{"gene":"IL13RA2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1997,"finding":"IL-13Rα1 (not IL13RA2) forms a heterodimeric signaling complex with IL-4Rα that binds IL-13 with high affinity (~30 pM) and activates STAT6; IL13RA2 (27% identical to IL-13Rα1) binds IL-13 independently but this paper establishes the signaling complex does not include IL13RA2.","method":"CHO cell co-expression, radioligand binding, EMSA for STAT6 activation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution in CHO cells with functional STAT6 readout, single lab; primarily about IL-13Rα1 but contextualizes IL13RA2 as a distinct, non-signaling paralog","pmids":["9013879"],"is_preprint":false},{"year":2002,"finding":"IL-13Rα2 acts as a decoy receptor that inhibits not only IL-13- but also IL-4-mediated STAT6 signaling; the inhibition mechanism involves physical interaction between the short intracellular domain of IL-13Rα2 and the cytoplasmic domain of IL-4Rα (which harbors STAT6 docking sites), independent of ligand binding.","method":"Transient transfection of IL13RA2 in heterologous cells, STAT6 activation assay, co-immunoprecipitation of IL-13Rα2 intracellular domain with IL-4Rα cytoplasmic domain","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays plus co-IP in single lab; two orthogonal methods (signaling inhibition + physical interaction)","pmids":["11861389"],"is_preprint":false},{"year":2006,"finding":"IL-13Rα2 distribution is predominantly intracellular; surface IL-13Rα2 is continually released in soluble form yet surface levels remain constant, indicating active receptor trafficking to the cell surface. IL-13Rα2 inhibits IL-13 signaling proportionally to its expression level, and this inhibition can be overcome with high IL-13 concentrations.","method":"Subcellular fractionation, flow cytometry, ELISA for soluble form, IL-13 signaling (STAT6) assay in transfected and primary cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple orthogonal methods, single lab","pmids":["16751396"],"is_preprint":false},{"year":2006,"finding":"N-linked glycosylation of IL-13Rα2 extracellular domain (ECD) is essential for optimal IL-13 inhibitory activity; deglycosylation by PNGase F reduced inhibitory potency. Glycosylated ECD inhibited IL-13-induced STAT6 phosphorylation, IL-13 binding, and IL-13 cytotoxin cytotoxicity, but did not inhibit IL-4-induced STAT6 phosphorylation, demonstrating receptor-specific inhibition.","method":"Expression of ECD in E. coli vs. mammalian cells, PNGase F deglycosylation, STAT6 phosphorylation assay, ligand binding assay, cytotoxicity assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic deglycosylation with mutagenic-equivalent functional readout, multiple orthogonal assays, single lab","pmids":["17023392"],"is_preprint":false},{"year":2008,"finding":"In humans, soluble IL-13Rα2 is generated exclusively from membrane IL-13Rα2 by MMP/MMP-8-mediated cleavage of the membrane-bound form (not by alternative splicing as in mice). siRNA depletion of full-length human IL-13Rα2 decreased both membrane and soluble forms, and MMP/MMP-8 inhibition abolished soluble IL-13Rα2 production.","method":"siRNA-mediated depletion of specific transcripts, MMP inhibitor treatment, ELISA for soluble IL-13Rα2, RT-PCR for transcript variants","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct mechanistic dissection using siRNA + pharmacological inhibition with two orthogonal methods, single lab","pmids":["20007572"],"is_preprint":false},{"year":2008,"finding":"IL-13 signaling via IL-13Rα2 initiates a fibrotic program in chronic colitis by driving TGF-β1 activation, IGF-I and Egr-1 expression; Egr-1 promotes myofibroblast apoptosis and urokinase plasminogen activator production (which activates TGF-β1), and IGF-I (with TGF-β1) stimulates myofibroblast collagen deposition.","method":"siRNA and decoy oligonucleotide blockade of IL-13Rα2 and TGF-β1 signaling in TNBS colitis mouse model, ELISA, Western blot for fibrogenic factors, collagen measurement","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis/pathway placement via in vivo RNAi blockade with multiple downstream readouts, single lab","pmids":["18938165"],"is_preprint":false},{"year":2005,"finding":"IL-13Rα2 is the primary IL-13 binding and internalization component required for IL-13 cytotoxin (IL13-PE38QQR) cytotoxicity in GBM cells; antisense/siRNA knockdown of IL-13Rα2 decreased ligand binding and reduced sensitivity to cytotoxin, while overexpression of IL-13Rα2 in tumors enhanced cytotoxin-mediated tumor regression and survival.","method":"Antisense oligonucleotide and siRNA knockdown, plasmid-mediated overexpression, IL-13 binding assay, in vivo tumor treatment with convection-enhanced delivery","journal":"Journal of immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readout (ligand binding + cytotoxicity), single lab","pmids":["15838375"],"is_preprint":false},{"year":2003,"finding":"The human IL-13Rα2 gene promoter contains TATA boxes, a CCAAT site, and functional binding sites for NFAT, AP1 (c-JUN, c-FOS), AP2, and other transcription factors; a 64-bp region containing AP1, NFAT, and AP2 cis-elements is necessary for promoter activity. AP1 role was confirmed by in vitro mutagenesis and JNK inhibition.","method":"Promoter cloning, secreted alkaline phosphatase reporter assay, deletion analysis, in vitro mutagenesis, JNK inhibition, methylation analysis","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — functional promoter dissection with mutagenesis and inhibitor experiments, single lab","pmids":["12816724"],"is_preprint":false},{"year":2010,"finding":"NFAT and AP1 transcription factors are necessary and essential for expression of a GBM-specific IL-13Rα2 transcript; this transcript produces a secreted (soluble) form of IL-13Rα2. The IL-13Rα2 gene has at least 2 promoters and 4 transcripts.","method":"Mutation analysis, quantitative RT-PCR, flow cytometry, transcription factor binding assay, ELISA","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcription factor binding assay with mutation analysis, multiple methods, single lab","pmids":["20448330"],"is_preprint":false},{"year":2015,"finding":"IL13RA2 expression promotes sunitinib resistance in clear cell renal cell carcinoma; IL13RA2 overexpression in sensitive cells conferred resistance in vivo, and shRNA-mediated knockdown reversed resistance in Caki-1 cells. Mechanistically, IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature.","method":"Xenograft models, shRNA knockdown, IL13RA2 overexpression, histopathological apoptosis analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss- and gain-of-function with in vivo readout, single lab","pmids":["26114873"],"is_preprint":false},{"year":2015,"finding":"IL13RA2 expression is induced by ingenol mebutate through PKC/MEK/ERK signaling in keratinocytes; siRNA knockdown of IL13RA2 partially rescued ingenol mebutate-treated cells, functionally linking IL13RA2 induction to reduced cell viability downstream of PKCδ/MEK/ERK.","method":"Transcriptional profiling, pathway inhibition, siRNA knockdown, phosphorylation screen, viability assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via siRNA rescue + pharmacological pathway inhibition, multiple orthogonal methods, single lab","pmids":["26116359"],"is_preprint":false},{"year":2019,"finding":"IL13RA2 promotes cell migration and epithelial-mesenchymal transition (EMT) in papillary thyroid carcinoma; knockdown reduced cell viability, migration, and EMT markers (N-cadherin, Vimentin, Snail), while overexpression increased migration and EMT without affecting proliferation.","method":"siRNA knockdown, exogenous overexpression, CCK-8 proliferation, transwell migration, Western blot and qRT-PCR for EMT markers","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss- and gain-of-function with defined molecular pathway readout, single lab","pmids":["31290966"],"is_preprint":false},{"year":2020,"finding":"Silencing of IL13RA2 in hepatocellular carcinoma cells promotes partial EMT and increases invasiveness via activation of ERK phosphorylation.","method":"siRNA knockdown, Western blot for p-ERK, invasion assay","journal":"FEBS open bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with limited mechanistic follow-up","pmids":["31823484"],"is_preprint":false},{"year":2023,"finding":"IL-13RA2 downregulation in keloid fibroblasts leads to elevated STAT6 phosphorylation (via JAK/STAT6 activation); ectopic expression of IL-13RA2 in keloid fibroblasts inhibited STAT6 phosphorylation, cell proliferation, migration, invasion, ECM secretion, and myofibroblast marker expression.","method":"Western blot for p-STAT6, ectopic IL-13RA2 expression, IL-13RA2 knockdown in normal fibroblasts, patient-derived xenograft mouse model with STAT6 inhibitor","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined signaling readout plus in vivo validation, single lab","pmids":["36757802"],"is_preprint":false},{"year":2024,"finding":"IL13RA2 interacts physically with β-catenin and activates the Wnt/β-catenin pathway in haemangioma-derived endothelial cells, promoting proliferation, migration, invasion, and glycolysis; these effects were confirmed with a glycolysis inhibitor.","method":"Co-immunoprecipitation (IL13RA2-β-catenin interaction), overexpression/knockdown, Wnt/β-catenin pathway Western blot, glycolysis inhibitor rescue","journal":"Oncology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus functional assays, single lab, limited mechanistic follow-up","pmids":["39220137"],"is_preprint":false},{"year":2024,"finding":"Moscatilin binds directly to IL13RA2 (confirmed by cellular thermal shift assay) and augments IL13RA2 expression; IL13RA2 is reduced during osteogenic differentiation of HASMCs, leading to STAT3-mediated inflammatory factor secretion. Moscatilin suppresses vascular calcification via the IL13RA2/STAT3 and WNT3/β-catenin axes.","method":"Cellular thermal shift assay (direct binding), transcriptional profiling, in vitro HASMC osteogenesis model, in vivo mouse vascular calcification model","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by thermal shift assay plus in vitro and in vivo functional validation, single lab","pmids":["38432393"],"is_preprint":false},{"year":2025,"finding":"Loss of IL13RA2 in triple-negative breast cancer cells increases AKT and NF-κB signaling, enhancing cell survival in vitro and augmenting metastatic tumor growth in vivo; IL13RA2-deficient cells are sensitive to AKT inhibition.","method":"CRISPR knockout, Western blot for p-AKT and NF-κB, in vivo intracardiac metastasis model, pathway inhibitor sensitivity assay","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined signaling pathway readout and in vivo phenotype, single lab","pmids":["40663259"],"is_preprint":false},{"year":2024,"finding":"IL-13 promotes angiosarcoma cell proliferation specifically through IL-13Rα2; siRNA knockdown of IL13RA2 or neutralizing anti-IL-13 antibodies blocked this proliferative effect. IL-13 stimulation increased IL13RA2 and VEGFA mRNA levels in a STAT6-dependent positive feedback loop (blocked by STAT6 inhibitor).","method":"siRNA knockdown, neutralizing antibodies, proliferation assays, STAT6 inhibitor treatment, qRT-PCR","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, siRNA knockdown with functional readout but limited mechanistic depth","pmids":["bio_10.1101_2024.10.24.619789"],"is_preprint":true},{"year":2024,"finding":"GOLIM4 silencing (downstream of IRE1/XBP1s) reduces surface expression of IL13RA2 in glioblastoma cells without altering IL13RA2 transcript levels, indicating that GOLIM4 controls post-translational trafficking of IL13RA2 to the cell surface.","method":"GOLIM4 siRNA knockdown, flow cytometry for surface IL13RA2, RT-PCR for transcript levels","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single knockdown experiment, IL13RA2 is a secondary finding in a paper primarily about GOLIM4","pmids":["bio_10.1101_2024.10.22.619629"],"is_preprint":true}],"current_model":"IL13RA2 is a high-affinity IL-13 decoy receptor that lacks intrinsic signaling capacity; it inhibits IL-13 and IL-4 signaling by sequestering IL-13 and by physically interacting with IL-4Rα to block STAT6 activation, exists predominantly in intracellular pools with surface forms continuously shed by MMP/MMP-8-mediated cleavage, requires N-linked glycosylation for full inhibitory potency, is transcriptionally regulated by NFAT and AP1 acting on a defined promoter, and in various cellular contexts (fibroblasts, cancer cells) modulates downstream pathways including JAK/STAT6, ERK, AKT/NF-κB, and Wnt/β-catenin to influence fibrosis, EMT, apoptosis resistance, and metastasis."},"narrative":{"mechanistic_narrative":"IL13RA2 (IL-13Rα2) is a high-affinity IL-13 binding receptor that functions as a signaling-incompetent decoy, restraining type-2 cytokine responses and shaping fibrotic and oncogenic programs across diverse tissues [PMID:11861389, PMID:16751396]. It was distinguished early from the signal-transducing IL-13Rα1/IL-4Rα complex as a distinct, non-signaling paralog that nonetheless binds IL-13 independently [PMID:9013879]. As a decoy it suppresses both IL-13- and IL-4-driven STAT6 activation: in addition to sequestering ligand, its short intracellular domain physically engages the cytoplasmic tail of IL-4Rα to block STAT6 docking independent of ligand binding [PMID:11861389], and its inhibitory potency scales with expression and depends on N-linked glycosylation of the extracellular domain [PMID:16751396, PMID:17023392]. The receptor resides predominantly in intracellular pools, with surface forms continuously released as soluble IL-13Rα2 generated in humans by MMP/MMP-8-mediated cleavage rather than alternative splicing [PMID:16751396, PMID:20007572]. Transcription is driven by a defined promoter bearing functional NFAT and AP1 (c-JUN/c-FOS) cis-elements, with AP1 acting through JNK [PMID:12816724, PMID:20448330]. In disease contexts IL13RA2 has opposing roles: it drives an IL-13-dependent fibrotic program through TGF-β1, IGF-I and Egr-1 in colitis [PMID:18938165], yet acts as a brake on fibroblast STAT6 activation, proliferation and ECM secretion in keloids [PMID:36757802]. In cancer it modulates ERK, AKT/NF-κB and Wnt/β-catenin signaling—promoting EMT and migration in thyroid carcinoma [PMID:31290966], conferring sunitinib resistance and apoptosis evasion in renal carcinoma [PMID:26114873], and restraining AKT/NF-κB-driven survival and metastasis in triple-negative breast cancer [PMID:40663259]. It also serves as the principal binding and internalization component exploited by IL-13 cytotoxin for glioblastoma targeting [PMID:15838375].","teleology":[{"year":1997,"claim":"Established that the functional IL-13 signaling complex is built from IL-13Rα1 and IL-4Rα and does NOT include IL13RA2, framing IL13RA2 as a distinct ligand-binding paralog without a defined signaling role.","evidence":"CHO co-expression with radioligand binding and EMSA for STAT6 activation","pmids":["9013879"],"confidence":"Medium","gaps":["Did not determine what IL13RA2 does biologically","IL13RA2 binding affinity and structural basis not characterized here"]},{"year":2002,"claim":"Answered how a non-signaling receptor inhibits cytokine signaling, showing IL13RA2 blocks both IL-13 and IL-4 STAT6 responses via direct interaction of its intracellular domain with the IL-4Rα cytoplasmic tail, beyond simple ligand sequestration.","evidence":"Transient transfection, STAT6 activation assays, co-IP of intracellular domains in heterologous cells","pmids":["11861389"],"confidence":"Medium","gaps":["Co-IP in single lab without structural mapping of the interaction interface","Physiological relevance of intracellular-domain interaction vs. sequestration not quantified"]},{"year":2003,"claim":"Defined the transcriptional control of IL13RA2 by dissecting a promoter with functional NFAT, AP1, and AP2 cis-elements, identifying how the gene is regulated.","evidence":"Promoter cloning, reporter assays, deletion analysis, mutagenesis, JNK inhibition","pmids":["12816724"],"confidence":"Medium","gaps":["Signals upstream of NFAT/AP1 activation not defined","Cell-type specificity of promoter usage not addressed"]},{"year":2005,"claim":"Demonstrated IL13RA2 is the rate-limiting ligand-binding and internalization component for IL-13 cytotoxin killing, establishing it as a therapeutic target in glioblastoma.","evidence":"Antisense/siRNA knockdown and overexpression with ligand-binding, cytotoxicity, and in vivo tumor treatment","pmids":["15838375"],"confidence":"Medium","gaps":["Endogenous IL-13 signaling role distinct from cytotoxin delivery not resolved","Trafficking/internalization machinery not identified"]},{"year":2006,"claim":"Resolved the receptor's localization paradox—predominantly intracellular with constant surface levels despite continuous soluble release—and quantified that decoy inhibition scales with expression and is overcome by high ligand.","evidence":"Subcellular fractionation, flow cytometry, soluble-form ELISA, STAT6 assays; plus PNGase F deglycosylation establishing N-glycosylation requirement","pmids":["16751396","17023392"],"confidence":"High","gaps":["Trafficking machinery controlling surface delivery not identified","Functional role of intracellular pool unclear"]},{"year":2008,"claim":"Identified the human-specific source of soluble IL13RA2 as MMP/MMP-8 cleavage of the membrane form (not splicing as in mouse), and placed IL13RA2 within an IL-13-driven fibrotic cascade engaging TGF-β1, IGF-I, and Egr-1.","evidence":"siRNA depletion, MMP inhibition, ELISA, RT-PCR; and in vivo TNBS colitis with siRNA/decoy blockade of fibrogenic readouts","pmids":["20007572","18938165"],"confidence":"High","gaps":["How IL13RA2 transduces a pro-fibrotic signal despite lacking signaling motifs unresolved","Identity of the protease-cleavage site not mapped"]},{"year":2010,"claim":"Showed NFAT and AP1 drive a GBM-specific transcript encoding a secreted IL13RA2 form, refining promoter usage and transcript diversity.","evidence":"Mutation analysis, qRT-PCR, transcription-factor binding assay, flow cytometry, ELISA","pmids":["20448330"],"confidence":"Medium","gaps":["Function of the secreted GBM transcript vs. cleaved soluble form not distinguished","Tumor-specific regulatory signals not identified"]},{"year":2019,"claim":"Extended IL13RA2 function into cancer cell biology, showing it promotes migration and EMT in papillary thyroid carcinoma independent of proliferation.","evidence":"Reciprocal siRNA knockdown and overexpression with migration assays and EMT marker readouts","pmids":["31290966"],"confidence":"Medium","gaps":["Signaling pathway linking IL13RA2 to EMT markers not defined","Single tumor type"]},{"year":2023,"claim":"Established that IL13RA2 acts as a brake on fibroblast activation, with its loss elevating JAK/STAT6 signaling, proliferation, and ECM secretion in keloids—reconciling its decoy function with a fibrosis-restraining role.","evidence":"Reciprocal gain/loss-of-function, p-STAT6 Western blot, patient-derived xenograft with STAT6 inhibitor","pmids":["36757802"],"confidence":"Medium","gaps":["Tissue-context basis for pro- vs. anti-fibrotic roles not unified","Mechanism of STAT6 suppression in fibroblasts vs. epithelial cells not directly compared"]},{"year":2024,"claim":"Probed additional signaling outputs and trafficking control: IL13RA2 binds β-catenin and activates Wnt/glycolysis in hemangioma endothelium, modulates an IL13RA2/STAT3 calcification axis, and is delivered to the cell surface by GOLIM4 post-translationally.","evidence":"Co-IP, overexpression/knockdown, glycolysis inhibition; cellular thermal shift binding; GOLIM4 siRNA with surface flow cytometry (two preprints)","pmids":["39220137","38432393","bio_10.1101_2024.10.22.619629"],"confidence":"Low","gaps":["β-catenin Co-IP not reciprocally validated","GOLIM4-IL13RA2 trafficking link from single knockdown preprint","STAT3 axis mechanism not dissected"]},{"year":2025,"claim":"Defined a tumor-suppressive arm in triple-negative breast cancer, where IL13RA2 loss derepresses AKT/NF-κB signaling to enhance survival and metastasis, creating an AKT-inhibitor vulnerability.","evidence":"CRISPR knockout, p-AKT/NF-κB Western blot, intracardiac metastasis model, inhibitor sensitivity","pmids":["40663259"],"confidence":"Medium","gaps":["Mechanistic link from IL13RA2 to AKT/NF-κB restraint not defined","Whether decoy/ligand-binding function is involved unclear"]},{"year":null,"claim":"How a receptor lacking signaling motifs produces context-opposite outcomes—pro-fibrotic vs. anti-fibrotic, pro- vs. anti-metastatic—through ERK, AKT/NF-κB, Wnt/β-catenin, and STAT3/STAT6 remains unresolved, as does the structural basis of its intracellular IL-4Rα interaction and the trafficking machinery governing its surface vs. intracellular distribution.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model for cell-type-dependent signaling outputs","No structure of the IL13RA2 intracellular domain bound to IL-4Rα","Trafficking/internalization machinery only partially identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,13,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,11,16]}],"complexes":[],"partners":["IL4R","CTNNB1","MMP8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14627","full_name":"Interleukin-13 receptor subunit alpha-2","aliases":["Interleukin-13-binding protein"],"length_aa":380,"mass_kda":44.2,"function":"Cell surface receptor that plays a role in the regulation of IL-13-mediated responses (PubMed:11861389, PubMed:17030238). Functions as a decoy receptor that inhibits IL-13- and IL-4-mediated signal transduction via the JAK-STAT pathway and thereby modulates immune responses and inflammation (PubMed:11861389, PubMed:17030238). Serves as a functional signaling receptor for IL-13 in an alternative pathway involving AP-1 ultimately leading to the production of TGFB1 (PubMed:16327802)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14627/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL13RA2","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/IL13RA2","total_profiled":1310},"omim":[{"mim_id":"620290","title":"TRANSMEMBRANE PROTEIN 219; TMEM219","url":"https://www.omim.org/entry/620290"},{"mim_id":"300130","title":"INTERLEUKIN 13 RECEPTOR, ALPHA-2; IL13RA2","url":"https://www.omim.org/entry/300130"},{"mim_id":"300119","title":"INTERLEUKIN 13 RECEPTOR, ALPHA-1; IL13RA1","url":"https://www.omim.org/entry/300119"},{"mim_id":"147781","title":"INTERLEUKIN 4 RECEPTOR; IL4R","url":"https://www.omim.org/entry/147781"},{"mim_id":"147780","title":"INTERLEUKIN 4; IL4","url":"https://www.omim.org/entry/147780"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":30.5},{"tissue":"testis","ntpm":28.0}],"url":"https://www.proteinatlas.org/search/IL13RA2"},"hgnc":{"alias_symbol":["IL-13R","IL13BP","CD213a2","CT19"],"prev_symbol":[]},"alphafold":{"accession":"Q14627","domains":[{"cath_id":"2.60.40.10","chopping":"37-129","consensus_level":"high","plddt":93.419,"start":37,"end":129},{"cath_id":"2.60.40.10","chopping":"137-237","consensus_level":"high","plddt":93.4183,"start":137,"end":237},{"cath_id":"2.60.40.10","chopping":"239-333","consensus_level":"high","plddt":91.7463,"start":239,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14627","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14627-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14627-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL13RA2","jax_strain_url":"https://www.jax.org/strain/search?query=IL13RA2"},"sequence":{"accession":"Q14627","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14627.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14627/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14627"}},"corpus_meta":[{"pmid":"9013879","id":"PMC_9013879","title":"Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex.","date":"1997","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9013879","citation_count":185,"is_preprint":false},{"pmid":"11861389","id":"PMC_11861389","title":"IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11861389","citation_count":151,"is_preprint":false},{"pmid":"18938165","id":"PMC_18938165","title":"IL-13 signaling via IL-13R alpha2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis.","date":"2008","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18938165","citation_count":135,"is_preprint":false},{"pmid":"16918506","id":"PMC_16918506","title":"Mast cells express IL-13R alpha 1: IL-13 promotes human lung mast cell proliferation and Fc epsilon RI expression.","date":"2006","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/16918506","citation_count":76,"is_preprint":false},{"pmid":"28562337","id":"PMC_28562337","title":"IL13RA2 targeted alpha particle therapy against glioblastomas.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28562337","citation_count":74,"is_preprint":false},{"pmid":"30663072","id":"PMC_30663072","title":"Mucosal IL13RA2 expression predicts nonresponse to anti-TNF therapy in Crohn's disease.","date":"2019","source":"Alimentary pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/30663072","citation_count":59,"is_preprint":false},{"pmid":"15047912","id":"PMC_15047912","title":"A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model.","date":"2004","source":"Protein engineering, design & selection : 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is overexpressed in malignant gliomas and related to clinical outcome of patients.","date":"2020","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/32913543","citation_count":46,"is_preprint":false},{"pmid":"16981293","id":"PMC_16981293","title":"IL13RA2 gene polymorphisms are associated with systemic sclerosis.","date":"2006","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/16981293","citation_count":41,"is_preprint":false},{"pmid":"24147065","id":"PMC_24147065","title":"New agents for targeting of IL-13RA2 expressed in primary human and canine brain tumors.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24147065","citation_count":41,"is_preprint":false},{"pmid":"26114873","id":"PMC_26114873","title":"Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.","date":"2015","source":"PloS 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IL13RA2 (27% identical to IL-13Rα1) binds IL-13 independently but this paper establishes the signaling complex does not include IL13RA2.\",\n      \"method\": \"CHO cell co-expression, radioligand binding, EMSA for STAT6 activation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution in CHO cells with functional STAT6 readout, single lab; primarily about IL-13Rα1 but contextualizes IL13RA2 as a distinct, non-signaling paralog\",\n      \"pmids\": [\"9013879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-13Rα2 acts as a decoy receptor that inhibits not only IL-13- but also IL-4-mediated STAT6 signaling; the inhibition mechanism involves physical interaction between the short intracellular domain of IL-13Rα2 and the cytoplasmic domain of IL-4Rα (which harbors STAT6 docking sites), independent of ligand binding.\",\n      \"method\": \"Transient transfection of IL13RA2 in heterologous cells, STAT6 activation assay, co-immunoprecipitation of IL-13Rα2 intracellular domain with IL-4Rα cytoplasmic domain\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays plus co-IP in single lab; two orthogonal methods (signaling inhibition + physical interaction)\",\n      \"pmids\": [\"11861389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-13Rα2 distribution is predominantly intracellular; surface IL-13Rα2 is continually released in soluble form yet surface levels remain constant, indicating active receptor trafficking to the cell surface. IL-13Rα2 inhibits IL-13 signaling proportionally to its expression level, and this inhibition can be overcome with high IL-13 concentrations.\",\n      \"method\": \"Subcellular fractionation, flow cytometry, ELISA for soluble form, IL-13 signaling (STAT6) assay in transfected and primary cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16751396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"N-linked glycosylation of IL-13Rα2 extracellular domain (ECD) is essential for optimal IL-13 inhibitory activity; deglycosylation by PNGase F reduced inhibitory potency. Glycosylated ECD inhibited IL-13-induced STAT6 phosphorylation, IL-13 binding, and IL-13 cytotoxin cytotoxicity, but did not inhibit IL-4-induced STAT6 phosphorylation, demonstrating receptor-specific inhibition.\",\n      \"method\": \"Expression of ECD in E. coli vs. mammalian cells, PNGase F deglycosylation, STAT6 phosphorylation assay, ligand binding assay, cytotoxicity assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic deglycosylation with mutagenic-equivalent functional readout, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"17023392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In humans, soluble IL-13Rα2 is generated exclusively from membrane IL-13Rα2 by MMP/MMP-8-mediated cleavage of the membrane-bound form (not by alternative splicing as in mice). siRNA depletion of full-length human IL-13Rα2 decreased both membrane and soluble forms, and MMP/MMP-8 inhibition abolished soluble IL-13Rα2 production.\",\n      \"method\": \"siRNA-mediated depletion of specific transcripts, MMP inhibitor treatment, ELISA for soluble IL-13Rα2, RT-PCR for transcript variants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct mechanistic dissection using siRNA + pharmacological inhibition with two orthogonal methods, single lab\",\n      \"pmids\": [\"20007572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-13 signaling via IL-13Rα2 initiates a fibrotic program in chronic colitis by driving TGF-β1 activation, IGF-I and Egr-1 expression; Egr-1 promotes myofibroblast apoptosis and urokinase plasminogen activator production (which activates TGF-β1), and IGF-I (with TGF-β1) stimulates myofibroblast collagen deposition.\",\n      \"method\": \"siRNA and decoy oligonucleotide blockade of IL-13Rα2 and TGF-β1 signaling in TNBS colitis mouse model, ELISA, Western blot for fibrogenic factors, collagen measurement\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis/pathway placement via in vivo RNAi blockade with multiple downstream readouts, single lab\",\n      \"pmids\": [\"18938165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-13Rα2 is the primary IL-13 binding and internalization component required for IL-13 cytotoxin (IL13-PE38QQR) cytotoxicity in GBM cells; antisense/siRNA knockdown of IL-13Rα2 decreased ligand binding and reduced sensitivity to cytotoxin, while overexpression of IL-13Rα2 in tumors enhanced cytotoxin-mediated tumor regression and survival.\",\n      \"method\": \"Antisense oligonucleotide and siRNA knockdown, plasmid-mediated overexpression, IL-13 binding assay, in vivo tumor treatment with convection-enhanced delivery\",\n      \"journal\": \"Journal of immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readout (ligand binding + cytotoxicity), single lab\",\n      \"pmids\": [\"15838375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The human IL-13Rα2 gene promoter contains TATA boxes, a CCAAT site, and functional binding sites for NFAT, AP1 (c-JUN, c-FOS), AP2, and other transcription factors; a 64-bp region containing AP1, NFAT, and AP2 cis-elements is necessary for promoter activity. AP1 role was confirmed by in vitro mutagenesis and JNK inhibition.\",\n      \"method\": \"Promoter cloning, secreted alkaline phosphatase reporter assay, deletion analysis, in vitro mutagenesis, JNK inhibition, methylation analysis\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional promoter dissection with mutagenesis and inhibitor experiments, single lab\",\n      \"pmids\": [\"12816724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NFAT and AP1 transcription factors are necessary and essential for expression of a GBM-specific IL-13Rα2 transcript; this transcript produces a secreted (soluble) form of IL-13Rα2. The IL-13Rα2 gene has at least 2 promoters and 4 transcripts.\",\n      \"method\": \"Mutation analysis, quantitative RT-PCR, flow cytometry, transcription factor binding assay, ELISA\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcription factor binding assay with mutation analysis, multiple methods, single lab\",\n      \"pmids\": [\"20448330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL13RA2 expression promotes sunitinib resistance in clear cell renal cell carcinoma; IL13RA2 overexpression in sensitive cells conferred resistance in vivo, and shRNA-mediated knockdown reversed resistance in Caki-1 cells. Mechanistically, IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature.\",\n      \"method\": \"Xenograft models, shRNA knockdown, IL13RA2 overexpression, histopathological apoptosis analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss- and gain-of-function with in vivo readout, single lab\",\n      \"pmids\": [\"26114873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL13RA2 expression is induced by ingenol mebutate through PKC/MEK/ERK signaling in keratinocytes; siRNA knockdown of IL13RA2 partially rescued ingenol mebutate-treated cells, functionally linking IL13RA2 induction to reduced cell viability downstream of PKCδ/MEK/ERK.\",\n      \"method\": \"Transcriptional profiling, pathway inhibition, siRNA knockdown, phosphorylation screen, viability assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via siRNA rescue + pharmacological pathway inhibition, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26116359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL13RA2 promotes cell migration and epithelial-mesenchymal transition (EMT) in papillary thyroid carcinoma; knockdown reduced cell viability, migration, and EMT markers (N-cadherin, Vimentin, Snail), while overexpression increased migration and EMT without affecting proliferation.\",\n      \"method\": \"siRNA knockdown, exogenous overexpression, CCK-8 proliferation, transwell migration, Western blot and qRT-PCR for EMT markers\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss- and gain-of-function with defined molecular pathway readout, single lab\",\n      \"pmids\": [\"31290966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Silencing of IL13RA2 in hepatocellular carcinoma cells promotes partial EMT and increases invasiveness via activation of ERK phosphorylation.\",\n      \"method\": \"siRNA knockdown, Western blot for p-ERK, invasion assay\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with limited mechanistic follow-up\",\n      \"pmids\": [\"31823484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-13RA2 downregulation in keloid fibroblasts leads to elevated STAT6 phosphorylation (via JAK/STAT6 activation); ectopic expression of IL-13RA2 in keloid fibroblasts inhibited STAT6 phosphorylation, cell proliferation, migration, invasion, ECM secretion, and myofibroblast marker expression.\",\n      \"method\": \"Western blot for p-STAT6, ectopic IL-13RA2 expression, IL-13RA2 knockdown in normal fibroblasts, patient-derived xenograft mouse model with STAT6 inhibitor\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined signaling readout plus in vivo validation, single lab\",\n      \"pmids\": [\"36757802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL13RA2 interacts physically with β-catenin and activates the Wnt/β-catenin pathway in haemangioma-derived endothelial cells, promoting proliferation, migration, invasion, and glycolysis; these effects were confirmed with a glycolysis inhibitor.\",\n      \"method\": \"Co-immunoprecipitation (IL13RA2-β-catenin interaction), overexpression/knockdown, Wnt/β-catenin pathway Western blot, glycolysis inhibitor rescue\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus functional assays, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"39220137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Moscatilin binds directly to IL13RA2 (confirmed by cellular thermal shift assay) and augments IL13RA2 expression; IL13RA2 is reduced during osteogenic differentiation of HASMCs, leading to STAT3-mediated inflammatory factor secretion. Moscatilin suppresses vascular calcification via the IL13RA2/STAT3 and WNT3/β-catenin axes.\",\n      \"method\": \"Cellular thermal shift assay (direct binding), transcriptional profiling, in vitro HASMC osteogenesis model, in vivo mouse vascular calcification model\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by thermal shift assay plus in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"38432393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of IL13RA2 in triple-negative breast cancer cells increases AKT and NF-κB signaling, enhancing cell survival in vitro and augmenting metastatic tumor growth in vivo; IL13RA2-deficient cells are sensitive to AKT inhibition.\",\n      \"method\": \"CRISPR knockout, Western blot for p-AKT and NF-κB, in vivo intracardiac metastasis model, pathway inhibitor sensitivity assay\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined signaling pathway readout and in vivo phenotype, single lab\",\n      \"pmids\": [\"40663259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-13 promotes angiosarcoma cell proliferation specifically through IL-13Rα2; siRNA knockdown of IL13RA2 or neutralizing anti-IL-13 antibodies blocked this proliferative effect. IL-13 stimulation increased IL13RA2 and VEGFA mRNA levels in a STAT6-dependent positive feedback loop (blocked by STAT6 inhibitor).\",\n      \"method\": \"siRNA knockdown, neutralizing antibodies, proliferation assays, STAT6 inhibitor treatment, qRT-PCR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, siRNA knockdown with functional readout but limited mechanistic depth\",\n      \"pmids\": [\"bio_10.1101_2024.10.24.619789\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GOLIM4 silencing (downstream of IRE1/XBP1s) reduces surface expression of IL13RA2 in glioblastoma cells without altering IL13RA2 transcript levels, indicating that GOLIM4 controls post-translational trafficking of IL13RA2 to the cell surface.\",\n      \"method\": \"GOLIM4 siRNA knockdown, flow cytometry for surface IL13RA2, RT-PCR for transcript levels\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single knockdown experiment, IL13RA2 is a secondary finding in a paper primarily about GOLIM4\",\n      \"pmids\": [\"bio_10.1101_2024.10.22.619629\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL13RA2 is a high-affinity IL-13 decoy receptor that lacks intrinsic signaling capacity; it inhibits IL-13 and IL-4 signaling by sequestering IL-13 and by physically interacting with IL-4Rα to block STAT6 activation, exists predominantly in intracellular pools with surface forms continuously shed by MMP/MMP-8-mediated cleavage, requires N-linked glycosylation for full inhibitory potency, is transcriptionally regulated by NFAT and AP1 acting on a defined promoter, and in various cellular contexts (fibroblasts, cancer cells) modulates downstream pathways including JAK/STAT6, ERK, AKT/NF-κB, and Wnt/β-catenin to influence fibrosis, EMT, apoptosis resistance, and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL13RA2 (IL-13Rα2) is a high-affinity IL-13 binding receptor that functions as a signaling-incompetent decoy, restraining type-2 cytokine responses and shaping fibrotic and oncogenic programs across diverse tissues [#1, #2]. It was distinguished early from the signal-transducing IL-13Rα1/IL-4Rα complex as a distinct, non-signaling paralog that nonetheless binds IL-13 independently [#0]. As a decoy it suppresses both IL-13- and IL-4-driven STAT6 activation: in addition to sequestering ligand, its short intracellular domain physically engages the cytoplasmic tail of IL-4Rα to block STAT6 docking independent of ligand binding [#1], and its inhibitory potency scales with expression and depends on N-linked glycosylation of the extracellular domain [#2, #3]. The receptor resides predominantly in intracellular pools, with surface forms continuously released as soluble IL-13Rα2 generated in humans by MMP/MMP-8-mediated cleavage rather than alternative splicing [#2, #4]. Transcription is driven by a defined promoter bearing functional NFAT and AP1 (c-JUN/c-FOS) cis-elements, with AP1 acting through JNK [#7, #8]. In disease contexts IL13RA2 has opposing roles: it drives an IL-13-dependent fibrotic program through TGF-β1, IGF-I and Egr-1 in colitis [#5], yet acts as a brake on fibroblast STAT6 activation, proliferation and ECM secretion in keloids [#13]. In cancer it modulates ERK, AKT/NF-κB and Wnt/β-catenin signaling—promoting EMT and migration in thyroid carcinoma [#11], conferring sunitinib resistance and apoptosis evasion in renal carcinoma [#9], and restraining AKT/NF-κB-driven survival and metastasis in triple-negative breast cancer [#16]. It also serves as the principal binding and internalization component exploited by IL-13 cytotoxin for glioblastoma targeting [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that the functional IL-13 signaling complex is built from IL-13Rα1 and IL-4Rα and does NOT include IL13RA2, framing IL13RA2 as a distinct ligand-binding paralog without a defined signaling role.\",\n      \"evidence\": \"CHO co-expression with radioligand binding and EMSA for STAT6 activation\",\n      \"pmids\": [\"9013879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not determine what IL13RA2 does biologically\", \"IL13RA2 binding affinity and structural basis not characterized here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Answered how a non-signaling receptor inhibits cytokine signaling, showing IL13RA2 blocks both IL-13 and IL-4 STAT6 responses via direct interaction of its intracellular domain with the IL-4Rα cytoplasmic tail, beyond simple ligand sequestration.\",\n      \"evidence\": \"Transient transfection, STAT6 activation assays, co-IP of intracellular domains in heterologous cells\",\n      \"pmids\": [\"11861389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP in single lab without structural mapping of the interaction interface\", \"Physiological relevance of intracellular-domain interaction vs. sequestration not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the transcriptional control of IL13RA2 by dissecting a promoter with functional NFAT, AP1, and AP2 cis-elements, identifying how the gene is regulated.\",\n      \"evidence\": \"Promoter cloning, reporter assays, deletion analysis, mutagenesis, JNK inhibition\",\n      \"pmids\": [\"12816724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals upstream of NFAT/AP1 activation not defined\", \"Cell-type specificity of promoter usage not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated IL13RA2 is the rate-limiting ligand-binding and internalization component for IL-13 cytotoxin killing, establishing it as a therapeutic target in glioblastoma.\",\n      \"evidence\": \"Antisense/siRNA knockdown and overexpression with ligand-binding, cytotoxicity, and in vivo tumor treatment\",\n      \"pmids\": [\"15838375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous IL-13 signaling role distinct from cytotoxin delivery not resolved\", \"Trafficking/internalization machinery not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the receptor's localization paradox—predominantly intracellular with constant surface levels despite continuous soluble release—and quantified that decoy inhibition scales with expression and is overcome by high ligand.\",\n      \"evidence\": \"Subcellular fractionation, flow cytometry, soluble-form ELISA, STAT6 assays; plus PNGase F deglycosylation establishing N-glycosylation requirement\",\n      \"pmids\": [\"16751396\", \"17023392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery controlling surface delivery not identified\", \"Functional role of intracellular pool unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the human-specific source of soluble IL13RA2 as MMP/MMP-8 cleavage of the membrane form (not splicing as in mouse), and placed IL13RA2 within an IL-13-driven fibrotic cascade engaging TGF-β1, IGF-I, and Egr-1.\",\n      \"evidence\": \"siRNA depletion, MMP inhibition, ELISA, RT-PCR; and in vivo TNBS colitis with siRNA/decoy blockade of fibrogenic readouts\",\n      \"pmids\": [\"20007572\", \"18938165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IL13RA2 transduces a pro-fibrotic signal despite lacking signaling motifs unresolved\", \"Identity of the protease-cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed NFAT and AP1 drive a GBM-specific transcript encoding a secreted IL13RA2 form, refining promoter usage and transcript diversity.\",\n      \"evidence\": \"Mutation analysis, qRT-PCR, transcription-factor binding assay, flow cytometry, ELISA\",\n      \"pmids\": [\"20448330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the secreted GBM transcript vs. cleaved soluble form not distinguished\", \"Tumor-specific regulatory signals not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended IL13RA2 function into cancer cell biology, showing it promotes migration and EMT in papillary thyroid carcinoma independent of proliferation.\",\n      \"evidence\": \"Reciprocal siRNA knockdown and overexpression with migration assays and EMT marker readouts\",\n      \"pmids\": [\"31290966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway linking IL13RA2 to EMT markers not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that IL13RA2 acts as a brake on fibroblast activation, with its loss elevating JAK/STAT6 signaling, proliferation, and ECM secretion in keloids—reconciling its decoy function with a fibrosis-restraining role.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function, p-STAT6 Western blot, patient-derived xenograft with STAT6 inhibitor\",\n      \"pmids\": [\"36757802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-context basis for pro- vs. anti-fibrotic roles not unified\", \"Mechanism of STAT6 suppression in fibroblasts vs. epithelial cells not directly compared\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Probed additional signaling outputs and trafficking control: IL13RA2 binds β-catenin and activates Wnt/glycolysis in hemangioma endothelium, modulates an IL13RA2/STAT3 calcification axis, and is delivered to the cell surface by GOLIM4 post-translationally.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, glycolysis inhibition; cellular thermal shift binding; GOLIM4 siRNA with surface flow cytometry (two preprints)\",\n      \"pmids\": [\"39220137\", \"38432393\", \"bio_10.1101_2024.10.22.619629\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"β-catenin Co-IP not reciprocally validated\", \"GOLIM4-IL13RA2 trafficking link from single knockdown preprint\", \"STAT3 axis mechanism not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a tumor-suppressive arm in triple-negative breast cancer, where IL13RA2 loss derepresses AKT/NF-κB signaling to enhance survival and metastasis, creating an AKT-inhibitor vulnerability.\",\n      \"evidence\": \"CRISPR knockout, p-AKT/NF-κB Western blot, intracardiac metastasis model, inhibitor sensitivity\",\n      \"pmids\": [\"40663259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from IL13RA2 to AKT/NF-κB restraint not defined\", \"Whether decoy/ligand-binding function is involved unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a receptor lacking signaling motifs produces context-opposite outcomes—pro-fibrotic vs. anti-fibrotic, pro- vs. anti-metastatic—through ERK, AKT/NF-κB, Wnt/β-catenin, and STAT3/STAT6 remains unresolved, as does the structural basis of its intracellular IL-4Rα interaction and the trafficking machinery governing its surface vs. intracellular distribution.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model for cell-type-dependent signaling outputs\", \"No structure of the IL13RA2 intracellular domain bound to IL-4Rα\", \"Trafficking/internalization machinery only partially identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 13, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 11, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL4R\", \"CTNNB1\", \"MMP8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}