{"gene":"IL13RA2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1997,"finding":"IL-13Rα1 (IL13RA1) reconstituted with IL-4Rα forms a functional high-affinity heterodimeric receptor complex for IL-13 (Kd ~30 pM) that activates STAT6; IL-13Rα1 alone binds IL-13 with lower affinity (~4 nM) but cannot signal alone, and neither can IL-4Rα alone.","method":"CHO cell reconstitution, ligand binding assays, EMSA for STAT6 activation","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of receptor complex with functional readout, multiple methods","pmids":["9013879"],"is_preprint":false},{"year":2002,"finding":"IL-13Rα2 acts as a decoy receptor in glioblastoma cells, sequestering IL-13 and inhibiting IL-13-mediated STAT6 activation; additionally, the short intracellular domain of IL-13Rα2 physically interacts with the cytoplasmic domain of IL-4Rα (which harbors STAT6 docking sites), thereby inhibiting IL-4-dependent signaling independently of ligand binding.","method":"Transient transfection of IL-13Rα2 in non-expressing cells, STAT6 activation assay, co-immunoprecipitation of IL-13Rα2 intracellular domain with IL-4Rα cytoplasmic domain","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (functional signaling assay + physical interaction), mechanistic follow-up in primary cells and heterologous system","pmids":["11861389"],"is_preprint":false},{"year":2006,"finding":"IL-13Rα2 distribution is predominantly intracellular (majority of protein in intracellular pools), with surface IL-13Rα2 continuously released as soluble form while surface expression is maintained by ongoing receptor trafficking; IL-13Rα2 inhibits IL-13 signaling proportionally to its expression level, and this inhibition can be overcome by high IL-13 concentrations.","method":"Flow cytometry, subcellular fractionation, transfection in multiple cell types, IL-13 signaling assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence, single lab with multiple methods","pmids":["16751396"],"is_preprint":false},{"year":2006,"finding":"N-linked glycosylation of the IL-13Rα2 extracellular domain (ECD) is essential for optimal IL-13 inhibitory activity; mammalian-derived glycosylated ECD (60 kDa) is superior to E. coli-derived non-glycosylated ECD (42 kDa) in inhibiting IL-13-induced STAT6 phosphorylation, IL-13 binding, and cytotoxin cytotoxicity; deglycosylation by PNGase F reduces inhibitory activity.","method":"Recombinant protein expression in E. coli vs. mammalian cells, PNGase F deglycosylation, STAT6 phosphorylation assay, binding competition assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assay with mutagenesis-equivalent (enzymatic deglycosylation) and multiple functional readouts","pmids":["17023392"],"is_preprint":false},{"year":2008,"finding":"IL-13 signaling via IL-13Rα2 drives intestinal fibrosis by activating a downstream program including TGF-β1 production, IGF-I and Egr-1 expression; Egr-1 mediates early myofibroblast apoptosis and urokinase plasminogen activator production (which activates TGF-β1), while IGF-I acts with TGF-β1 to stimulate collagen deposition.","method":"siRNA blockade of IL-13Rα2 and TGF-β1 signaling in TNBS colitis mouse model, ELISA, Western blot, collagen measurement","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via siRNA knockdown with multiple downstream readouts, single lab","pmids":["18938165"],"is_preprint":false},{"year":2009,"finding":"In humans, soluble IL-13Rα2 (sIL-13Rα2) is generated exclusively from the membrane-bound full-length transcript via matrix metalloproteinase (MMP/MMP-8)-mediated cleavage of membrane IL-13Rα2; in mice, a separate alternatively spliced transcript (ΔEx10) encodes the soluble form independently of the membrane form.","method":"siRNA depletion of specific transcripts, MMP inhibitor treatment, Western blot, ELISA for soluble and membrane forms","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1/2 — mechanistic dissection using isoform-specific siRNA and pharmacological inhibition, multiple orthogonal methods","pmids":["20007572"],"is_preprint":false},{"year":2005,"finding":"IL-13Rα2 is the primary IL-13 binding and internalization component in glioblastoma cells; antisense oligonucleotide or siRNA knockdown of IL-13Rα2 in GBM cells reduces IL-13 ligand binding and decreases sensitivity to IL-13 cytotoxin, while IL-13Rα2 gene transfer into low-expressing cells increases cytotoxin efficacy.","method":"Antisense oligonucleotide and siRNA knockdown, ligand binding assay, cytotoxicity assay, plasmid-mediated gene transfer in vivo","journal":"Journal of immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with specific molecular readout (ligand binding and cytotoxin sensitivity)","pmids":["15838375"],"is_preprint":false},{"year":2010,"finding":"IL-13Rα2 expression in glioblastoma is regulated at the transcriptional level by at least 2 promoters generating 4 transcripts; transcription factors NFAT and AP1 (c-JUN, c-FOS) are necessary and sufficient for expression of a GBM-specific IL-13Rα2 transcript, and one transcript produces a secreted soluble form of IL-13Rα2.","method":"Promoter cloning, deletion analysis, in vitro mutagenesis, c-JUN N-terminal kinase inhibition, transcription factor binding assay, quantitative RT-PCR, flow cytometry","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter mutagenesis and transcription factor binding assays with functional validation in multiple GBM cell lines","pmids":["20448330"],"is_preprint":false},{"year":2015,"finding":"IL13RA2 promotes resistance to sunitinib in clear cell renal cell carcinoma by suppressing sunitinib-induced apoptosis; shRNA-mediated knockdown of IL13RA2 in Caki-1 cells overcomes sunitinib resistance, while overexpression of IL13RA2 in sunitinib-sensitive 786-O cells confers resistance in vivo.","method":"shRNA knockdown, IL13RA2 overexpression in xenograft models, histopathological apoptosis analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain- and loss-of-function experiments with defined cellular phenotype (apoptosis suppression)","pmids":["26114873"],"is_preprint":false},{"year":2015,"finding":"Ingenol mebutate induces IL13RA2 expression in keratinocytes via the PKCδ/MEK/ERK signaling pathway, and siRNA knockdown of IL13RA2 partially rescues keratinocytes from ingenol mebutate-induced cell death, functionally linking IL13RA2 induction to reduced cell viability.","method":"Transcriptional profiling, pathway inhibitor studies, siRNA knockdown, cell viability assay","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2/3 — siRNA knockdown with functional rescue and pathway inhibitor corroboration","pmids":["26116359"],"is_preprint":false},{"year":2019,"finding":"IL13RA2 promotes cell migration and epithelial-mesenchymal transition (EMT) in papillary thyroid carcinoma; knockdown of IL13RA2 reduces cell viability, migration, and EMT markers (N-cadherin, Vimentin, Snail), while exogenous overexpression increases cell migration and EMT markers.","method":"siRNA knockdown, exogenous overexpression, transwell migration assay, Western blot for EMT markers, CCK-8 proliferation assay","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain- and loss-of-function with multiple cellular phenotype readouts","pmids":["31290966"],"is_preprint":false},{"year":2020,"finding":"Silencing of IL13RA2 in hepatocellular carcinoma cells promotes partial epithelial-mesenchymal transition and invasive potential via increased ERK phosphorylation.","method":"IL13RA2 knockdown, Western blot for p-ERK, invasion assay","journal":"FEBS open bio","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single knockdown approach with limited mechanistic follow-up","pmids":["31823484"],"is_preprint":false},{"year":2023,"finding":"Downregulation of IL-13RA2 in keloid fibroblasts leads to increased STAT6 phosphorylation and fibrotic phenotypes; ectopic re-expression of IL-13RA2 in keloid fibroblasts inhibits STAT6 phosphorylation, cell proliferation, migration, invasion, extracellular matrix secretion, and myofibroblast marker expression while increasing apoptosis, establishing IL-13RA2 as a negative regulator of JAK/STAT6 signaling in fibroblasts.","method":"Western blot, ectopic expression, siRNA knockdown, patient-derived xenograft mouse model, STAT6 inhibitor (AS1517499)","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain- and loss-of-function in primary cells and in vivo model with multiple readouts","pmids":["36757802"],"is_preprint":false},{"year":2024,"finding":"IL13RA2 suppresses vascular calcification by binding to and augmenting expression of downstream signaling components; IL13RA2 activation inhibits STAT3 signaling and attenuates WNT3/β-catenin pathway to reduce osteogenic differentiation of human aortic smooth muscle cells.","method":"Cellular thermal shift assay (direct binding), transcriptional profiling, IL13RA2 knockdown/overexpression, in vitro and in vivo vascular calcification models","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding assay plus functional epistasis experiments in vitro and in vivo","pmids":["38432393"],"is_preprint":false},{"year":2024,"finding":"GOLIM4, regulated downstream of IRE1/XBP1s, controls surface expression of IL13RA2 in glioblastoma cells; GOLIM4 silencing decreases surface IL13RA2 without altering its transcript levels, indicating post-transcriptional/secretory pathway control of IL13RA2 membrane localization.","method":"siRNA silencing of GOLIM4, flow cytometry for surface IL13RA2, transcriptomics","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, indirect regulation of IL13RA2 surface expression","pmids":["bio_10.1101_2024.10.22.619629"],"is_preprint":true},{"year":2024,"finding":"IL-13 signaling through IL-13Rα2 promotes angiosarcoma cell proliferation; siRNA-mediated knockdown of IL13RA2 or neutralizing antibodies against IL-13 inhibit IL-13-induced proliferation; IL-13 stimulation upregulates IL13RA2 and VEGFA mRNA via STAT6, creating a positive feedback loop.","method":"siRNA knockdown, neutralizing antibody, STAT6 inhibitor, proliferation assay, RT-PCR","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, mechanistic follow-up present but not peer-reviewed","pmids":["bio_10.1101_2024.10.24.619789"],"is_preprint":true},{"year":2025,"finding":"Loss of IL13RA2 in triple-negative breast cancer cells increases AKT and NF-κB signaling, enhancing cell survival and metastatic growth; IL13RA2-deficient cells are sensitive to AKT pathway inhibition, placing IL13RA2 upstream of AKT/NF-κB as a negative regulator of these pro-survival pathways.","method":"CRISPR knockout in human and murine breast cancer cell lines, Western blot for p-AKT and NF-κB, intracardiac in vivo metastasis model, pathway inhibitor sensitivity assays","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with pathway mechanistic readout in two species, in vitro and in vivo validation","pmids":["40663259"],"is_preprint":false}],"current_model":"IL13RA2 is a high-affinity IL-13 decoy receptor that sequesters IL-13 at the cell surface, inhibits STAT6 activation both by ligand sequestration and through direct physical interaction of its intracellular domain with IL-4Rα, undergoes MMP/MMP-8-mediated ectodomain shedding to generate soluble receptor in humans, requires N-linked glycosylation for optimal inhibitory activity, and acts as a negative regulator of downstream pro-fibrotic/pro-tumorigenic signaling (JAK/STAT6, AKT/NF-κB, ERK, WNT/β-catenin) in contexts including fibroblasts, vascular smooth muscle cells, and breast cancer, while paradoxically driving pro-tumorigenic IL-13-dependent STAT6 signaling in some settings such as angiosarcoma."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing the signaling receptor complex for IL-13 revealed that IL-13Rα1/IL-4Rα heterodimerization is required for STAT6 activation, setting the stage for understanding how IL13RA2 competes for IL-13 binding outside this signaling complex.","evidence":"CHO cell reconstitution with ligand binding assays and EMSA for STAT6","pmids":["9013879"],"confidence":"High","gaps":["Does not address IL13RA2 function directly","Affinity measurements limited to one heterologous system"]},{"year":2002,"claim":"The central mechanistic question—whether IL13RA2 is merely a passive sink for IL-13 or actively inhibits signaling—was resolved by showing it functions as a decoy receptor that both sequesters IL-13 and physically interacts with IL-4Rα's cytoplasmic domain to block STAT6 activation independently of ligand binding.","evidence":"Transient transfection in glioblastoma cells, STAT6 activation assays, co-immunoprecipitation of intracellular domains","pmids":["11861389"],"confidence":"High","gaps":["Co-IP of intracellular domains not confirmed by reciprocal endogenous pulldown","Structural basis of intracellular domain interaction unknown"]},{"year":2005,"claim":"IL13RA2 was established as the primary IL-13 binding and internalization receptor on glioblastoma cells, explaining why these tumors are selectively targeted by IL-13-based cytotoxins.","evidence":"Antisense and siRNA knockdown with ligand binding and cytotoxin sensitivity assays; gene transfer rescue in low-expressing cells","pmids":["15838375"],"confidence":"Medium","gaps":["Internalization mechanism not defined","Relevance to normal (non-tumor) cells unclear"]},{"year":2006,"claim":"Two key properties of IL13RA2 were established: its predominantly intracellular distribution with continuous surface trafficking and shedding, and the requirement for N-linked glycosylation of its extracellular domain for optimal IL-13 inhibitory activity.","evidence":"Subcellular fractionation, flow cytometry, recombinant glycosylated vs. non-glycosylated ECD production, PNGase F deglycosylation with STAT6 phosphorylation readouts","pmids":["16751396","17023392"],"confidence":"High","gaps":["Specific glycosylation sites contributing to function not mapped","Identity of proteases responsible for surface shedding not yet known at this point"]},{"year":2008,"claim":"Contrary to its established decoy role, IL13RA2 was shown to transduce IL-13 signals in intestinal fibrosis, activating a TGF-β1/IGF-I/Egr-1 program that drives collagen deposition—revealing context-dependent signaling capacity.","evidence":"siRNA blockade in TNBS colitis mouse model with downstream pathway analysis by ELISA and Western blot","pmids":["18938165"],"confidence":"Medium","gaps":["Adaptor proteins linking IL13RA2 short cytoplasmic tail to TGF-β1 induction not identified","Whether this signaling mode operates outside the gut is unknown"]},{"year":2009,"claim":"The mechanism generating soluble IL13RA2 was resolved: in humans, MMP-8-mediated ectodomain cleavage of the membrane form is the sole source, whereas mice use an alternatively spliced transcript.","evidence":"Isoform-specific siRNA, broad-spectrum and selective MMP inhibitors, Western blot and ELISA","pmids":["20007572"],"confidence":"High","gaps":["Cleavage site not mapped at residue level","Physiological regulation of MMP-8 activity toward IL13RA2 not characterized"]},{"year":2010,"claim":"Transcriptional regulation of IL13RA2 in glioblastoma was mapped to multiple promoters, with NFAT and AP-1 (c-JUN/c-FOS) identified as necessary and sufficient drivers of a tumor-specific transcript.","evidence":"Promoter cloning, deletion/mutagenesis analysis, JNK inhibition, transcription factor binding assays in GBM cell lines","pmids":["20448330"],"confidence":"Medium","gaps":["Epigenetic regulation not addressed","Whether NFAT/AP-1 regulation extends beyond GBM unknown"]},{"year":2019,"claim":"IL13RA2 was shown to promote epithelial-mesenchymal transition and migration in papillary thyroid carcinoma, expanding its functional repertoire beyond cytokine decoy activity to direct regulation of cell motility programs.","evidence":"Reciprocal siRNA knockdown and overexpression with EMT marker and migration assays","pmids":["31290966"],"confidence":"Medium","gaps":["Downstream signaling pathway mediating EMT induction not fully delineated","Ligand dependence of this EMT-promoting function not tested"]},{"year":2023,"claim":"IL13RA2 was established as a negative regulator of fibrotic signaling in human fibroblasts: its loss in keloid tissue leads to STAT6 hyperactivation and fibrosis, while re-expression suppresses fibrotic phenotypes.","evidence":"Reciprocal gain/loss-of-function in patient-derived keloid fibroblasts, xenograft model, STAT6 inhibitor rescue","pmids":["36757802"],"confidence":"Medium","gaps":["Whether IL13RA2 loss is cause or consequence of keloid pathogenesis not resolved","Mechanism of IL13RA2 downregulation in keloid tissue unknown"]},{"year":2024,"claim":"IL13RA2 was shown to suppress vascular calcification by inhibiting STAT3 and WNT3/β-catenin signaling in aortic smooth muscle cells, extending its negative-regulatory role to a new tissue context and additional signaling axes.","evidence":"Cellular thermal shift assay for direct binding, transcriptional profiling, knockdown/overexpression in vascular calcification models in vitro and in vivo","pmids":["38432393"],"confidence":"Medium","gaps":["Direct binding partners identified by thermal shift not fully characterized","Whether STAT3 inhibition is direct or indirect not determined"]},{"year":2025,"claim":"CRISPR knockout studies in breast cancer cells resolved that IL13RA2 acts as a negative regulator of AKT/NF-κB pro-survival signaling, and its loss drives metastatic growth that can be rescued by AKT inhibition.","evidence":"CRISPR KO in human and murine TNBC lines, Western blot for p-AKT/NF-κB, intracardiac metastasis model, pathway inhibitor sensitivity","pmids":["40663259"],"confidence":"Medium","gaps":["Molecular mechanism linking IL13RA2 to AKT suppression not defined","Whether this function depends on IL-13 ligand not tested"]},{"year":null,"claim":"The molecular mechanism by which IL13RA2's short intracellular domain transduces or inhibits intracellular signals remains unresolved—no adaptor proteins or kinases directly recruited to the cytoplasmic tail have been identified, and no structural model of IL13RA2 in complex with IL-4Rα or signaling partners exists.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of IL13RA2 alone or in complex","Adaptor proteins recruited to the 17-amino-acid cytoplasmic tail unknown","Mechanistic basis for context-dependent switch between decoy and signaling functions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,12,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,4,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5,6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,12,13,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3]}],"complexes":[],"partners":["IL4R","IL13","STAT6","GOLIM4"],"other_free_text":[]},"mechanistic_narrative":"IL13RA2 is a high-affinity decoy receptor for IL-13 that functions as a negative regulator of IL-13/IL-4 signaling across multiple tissue contexts. It sequesters IL-13 at the cell surface and inhibits STAT6 activation both through ligand sequestration and through direct physical interaction of its short intracellular domain with the cytoplasmic domain of IL-4Rα, thereby blocking STAT6 docking [PMID:11861389]; N-linked glycosylation of its extracellular domain is required for optimal inhibitory activity [PMID:17023392]. The predominantly intracellular pool of IL13RA2 is continuously trafficked to the surface, where it is shed as a soluble form via MMP-8-mediated ectodomain cleavage in humans [PMID:16751396, PMID:20007572]. IL13RA2 negatively regulates pro-fibrotic JAK/STAT6 signaling in fibroblasts and pro-survival AKT/NF-κB signaling in breast cancer, while in certain contexts such as intestinal fibrosis it can transduce IL-13 signals via TGF-β1 and downstream effectors [PMID:36757802, PMID:40663259, PMID:18938165]."},"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":149,"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":134,"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 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IL-13Rα1 alone binds IL-13 with lower affinity (~4 nM) but cannot signal alone, and neither can IL-4Rα alone.\",\n      \"method\": \"CHO cell reconstitution, ligand binding assays, EMSA for STAT6 activation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of receptor complex with functional readout, multiple methods\",\n      \"pmids\": [\"9013879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-13Rα2 acts as a decoy receptor in glioblastoma cells, sequestering IL-13 and inhibiting IL-13-mediated STAT6 activation; additionally, the short intracellular domain of IL-13Rα2 physically interacts with the cytoplasmic domain of IL-4Rα (which harbors STAT6 docking sites), thereby inhibiting IL-4-dependent signaling independently of ligand binding.\",\n      \"method\": \"Transient transfection of IL-13Rα2 in non-expressing cells, STAT6 activation assay, co-immunoprecipitation of IL-13Rα2 intracellular domain with IL-4Rα cytoplasmic domain\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (functional signaling assay + physical interaction), mechanistic follow-up in primary cells and heterologous system\",\n      \"pmids\": [\"11861389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-13Rα2 distribution is predominantly intracellular (majority of protein in intracellular pools), with surface IL-13Rα2 continuously released as soluble form while surface expression is maintained by ongoing receptor trafficking; IL-13Rα2 inhibits IL-13 signaling proportionally to its expression level, and this inhibition can be overcome by high IL-13 concentrations.\",\n      \"method\": \"Flow cytometry, subcellular fractionation, transfection in multiple cell types, IL-13 signaling assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, single lab with multiple methods\",\n      \"pmids\": [\"16751396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"N-linked glycosylation of the IL-13Rα2 extracellular domain (ECD) is essential for optimal IL-13 inhibitory activity; mammalian-derived glycosylated ECD (60 kDa) is superior to E. coli-derived non-glycosylated ECD (42 kDa) in inhibiting IL-13-induced STAT6 phosphorylation, IL-13 binding, and cytotoxin cytotoxicity; deglycosylation by PNGase F reduces inhibitory activity.\",\n      \"method\": \"Recombinant protein expression in E. coli vs. mammalian cells, PNGase F deglycosylation, STAT6 phosphorylation assay, binding competition assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay with mutagenesis-equivalent (enzymatic deglycosylation) and multiple functional readouts\",\n      \"pmids\": [\"17023392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-13 signaling via IL-13Rα2 drives intestinal fibrosis by activating a downstream program including TGF-β1 production, IGF-I and Egr-1 expression; Egr-1 mediates early myofibroblast apoptosis and urokinase plasminogen activator production (which activates TGF-β1), while IGF-I acts with TGF-β1 to stimulate collagen deposition.\",\n      \"method\": \"siRNA blockade of IL-13Rα2 and TGF-β1 signaling in TNBS colitis mouse model, ELISA, Western blot, collagen measurement\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via siRNA knockdown with multiple downstream readouts, single lab\",\n      \"pmids\": [\"18938165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In humans, soluble IL-13Rα2 (sIL-13Rα2) is generated exclusively from the membrane-bound full-length transcript via matrix metalloproteinase (MMP/MMP-8)-mediated cleavage of membrane IL-13Rα2; in mice, a separate alternatively spliced transcript (ΔEx10) encodes the soluble form independently of the membrane form.\",\n      \"method\": \"siRNA depletion of specific transcripts, MMP inhibitor treatment, Western blot, ELISA for soluble and membrane forms\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mechanistic dissection using isoform-specific siRNA and pharmacological inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"20007572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-13Rα2 is the primary IL-13 binding and internalization component in glioblastoma cells; antisense oligonucleotide or siRNA knockdown of IL-13Rα2 in GBM cells reduces IL-13 ligand binding and decreases sensitivity to IL-13 cytotoxin, while IL-13Rα2 gene transfer into low-expressing cells increases cytotoxin efficacy.\",\n      \"method\": \"Antisense oligonucleotide and siRNA knockdown, ligand binding assay, cytotoxicity assay, plasmid-mediated gene transfer in vivo\",\n      \"journal\": \"Journal of immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with specific molecular readout (ligand binding and cytotoxin sensitivity)\",\n      \"pmids\": [\"15838375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-13Rα2 expression in glioblastoma is regulated at the transcriptional level by at least 2 promoters generating 4 transcripts; transcription factors NFAT and AP1 (c-JUN, c-FOS) are necessary and sufficient for expression of a GBM-specific IL-13Rα2 transcript, and one transcript produces a secreted soluble form of IL-13Rα2.\",\n      \"method\": \"Promoter cloning, deletion analysis, in vitro mutagenesis, c-JUN N-terminal kinase inhibition, transcription factor binding assay, quantitative RT-PCR, flow cytometry\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis and transcription factor binding assays with functional validation in multiple GBM cell lines\",\n      \"pmids\": [\"20448330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL13RA2 promotes resistance to sunitinib in clear cell renal cell carcinoma by suppressing sunitinib-induced apoptosis; shRNA-mediated knockdown of IL13RA2 in Caki-1 cells overcomes sunitinib resistance, while overexpression of IL13RA2 in sunitinib-sensitive 786-O cells confers resistance in vivo.\",\n      \"method\": \"shRNA knockdown, IL13RA2 overexpression in xenograft models, histopathological apoptosis analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain- and loss-of-function experiments with defined cellular phenotype (apoptosis suppression)\",\n      \"pmids\": [\"26114873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ingenol mebutate induces IL13RA2 expression in keratinocytes via the PKCδ/MEK/ERK signaling pathway, and siRNA knockdown of IL13RA2 partially rescues keratinocytes from ingenol mebutate-induced cell death, functionally linking IL13RA2 induction to reduced cell viability.\",\n      \"method\": \"Transcriptional profiling, pathway inhibitor studies, siRNA knockdown, cell viability assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — siRNA knockdown with functional rescue and pathway inhibitor corroboration\",\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 of IL13RA2 reduces cell viability, migration, and EMT markers (N-cadherin, Vimentin, Snail), while exogenous overexpression increases cell migration and EMT markers.\",\n      \"method\": \"siRNA knockdown, exogenous overexpression, transwell migration assay, Western blot for EMT markers, CCK-8 proliferation assay\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain- and loss-of-function with multiple cellular phenotype readouts\",\n      \"pmids\": [\"31290966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Silencing of IL13RA2 in hepatocellular carcinoma cells promotes partial epithelial-mesenchymal transition and invasive potential via increased ERK phosphorylation.\",\n      \"method\": \"IL13RA2 knockdown, Western blot for p-ERK, invasion assay\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single knockdown approach with limited mechanistic follow-up\",\n      \"pmids\": [\"31823484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Downregulation of IL-13RA2 in keloid fibroblasts leads to increased STAT6 phosphorylation and fibrotic phenotypes; ectopic re-expression of IL-13RA2 in keloid fibroblasts inhibits STAT6 phosphorylation, cell proliferation, migration, invasion, extracellular matrix secretion, and myofibroblast marker expression while increasing apoptosis, establishing IL-13RA2 as a negative regulator of JAK/STAT6 signaling in fibroblasts.\",\n      \"method\": \"Western blot, ectopic expression, siRNA knockdown, patient-derived xenograft mouse model, STAT6 inhibitor (AS1517499)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain- and loss-of-function in primary cells and in vivo model with multiple readouts\",\n      \"pmids\": [\"36757802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL13RA2 suppresses vascular calcification by binding to and augmenting expression of downstream signaling components; IL13RA2 activation inhibits STAT3 signaling and attenuates WNT3/β-catenin pathway to reduce osteogenic differentiation of human aortic smooth muscle cells.\",\n      \"method\": \"Cellular thermal shift assay (direct binding), transcriptional profiling, IL13RA2 knockdown/overexpression, in vitro and in vivo vascular calcification models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay plus functional epistasis experiments in vitro and in vivo\",\n      \"pmids\": [\"38432393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GOLIM4, regulated downstream of IRE1/XBP1s, controls surface expression of IL13RA2 in glioblastoma cells; GOLIM4 silencing decreases surface IL13RA2 without altering its transcript levels, indicating post-transcriptional/secretory pathway control of IL13RA2 membrane localization.\",\n      \"method\": \"siRNA silencing of GOLIM4, flow cytometry for surface IL13RA2, transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, indirect regulation of IL13RA2 surface expression\",\n      \"pmids\": [\"bio_10.1101_2024.10.22.619629\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-13 signaling through IL-13Rα2 promotes angiosarcoma cell proliferation; siRNA-mediated knockdown of IL13RA2 or neutralizing antibodies against IL-13 inhibit IL-13-induced proliferation; IL-13 stimulation upregulates IL13RA2 and VEGFA mRNA via STAT6, creating a positive feedback loop.\",\n      \"method\": \"siRNA knockdown, neutralizing antibody, STAT6 inhibitor, proliferation assay, RT-PCR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, mechanistic follow-up present but not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.24.619789\"],\n      \"is_preprint\": true\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 and metastatic growth; IL13RA2-deficient cells are sensitive to AKT pathway inhibition, placing IL13RA2 upstream of AKT/NF-κB as a negative regulator of these pro-survival pathways.\",\n      \"method\": \"CRISPR knockout in human and murine breast cancer cell lines, Western blot for p-AKT and NF-κB, intracardiac in vivo metastasis model, pathway inhibitor sensitivity assays\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with pathway mechanistic readout in two species, in vitro and in vivo validation\",\n      \"pmids\": [\"40663259\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL13RA2 is a high-affinity IL-13 decoy receptor that sequesters IL-13 at the cell surface, inhibits STAT6 activation both by ligand sequestration and through direct physical interaction of its intracellular domain with IL-4Rα, undergoes MMP/MMP-8-mediated ectodomain shedding to generate soluble receptor in humans, requires N-linked glycosylation for optimal inhibitory activity, and acts as a negative regulator of downstream pro-fibrotic/pro-tumorigenic signaling (JAK/STAT6, AKT/NF-κB, ERK, WNT/β-catenin) in contexts including fibroblasts, vascular smooth muscle cells, and breast cancer, while paradoxically driving pro-tumorigenic IL-13-dependent STAT6 signaling in some settings such as angiosarcoma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL13RA2 is a high-affinity decoy receptor for IL-13 that functions as a negative regulator of IL-13/IL-4 signaling across multiple tissue contexts. It sequesters IL-13 at the cell surface and inhibits STAT6 activation both through ligand sequestration and through direct physical interaction of its short intracellular domain with the cytoplasmic domain of IL-4Rα, thereby blocking STAT6 docking [PMID:11861389]; N-linked glycosylation of its extracellular domain is required for optimal inhibitory activity [PMID:17023392]. The predominantly intracellular pool of IL13RA2 is continuously trafficked to the surface, where it is shed as a soluble form via MMP-8-mediated ectodomain cleavage in humans [PMID:16751396, PMID:20007572]. IL13RA2 negatively regulates pro-fibrotic JAK/STAT6 signaling in fibroblasts and pro-survival AKT/NF-κB signaling in breast cancer, while in certain contexts such as intestinal fibrosis it can transduce IL-13 signals via TGF-β1 and downstream effectors [PMID:36757802, PMID:40663259, PMID:18938165].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the signaling receptor complex for IL-13 revealed that IL-13Rα1/IL-4Rα heterodimerization is required for STAT6 activation, setting the stage for understanding how IL13RA2 competes for IL-13 binding outside this signaling complex.\",\n      \"evidence\": \"CHO cell reconstitution with ligand binding assays and EMSA for STAT6\",\n      \"pmids\": [\"9013879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address IL13RA2 function directly\", \"Affinity measurements limited to one heterologous system\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The central mechanistic question—whether IL13RA2 is merely a passive sink for IL-13 or actively inhibits signaling—was resolved by showing it functions as a decoy receptor that both sequesters IL-13 and physically interacts with IL-4Rα's cytoplasmic domain to block STAT6 activation independently of ligand binding.\",\n      \"evidence\": \"Transient transfection in glioblastoma cells, STAT6 activation assays, co-immunoprecipitation of intracellular domains\",\n      \"pmids\": [\"11861389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-IP of intracellular domains not confirmed by reciprocal endogenous pulldown\", \"Structural basis of intracellular domain interaction unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"IL13RA2 was established as the primary IL-13 binding and internalization receptor on glioblastoma cells, explaining why these tumors are selectively targeted by IL-13-based cytotoxins.\",\n      \"evidence\": \"Antisense and siRNA knockdown with ligand binding and cytotoxin sensitivity assays; gene transfer rescue in low-expressing cells\",\n      \"pmids\": [\"15838375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Internalization mechanism not defined\", \"Relevance to normal (non-tumor) cells unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two key properties of IL13RA2 were established: its predominantly intracellular distribution with continuous surface trafficking and shedding, and the requirement for N-linked glycosylation of its extracellular domain for optimal IL-13 inhibitory activity.\",\n      \"evidence\": \"Subcellular fractionation, flow cytometry, recombinant glycosylated vs. non-glycosylated ECD production, PNGase F deglycosylation with STAT6 phosphorylation readouts\",\n      \"pmids\": [\"16751396\", \"17023392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific glycosylation sites contributing to function not mapped\", \"Identity of proteases responsible for surface shedding not yet known at this point\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Contrary to its established decoy role, IL13RA2 was shown to transduce IL-13 signals in intestinal fibrosis, activating a TGF-β1/IGF-I/Egr-1 program that drives collagen deposition—revealing context-dependent signaling capacity.\",\n      \"evidence\": \"siRNA blockade in TNBS colitis mouse model with downstream pathway analysis by ELISA and Western blot\",\n      \"pmids\": [\"18938165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor proteins linking IL13RA2 short cytoplasmic tail to TGF-β1 induction not identified\", \"Whether this signaling mode operates outside the gut is unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The mechanism generating soluble IL13RA2 was resolved: in humans, MMP-8-mediated ectodomain cleavage of the membrane form is the sole source, whereas mice use an alternatively spliced transcript.\",\n      \"evidence\": \"Isoform-specific siRNA, broad-spectrum and selective MMP inhibitors, Western blot and ELISA\",\n      \"pmids\": [\"20007572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site not mapped at residue level\", \"Physiological regulation of MMP-8 activity toward IL13RA2 not characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Transcriptional regulation of IL13RA2 in glioblastoma was mapped to multiple promoters, with NFAT and AP-1 (c-JUN/c-FOS) identified as necessary and sufficient drivers of a tumor-specific transcript.\",\n      \"evidence\": \"Promoter cloning, deletion/mutagenesis analysis, JNK inhibition, transcription factor binding assays in GBM cell lines\",\n      \"pmids\": [\"20448330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epigenetic regulation not addressed\", \"Whether NFAT/AP-1 regulation extends beyond GBM unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL13RA2 was shown to promote epithelial-mesenchymal transition and migration in papillary thyroid carcinoma, expanding its functional repertoire beyond cytokine decoy activity to direct regulation of cell motility programs.\",\n      \"evidence\": \"Reciprocal siRNA knockdown and overexpression with EMT marker and migration assays\",\n      \"pmids\": [\"31290966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway mediating EMT induction not fully delineated\", \"Ligand dependence of this EMT-promoting function not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IL13RA2 was established as a negative regulator of fibrotic signaling in human fibroblasts: its loss in keloid tissue leads to STAT6 hyperactivation and fibrosis, while re-expression suppresses fibrotic phenotypes.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function in patient-derived keloid fibroblasts, xenograft model, STAT6 inhibitor rescue\",\n      \"pmids\": [\"36757802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL13RA2 loss is cause or consequence of keloid pathogenesis not resolved\", \"Mechanism of IL13RA2 downregulation in keloid tissue unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IL13RA2 was shown to suppress vascular calcification by inhibiting STAT3 and WNT3/β-catenin signaling in aortic smooth muscle cells, extending its negative-regulatory role to a new tissue context and additional signaling axes.\",\n      \"evidence\": \"Cellular thermal shift assay for direct binding, transcriptional profiling, knockdown/overexpression in vascular calcification models in vitro and in vivo\",\n      \"pmids\": [\"38432393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners identified by thermal shift not fully characterized\", \"Whether STAT3 inhibition is direct or indirect not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR knockout studies in breast cancer cells resolved that IL13RA2 acts as a negative regulator of AKT/NF-κB pro-survival signaling, and its loss drives metastatic growth that can be rescued by AKT inhibition.\",\n      \"evidence\": \"CRISPR KO in human and murine TNBC lines, Western blot for p-AKT/NF-κB, intracardiac metastasis model, pathway inhibitor sensitivity\",\n      \"pmids\": [\"40663259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking IL13RA2 to AKT suppression not defined\", \"Whether this function depends on IL-13 ligand not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which IL13RA2's short intracellular domain transduces or inhibits intracellular signals remains unresolved—no adaptor proteins or kinases directly recruited to the cytoplasmic tail have been identified, and no structural model of IL13RA2 in complex with IL-4Rα or signaling partners exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of IL13RA2 alone or in complex\", \"Adaptor proteins recruited to the 17-amino-acid cytoplasmic tail unknown\", \"Mechanistic basis for context-dependent switch between decoy and signaling functions unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 12, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 4, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 12, 13, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL4R\",\n      \"IL13\",\n      \"STAT6\",\n      \"GOLIM4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}