_preprint":false},{"year":2024,"finding":"IL11RA promotes melanoma cell migration and invasion, and its genetic knockout in mice substantially reduces hepatic melanoma metastasis; IL11RA signaling correlates with and activates the STAT3 pathway, and its loss decreases MMP2 expression in liver tissue.","method":"siRNA knockdown (wound healing, Transwell invasion assays), Il11ra knockout mouse model (splenic injection of B16-F10 cells), RT-qPCR, Western blotting, STAT3 pathway analysis","journal":"Skin research and technology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo KO with defined phenotypic readouts, but single lab study","pmids":["38468436"],"is_preprint":false},{"year":2025,"finding":"Four missense variants of IL11RA associated with craniosynostosis (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for maintaining the protein's tertiary structure and significantly reduce ligand-binding affinity to both IL-11 and gp130, as modeled by 3D protein structure modeling and molecular docking.","method":"3D protein structure modeling, molecular docking simulation","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no experimental validation","pmids":["40353334"],"is_preprint":false},{"year":2024,"finding":"Cell-cell interactions mediated by the IL11-IL11RA axis drive pro-fibrotic community formation between chondrocytes, macrophages, and fibroblasts in wound healing, limiting regeneration in scarring-healing mice.","method":"Spatial transcriptomics deconvolution, cell-cell interaction analysis in murine wound healing models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — computational/spatial analysis without direct experimental validation of the IL11-IL11RA interaction; preprint","pmids":[],"is_preprint":true}],"current_model":"IL11RA encodes the alpha subunit of the IL-11 receptor, forming a heterodimeric complex with gp130; ligand binding activates STAT3 phosphorylation and downstream signaling, is required for normal cranial suture development and tissue regeneration, promotes cell migration/invasion via STAT3 and MMP pathways, and while dispensable for adult steady-state hematopoiesis, loss-of-function mutations cause autosomal recessive Crouzon-like craniosynostosis by abolishing IL-11/STAT3 signaling in cranial mesenchyme."},"narrative":{"teleology":[{"year":1996,"claim":"Determining the molecular composition of the IL-11 receptor established that IL11RA heterodimerizes with gp130, placing it in the shared gp130 cytokine receptor family alongside the CNTF and IL-6 receptor alpha chains.","evidence":"Genomic cloning, exon-intron analysis, and FISH mapping of the IL11RA gene","pmids":["8808281","8786120"],"confidence":"High","gaps":["No crystal structure of the IL11RA/gp130/IL-11 ternary complex from experiment","Stoichiometry of the signaling-competent complex not resolved at the time","Post-translational modifications of IL11RA not characterized"]},{"year":1997,"claim":"Gene-targeted deletion of Il11ra in mice unexpectedly revealed that IL-11 receptor signaling is dispensable for adult steady-state and stress hematopoiesis, redirecting attention toward non-hematopoietic functions.","evidence":"Il11ra knockout mice assessed by colony assays, peripheral blood counts, and hematopoietic stress (5-FU, phenylhydrazine)","pmids":["9310465"],"confidence":"High","gaps":["Embryonic or neonatal hematopoietic roles not fully excluded","Potential compensation by other gp130-family receptors not tested","Non-hematopoietic phenotypes of the knockout not yet explored"]},{"year":2013,"claim":"Functional assays of patient-derived IL11RA mutations demonstrated that the receptor is essential for IL-11-mediated STAT3 phosphorylation, and its expression in cranial suture mesenchyme explained why loss-of-function causes craniosynostosis.","evidence":"STAT3 phosphorylation assays in HEK293T/COS7 cells expressing mutant IL11RA, exon trapping, in situ hybridization of cranial sutures","pmids":["24498618"],"confidence":"High","gaps":["Downstream transcriptional targets of IL-11/STAT3 in cranial mesenchyme not identified","Mechanism by which lost signaling leads to premature suture fusion not resolved","Whether soluble IL11RA isoforms contribute to suture biology not tested"]},{"year":2022,"claim":"CRISPR knockout and morpholino knockdown in Xenopus demonstrated that IL11RA-dependent STAT3 signaling is required for appendage regeneration, extending the receptor's functional importance beyond skeletal development.","evidence":"CRISPR il11ra.L knockout (phospho-STAT3 nuclear localization assay) and morpholino knockdown (tadpole tail regeneration)","pmids":["35115663"],"confidence":"High","gaps":["Whether mammalian tissue regeneration similarly requires IL11RA/STAT3 not established","Cell-autonomous versus non-cell-autonomous mechanisms not fully dissected","Identity of regeneration-specific target genes downstream of IL11RA/STAT3 unknown"]},{"year":2024,"claim":"IL11RA was shown to promote melanoma migration, invasion, and hepatic metastasis through STAT3 activation and MMP2 upregulation, revealing a pro-tumorigenic role for the receptor.","evidence":"siRNA knockdown and Il11ra knockout mice with splenic melanoma injection, Western blot and RT-qPCR for STAT3 and MMP2","pmids":["38468436"],"confidence":"Medium","gaps":["Single-lab study; independent replication needed","Whether IL11RA acts cell-autonomously in tumor cells versus stromal cells not resolved","Applicability beyond melanoma not tested"]},{"year":null,"claim":"An experimental structure of the IL-11/IL11RA/gp130 signaling complex is lacking, the transcriptional programs downstream of IL11RA/STAT3 in cranial suture and regenerative contexts are uncharacterized, and the relative contributions of membrane-bound versus soluble IL11RA to physiological signaling remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimentally determined ternary complex structure","Downstream transcriptional targets in cranial mesenchyme and regeneration not mapped","Role of soluble IL11RA shedding in modulating signaling not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]}],"complexes":["IL-11/IL11RA/gp130 receptor complex"],"partners":["IL6ST","IL11","STAT3"],"other_free_text":[]},"mechanistic_narrative":"IL11RA encodes the ligand-binding alpha subunit of the interleukin-11 receptor, which heterodimerizes with gp130 to form the high-affinity IL-11 signaling complex; this architecture is conserved within the hematopoietic cytokine receptor family alongside the CNTF and IL-6 receptor alpha chains [PMID:8808281, PMID:8786120]. IL11RA is required for IL-11-induced STAT3 phosphorylation and nuclear translocation, and loss-of-function mutations abolish this signaling, causing autosomal recessive craniosynostosis linked to its specific expression in cranial suture mesenchyme [PMID:24498618]. Despite its membership in the hematopoietic cytokine receptor family, IL11Ra-null mice display normal adult hematopoiesis and stress recovery, indicating dispensability for blood cell homeostasis [PMID:9310465]. IL11RA-dependent STAT3 signaling also promotes tissue regeneration in Xenopus tadpole tails and drives melanoma cell migration and metastasis through MMP2 expression [PMID:35115663, PMID:38468436]."},"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":"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":"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":12,"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":10492,"output_tokens":1686,"usd":0.028383},"stage2":{"model":"claude-opus-4-6","input_tokens":4941,"output_tokens":1762,"usd":0.103133},"total_usd":0.131516,"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\": \"IL11Ra null mice generated by gene targeting display normal adult hematopoiesis, including normal megakaryocytes, platelets, and recovery from hematopoietic stress, demonstrating that IL-11 receptor signaling via IL11Ra is dispensable for adult hematopoiesis.\",\n      \"method\": \"Gene targeting (knockout mouse), hematopoietic colony assays, peripheral blood analysis, bone marrow analysis, stress hematopoiesis (5-FU, phenylhydrazine)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — clean KO with multiple defined cellular phenotypic readouts, replicated across multiple hematopoietic assays\",\n      \"pmids\": [\"9310465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The IL-11 high-affinity receptor is a heterodimer composed of the IL-11R alpha chain (IL11RA) and gp130; IL11RA shares structural and evolutionary homology with the alpha chains of CNTF and IL-6 receptors, with exon-intron organization conserved within the hematopoietic cytokine receptor family.\",\n      \"method\": \"Genomic cloning, exon-intron boundary determination, sequence analysis, FISH chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural characterization with multiple orthogonal methods, replicated across two independent papers (PMID 8808281 and 8786120)\",\n      \"pmids\": [\"8808281\", \"8786120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in IL11RA (splice-site, missense, nonsense) dramatically reduce IL-11-mediated STAT3 phosphorylation, establishing that IL11RA is required for IL-11/STAT3 signal transduction; IL11RA protein is specifically expressed in cranial mesenchyme around coronal and lambdoidal suture tips.\",\n      \"method\": \"Transient coexpression in HEK293T and COS7 cells with STAT3 phosphorylation assay, in vitro exon trapping, immunofluorescence, in situ hybridization\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — functional signaling assay with multiple mutations tested, combined with localization data\",\n      \"pmids\": [\"24498618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Xenopus laevis, il11ra.L encodes a component of the IL-11 receptor complex; knockout of il11ra.L abolishes IL-11-induced nuclear localization of phosphorylated STAT3, and knockdown impairs tadpole tail regeneration, demonstrating that IL11RA mediates IL-11/STAT3 signaling in a non-cell-autonomous manner to support tissue regeneration.\",\n      \"method\": \"CRISPR knockout cell assay (phospho-STAT3 nuclear localization), morpholino knockdown in Xenopus tadpoles (tail regeneration assay)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO abolishes downstream signaling with direct readout, combined with in vivo loss-of-function phenotype\",\n      \"pmids\": [\"35115663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL11RA promotes melanoma cell migration and invasion, and its genetic knockout in mice substantially reduces hepatic melanoma metastasis; IL11RA signaling correlates with and activates the STAT3 pathway, and its loss decreases MMP2 expression in liver tissue.\",\n      \"method\": \"siRNA knockdown (wound healing, Transwell invasion assays), Il11ra knockout mouse model (splenic injection of B16-F10 cells), RT-qPCR, Western blotting, STAT3 pathway analysis\",\n      \"journal\": \"Skin research and technology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo KO with defined phenotypic readouts, but single lab study\",\n      \"pmids\": [\"38468436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Four missense variants of IL11RA associated with craniosynostosis (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for maintaining the protein's tertiary structure and significantly reduce ligand-binding affinity to both IL-11 and gp130, as modeled by 3D protein structure modeling and molecular docking.\",\n      \"method\": \"3D protein structure modeling, molecular docking simulation\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation\",\n      \"pmids\": [\"40353334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cell-cell interactions mediated by the IL11-IL11RA axis drive pro-fibrotic community formation between chondrocytes, macrophages, and fibroblasts in wound healing, limiting regeneration in scarring-healing mice.\",\n      \"method\": \"Spatial transcriptomics deconvolution, cell-cell interaction analysis in murine wound healing models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — computational/spatial analysis without direct experimental validation of the IL11-IL11RA interaction; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL11RA encodes the alpha subunit of the IL-11 receptor, forming a heterodimeric complex with gp130; ligand binding activates STAT3 phosphorylation and downstream signaling, is required for normal cranial suture development and tissue regeneration, promotes cell migration/invasion via STAT3 and MMP pathways, and while dispensable for adult steady-state hematopoiesis, loss-of-function mutations cause autosomal recessive Crouzon-like craniosynostosis by abolishing IL-11/STAT3 signaling in cranial mesenchyme.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL11RA encodes the ligand-binding alpha subunit of the interleukin-11 receptor, which heterodimerizes with gp130 to form the high-affinity IL-11 signaling complex; this architecture is conserved within the hematopoietic cytokine receptor family alongside the CNTF and IL-6 receptor alpha chains [PMID:8808281, PMID:8786120]. IL11RA is required for IL-11-induced STAT3 phosphorylation and nuclear translocation, and loss-of-function mutations abolish this signaling, causing autosomal recessive craniosynostosis linked to its specific expression in cranial suture mesenchyme [PMID:24498618]. Despite its membership in the hematopoietic cytokine receptor family, IL11Ra-null mice display normal adult hematopoiesis and stress recovery, indicating dispensability for blood cell homeostasis [PMID:9310465]. IL11RA-dependent STAT3 signaling also promotes tissue regeneration in Xenopus tadpole tails and drives melanoma cell migration and metastasis through MMP2 expression [PMID:35115663, PMID:38468436].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Determining the molecular composition of the IL-11 receptor established that IL11RA heterodimerizes with gp130, placing it in the shared gp130 cytokine receptor family alongside the CNTF and IL-6 receptor alpha chains.\",\n      \"evidence\": \"Genomic cloning, exon-intron analysis, and FISH mapping of the IL11RA gene\",\n      \"pmids\": [\"8808281\", \"8786120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure of the IL11RA/gp130/IL-11 ternary complex from experiment\",\n        \"Stoichiometry of the signaling-competent complex not resolved at the time\",\n        \"Post-translational modifications of IL11RA not characterized\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Gene-targeted deletion of Il11ra in mice unexpectedly revealed that IL-11 receptor signaling is dispensable for adult steady-state and stress hematopoiesis, redirecting attention toward non-hematopoietic functions.\",\n      \"evidence\": \"Il11ra knockout mice assessed by colony assays, peripheral blood counts, and hematopoietic stress (5-FU, phenylhydrazine)\",\n      \"pmids\": [\"9310465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Embryonic or neonatal hematopoietic roles not fully excluded\",\n        \"Potential compensation by other gp130-family receptors not tested\",\n        \"Non-hematopoietic phenotypes of the knockout not yet explored\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional assays of patient-derived IL11RA mutations demonstrated that the receptor is essential for IL-11-mediated STAT3 phosphorylation, and its expression in cranial suture mesenchyme explained why loss-of-function causes craniosynostosis.\",\n      \"evidence\": \"STAT3 phosphorylation assays in HEK293T/COS7 cells expressing mutant IL11RA, exon trapping, in situ hybridization of cranial sutures\",\n      \"pmids\": [\"24498618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream transcriptional targets of IL-11/STAT3 in cranial mesenchyme not identified\",\n        \"Mechanism by which lost signaling leads to premature suture fusion not resolved\",\n        \"Whether soluble IL11RA isoforms contribute to suture biology not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR knockout and morpholino knockdown in Xenopus demonstrated that IL11RA-dependent STAT3 signaling is required for appendage regeneration, extending the receptor's functional importance beyond skeletal development.\",\n      \"evidence\": \"CRISPR il11ra.L knockout (phospho-STAT3 nuclear localization assay) and morpholino knockdown (tadpole tail regeneration)\",\n      \"pmids\": [\"35115663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mammalian tissue regeneration similarly requires IL11RA/STAT3 not established\",\n        \"Cell-autonomous versus non-cell-autonomous mechanisms not fully dissected\",\n        \"Identity of regeneration-specific target genes downstream of IL11RA/STAT3 unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IL11RA was shown to promote melanoma migration, invasion, and hepatic metastasis through STAT3 activation and MMP2 upregulation, revealing a pro-tumorigenic role for the receptor.\",\n      \"evidence\": \"siRNA knockdown and Il11ra knockout mice with splenic melanoma injection, Western blot and RT-qPCR for STAT3 and MMP2\",\n      \"pmids\": [\"38468436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication needed\",\n        \"Whether IL11RA acts cell-autonomously in tumor cells versus stromal cells not resolved\",\n        \"Applicability beyond melanoma not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An experimental structure of the IL-11/IL11RA/gp130 signaling complex is lacking, the transcriptional programs downstream of IL11RA/STAT3 in cranial suture and regenerative contexts are uncharacterized, and the relative contributions of membrane-bound versus soluble IL11RA to physiological signaling remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No experimentally determined ternary complex structure\",\n        \"Downstream transcriptional targets in cranial mesenchyme and regeneration not mapped\",\n        \"Role of soluble IL11RA shedding in modulating signaling not explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\n      \"IL-11/IL11RA/gp130 receptor complex\"\n    ],\n    \"partners\": [\n      \"IL6ST\",\n      \"IL11\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}