{"gene":"IL4R","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1997,"finding":"IL-4Rα and IL-13Rα1 together reconstitute a functional high-affinity IL-4/IL-13 receptor complex: CHO cells co-expressing both chains bound IL-13 with Kd ~30 pM and allowed cross-competition of IL-13 and IL-4, whereas each chain alone could not activate STAT6; IL-4Rα alone did not bind IL-13.","method":"Receptor reconstitution in CHO cells (co-expression), radioligand binding, electrophoretic mobility shift assay (EMSA) for STAT6 activation","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of heterodimeric receptor complex with functional validation (STAT6 EMSA) and binding data","pmids":["9013879"],"is_preprint":false},{"year":1997,"finding":"IL-13 signals through IL-4Rα in human endothelial cells: a neutralizing anti-IL-4Rα monoclonal antibody blocked IL-13-induced MCP-1 expression; IL-13 and IL-4 both caused rapid tyrosine phosphorylation of immunoprecipitated IL-4Rα and activated STAT6.","method":"Neutralizing antibody blockade, immunoprecipitation with phosphotyrosine detection, EMSA for STAT6","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods (antibody blockade, Co-IP/phosphorylation, STAT6 EMSA) in a single study","pmids":["9301536"],"is_preprint":false},{"year":1998,"finding":"Tyrosine residues Y497 and Y713 within the cytoplasmic tail of IL-4Rα are required for IL-4-mediated protection from apoptosis; the domain containing the STAT6-docking tyrosines suppresses this protection. Transplantation of Y497 or Y713 domains to a truncated IL-2Rβ partially conferred protection, and Y→F mutation abolished it.","method":"Cytoplasmic domain transplant chimeras, site-directed mutagenesis (Y→F), apoptosis assays in 32D cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with domain transplants plus mutagenesis, functional readout (apoptosis protection)","pmids":["9670964"],"is_preprint":false},{"year":1998,"finding":"Glucocorticoids (dexamethasone) down-regulate IL-4Rα expression by two distinct posttranscriptional mechanisms: (1) PMA-induced IL-4Rα expression is suppressed by decreasing mRNA half-life; (2) IL-4-induced IL-4Rα expression is suppressed at the translational or posttranslational level without changing mRNA stability or transcription rate. The effect is glucocorticoid-receptor-dependent (reversed by RU486).","method":"Northern blot, nuclear run-on transcription assay, flow cytometry, mRNA stability assay, GR antagonist (RU486)","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods (run-on, Northern, FACS, RU486 reversal) in one study","pmids":["9847438"],"is_preprint":false},{"year":1999,"finding":"The allergy-associated IL-4Rα mutation Q576R (Q551R in some numbering) does not significantly alter IL-4-induced tyrosine phosphorylation, STAT6 DNA-binding, proliferation, apoptosis protection, or CD23 induction compared to wild-type receptor in murine cells expressing human IL-4Rα cDNA, indicating this variant does not directly enhance IL-4 signal transduction.","method":"Transfection of WT and mutant (Q576R, Y575F) human IL-4Rα cDNA in murine cells, phosphorylation assays, EMSA, proliferation and apoptosis assays, CD23 induction","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — direct functional testing of variant receptor with multiple readouts","pmids":["10201973"],"is_preprint":false},{"year":2001,"finding":"IL-13-induced airway hyperreactivity and eosinophilia can occur independently of IL-4Rα but requires STAT6, revealing a novel IL-13 signaling pathway through a different receptor component that involves STAT6 without IL-4Rα.","method":"Adoptive transfer of IL-13+/+ or IL-13−/− CD4+ T cells into WT and IL-4Rα−/− or STAT6−/− mice, airway hyperreactivity and eosinophilia readouts","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple knockout models and clear functional phenotype","pmids":["11466392"],"is_preprint":false},{"year":2004,"finding":"The IL-4Rα variant encoding isoleucine at position 50 (I50) acts as a gain-of-function allele relative to V50 for STAT6-dependent transcriptional activity, but this enhanced STAT6 signaling does not increase Th2 differentiation efficiency or IL-4-mediated repression of Th1 development.","method":"Transfection of I50 vs V50 variant IL-4Rα in primary T cells, STAT6 reporter assays, Th2 differentiation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct comparison of variant receptors with multiple readouts, single lab","pmids":["15383584"],"is_preprint":false},{"year":2004,"finding":"IL-13E13K (an IL-13 mutant antagonist) inhibits IL-4 binding and STAT6 phosphorylation in cells expressing the type II IL-4R (IL-4Rα/IL-13Rα1 heterodimer) but not type I IL-4R (IL-4Rα/γc), because Glu13 of IL-13 contacts IL-4Rα and its mutation to lysine prevents IL-13Rα1/IL-4Rα heterodimerization.","method":"Receptor-specific cell lines, competitive binding assay, STAT6 phosphorylation assay, protein synthesis inhibition assay","journal":"Cellular immunology","confidence":"High","confidence_rationale":"Tier 1/2 — mechanistic dissection of receptor subunit contributions with multiple functional readouts","pmids":["15331327"],"is_preprint":false},{"year":2005,"finding":"In primary T cells, IL-4Rα lacking all cytoplasmic tyrosines can still signal for STAT5 phosphorylation and S-phase entry via an intact ID-1 region; Y1 (first conserved tyrosine) activates the PI3K/mTOR pathway to promote G2/M progression, and rapamycin blocks cell-cycle completion but not S-phase entry downstream of IL-4Rα.","method":"Cytoplasmic tyrosine mutant IL-4Rα constructs in primary activated T cells, BrdU incorporation, rapamycin treatment, p70S6K phosphorylation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with multiple mutants plus pharmacological inhibition in primary cells","pmids":["16210622"],"is_preprint":false},{"year":2006,"finding":"IL-4Rα/STAT6 signaling in bone marrow-derived (hematopoietic) cells is both necessary and sufficient for protection against acute schistosomiasis by enabling alternatively activated macrophage generation and suppressing IL-12/TNF/IFN-γ-driven inflammation; IL-4Rα signaling in non-hematopoietic cells governs granuloma size and fibrosis but not survival.","method":"Bone marrow chimera experiments with IL-4Rα−/− and WT donors/recipients, cytokine measurements, pathology scoring","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using reciprocal bone marrow chimeras with clear cell-type-specific functional dissection","pmids":["18354220"],"is_preprint":false},{"year":2006,"finding":"IL-4Rα signaling is required for IL-10 production by an IL-10+ Th2 subpopulation, and IL-10 is the key IL-4Rα-dependent factor that suppresses Th1 responses to maintain Th2 dominance during nematode infection.","method":"IL-4Rα−/− mice infected with Nippostrongylus brasiliensis, cytokine profiling, Th1 neutralization rescue experiments","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with defined cellular and cytokine readouts, single lab","pmids":["16940042"],"is_preprint":false},{"year":2006,"finding":"Common intronic SNPs in IL4R (c.912-1003A>G, c.912-833T>C, c.912-630A>G, c.912-577A>G) affect alternative splicing of IL4R: minor alleles at these linked SNPs reduce exon 8 inclusion, decreasing expression of the soluble IL-4Rα isoform. This was demonstrated with an IL4R minigene construct and confirmed in human mRNA samples; splicing factors SRp20 and YT521-B modulate this.","method":"Minigene splicing assay, mRNA quantification in human samples, splicing factor overexpression","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 — minigene reconstitution plus validation in endogenous human mRNA, multiple SNPs tested","pmids":["16917945"],"is_preprint":false},{"year":2010,"finding":"IL-4Rα responsiveness in smooth muscle cells (non-hematopoietic) is required for IL-4/IL-13-mediated intestinal hypercontractility, which in turn promotes S. mansoni egg expulsion and host survival during acute schistosomiasis; smooth muscle cell-specific IL-4Rα deletion increased susceptibility independently of Th2 cytokine levels.","method":"Conditional knockout mice (SM-MHC-Cre × IL-4Rαfl/flox), S. mansoni infection, intestinal contractility assay, egg counts, survival","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with defined physiological phenotype","pmids":["20360135"],"is_preprint":false},{"year":2011,"finding":"IL-4Rα signaling in rhabdomyosarcoma activates STAT6, Akt, and MAPK pathways; IL-4 and IL-13 stimulation promotes tumor cell proliferation and downregulates MyoD and Myogenin (myogenic differentiation factors); neutralizing anti-IL-4Rα antibody in a mouse ARMS model significantly reduced lymph node and pulmonary metastases.","method":"In vitro IL-4/IL-13 stimulation of human RMS lines (RD, Rh30) and primary mouse ARMS cells; Western blotting for STAT6, Akt, MAPK, MyoD, Myogenin; in vivo neutralizing antibody in genetically engineered mouse model","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro signaling, protein expression, in vivo antibody blockade with survival/metastasis readout)","pmids":["21536546"],"is_preprint":false},{"year":2016,"finding":"An asthma-associated IL-4Rα variant (R576) promotes conversion of induced Treg cells to TH17-like cells by recruiting the GRB2 adaptor protein, which activates ERK → IL-6 → STAT3 signaling to drive IL-17 expression. Treg-specific deletion of IL6ra or Rorc (but not IL-4 or IL-13) prevented exacerbated airway inflammation in Il4ra(R576) knock-in mice.","method":"R576 knock-in mice, Treg-specific conditional knockouts (IL6ra, Rorc, IL-4, IL-13), GRB2 co-immunoprecipitation, ERK/STAT3 pathway analysis, anti-IL-6 antibody treatment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1/2 — Co-IP of GRB2/IL-4Rα R576, epistasis via multiple conditional KOs, neutralization rescue, mechanistic signaling data in one study","pmids":["27479084"],"is_preprint":false},{"year":2018,"finding":"Somatic IL4R mutations (most commonly I242N in the transmembrane domain) in primary mediastinal large B-cell lymphoma (PMBCL) are gain-of-function, causing constitutive JAK-STAT pathway activation, upregulation of downstream cytokine expression, and growth advantage in vivo in a mouse xenotransplantation model.","method":"Sequencing of primary PMBCL cases and cell lines, functional assays of I242N mutant IL4R, JAK-STAT signaling assays, xenotransplantation mouse model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function mutation characterized with signaling assays and in vivo xenograft model","pmids":["29467182"],"is_preprint":false},{"year":2021,"finding":"IL-4Rα on GABAergic (inhibitory) neurons mediates T cell (via IL-4) effects on synaptic plasticity and episodic memory: IL-4Rα knockout specifically in inhibitory neurons impaired contextual fear memory, and snRNA-seq implicated IL-4-driven regulation of synaptic function and plasticity pathways.","method":"Inhibitory neuron-specific IL-4Rα conditional knockout (Vgat-Cre), contextual fear memory assay, long-term potentiation recording, snRNA-seq, T-cell adoptive transfer in SCID and IL-4 KO backgrounds","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with defined behavioral and electrophysiological phenotypes, multiple orthogonal methods","pmids":["34793707"],"is_preprint":false},{"year":1991,"finding":"The IL4R gene was mapped to human chromosome 16p11.2–16p12.1 by in situ hybridization and mouse-human somatic cell hybrid Southern blotting, and the mouse homolog was positioned in the distal region of chromosome 7.","method":"In situ hybridization, Southern blot of somatic cell hybrid panel, interspecific backcross analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — two orthogonal mapping methods, foundational chromosomal localization","pmids":["1679753"],"is_preprint":false},{"year":2017,"finding":"IL-4Rα knockdown in hepatocellular carcinoma cell lines abolishes IL-4-induced activation of JAK1/STAT6 and JNK/ERK1/2 signaling pathways and results in enhanced apoptosis, impaired proliferation, and reduced invasion.","method":"siRNA knockdown of IL-4R in HCC cell lines, Western blot for JAK1/STAT6 and JNK/ERK1/2, flow cytometry for apoptosis and cell cycle, invasion assays","journal":"The International journal of biological markers","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined signaling and cellular phenotype readouts, single lab","pmids":["28665449"],"is_preprint":false},{"year":2021,"finding":"IL-4/IL-4Rα type I receptor signaling in osteoclast precursors (OCPs) activates ERK pathway to promote OCP proliferation during early bone metastasis of colorectal cancer; IL-4 is supplied by neutrophils in bone marrow. ERK antagonist Ravoxertinib inhibited OCP proliferation and prevented bone destruction.","method":"BrdU assay for OCP proliferation, IL-4 deficiency mice, tumor conditioned medium stimulation, ERK pathway Western blot, ERK inhibitor Ravoxertinib in vivo","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway identified with KO model and pharmacological inhibition, single lab","pmids":["34863091"],"is_preprint":false},{"year":1998,"finding":"The acidic motif of IL-4Rα cytoplasmic domain can functionally substitute for the acidic region (A-region) of IL-2Rβ to support c-junB and c-fos induction, while the haematopoietin box1 (S-region equivalent) of IL-4Rα cannot substitute for the S-region of IL-2Rβ for growth signaling; demonstrated by cytoplasmic domain chimeras.","method":"Chimeric receptor construction (IL-2Rβ/IL-4Rα domain swaps), stable transfection in BA/F3 cells, proto-oncogene induction assays, IL-2-driven proliferation assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 1 — domain transplant chimera reconstitution, single lab","pmids":["9619370"],"is_preprint":false},{"year":2022,"finding":"IL-3 maintains surface IL-4Rα (CD124) expression on mast cells through a Tyk2/STAT6/HSP90-dependent mechanism; inhibition of Tyk2, STAT6, or HSP90 impaired IL-3-induced IL-4Rα upregulation. Mast cells in this context do not express IL-13Rα1.","method":"Pharmacological inhibition of Tyk2, STAT6, HSP90 in mast cells; surface IL-4Rα flow cytometry; Western blot for signaling molecules","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple inhibitors with defined receptor expression readout, single lab","pmids":["36440951"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 (an RNA-binding protein) directly binds IL4R and IL13RA1 mRNAs, decreasing their stability; depletion of IGF2BP3 increased IL4R and IL13RA1 mRNA half-life, elevated IL-4Rα and IL-13Rα1 surface expression, and enhanced IL-13/IL-4-induced STAT6 phosphorylation in airway epithelial cells.","method":"RNA-binding protein immunoprecipitation (RIP), mRNA stability (half-life) assay, surface receptor flow cytometry after IGF2BP3 knockdown, STAT6 phosphorylation assay, RNA-seq","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct mRNA-binding demonstrated by RIP plus functional validation, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.07.19.665669"],"is_preprint":true}],"current_model":"IL-4Rα is the shared ligand-binding subunit of two distinct receptor complexes—the type I receptor (IL-4Rα/γc on hematopoietic cells) and the type II receptor (IL-4Rα/IL-13Rα1 on non-hematopoietic cells)—that upon IL-4 or IL-13 binding activate JAK1/JAK2/Tyk2 to phosphorylate STAT6 and also signal through IRS-1, PI3K/mTOR, Akt, ERK, and STAT5 via discrete cytoplasmic tyrosine-containing domains (Y497 and Y713 for anti-apoptosis; Y1/first tyrosine for PI3K/mTOR-driven cell-cycle G2/M; the ID-1 region for STAT5/proliferation); disease-associated variants (e.g., I242N transmembrane mutation causing constitutive JAK-STAT activation in lymphoma; R576 recruiting GRB2→ERK→IL-6→STAT3 to reprogram Tregs toward TH17) alter specific downstream pathway outputs, and the soluble isoform is regulated at the splicing level by intronic SNPs."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing the chromosomal location of IL4R (16p11.2–12.1) provided the foundation for subsequent genetic and functional studies of the receptor.","evidence":"In situ hybridization and somatic cell hybrid Southern blotting in human and interspecific backcross in mouse","pmids":["1679753"],"confidence":"High","gaps":["No protein-level characterization or signaling data at this stage"]},{"year":1997,"claim":"Demonstrating that IL-4Rα and IL-13Rα1 co-expression reconstitutes a high-affinity IL-4/IL-13 receptor resolved how IL-13 and IL-4 share a common signaling chain and compete for receptor binding.","evidence":"Receptor reconstitution in CHO cells with radioligand binding (Kd ~30 pM for IL-13) and STAT6 EMSA; antibody blockade and phosphorylation assays in endothelial cells","pmids":["9013879","9301536"],"confidence":"High","gaps":["Stoichiometry and structural basis of the heterodimer not determined","Contribution of γc versus IL-13Rα1 chains to differential signaling not yet dissected"]},{"year":1998,"claim":"Mapping individual cytoplasmic tyrosines to discrete functions (Y497/Y713 for anti-apoptosis; acidic domain for proto-oncogene induction) established that the IL-4Rα tail is a modular signaling scaffold rather than a single-output transducer.","evidence":"Domain transplant chimeras and Y→F mutagenesis in 32D cells; IL-2Rβ/IL-4Rα domain-swap chimeras in BA/F3 cells","pmids":["9670964","9619370"],"confidence":"High","gaps":["Kinase(s) directly phosphorylating Y497 and Y713 not identified","Downstream effectors coupling these tyrosines to survival signals not mapped"]},{"year":1998,"claim":"Discovering that glucocorticoids downregulate IL-4Rα through two distinct posttranscriptional mechanisms revealed that receptor abundance is actively controlled beyond transcription.","evidence":"Nuclear run-on, Northern blot, mRNA stability assays, and GR antagonist (RU486) reversal in PMA- and IL-4-stimulated cells","pmids":["9847438"],"confidence":"High","gaps":["Identity of the mRNA destabilizing factor(s) recruited by GR unknown","Translational/posttranslational mechanism for IL-4-induced receptor regulation not molecularly defined"]},{"year":1999,"claim":"Testing the atopy-associated Q576R variant and finding no enhanced IL-4 signaling in multiple assays challenged the assumption that this variant is a direct gain-of-function for canonical STAT6 output.","evidence":"WT versus Q576R IL-4Rα cDNA expressed in murine cells, with phosphorylation, EMSA, proliferation, apoptosis, and CD23 readouts","pmids":["10201973"],"confidence":"High","gaps":["Did not test non-canonical pathways (e.g., ERK, IL-6) that were later implicated","Murine cellular context may not capture human-specific signaling differences"]},{"year":2001,"claim":"Showing that IL-13 can drive airway hyperreactivity through STAT6 independently of IL-4Rα revealed an alternative IL-13 signaling route, refining the model that all IL-13 effects require IL-4Rα.","evidence":"Adoptive T-cell transfer into IL-4Rα−/− versus STAT6−/− mice with airway hyperreactivity and eosinophilia readouts","pmids":["11466392"],"confidence":"High","gaps":["Identity of the IL-4Rα-independent receptor complex mediating IL-13/STAT6 signaling not established","Whether this pathway operates outside the lung not tested"]},{"year":2004,"claim":"Discriminating type I (IL-4Rα/γc) from type II (IL-4Rα/IL-13Rα1) receptor function using an IL-13 mutant antagonist and showing that the I50V variant alters STAT6 transcriptional amplitude without changing Th2 differentiation revealed selective modularity of receptor-complex outputs.","evidence":"Receptor-specific cell lines with competitive binding and STAT6 phosphorylation; I50 vs V50 variant comparison with STAT6 reporters and Th2 assays","pmids":["15331327","15383584"],"confidence":"High","gaps":["Structural basis of how I50V variant augments STAT6 activation not solved","Whether type II-selective antagonism has distinct downstream transcriptional consequences not profiled"]},{"year":2005,"claim":"Demonstrating that a tyrosine-less IL-4Rα tail still drives S-phase entry via the ID-1/STAT5 axis, while Y1 engages PI3K/mTOR for G2/M completion, resolved how IL-4 couples receptor domains to distinct cell-cycle checkpoints.","evidence":"Multiple cytoplasmic tyrosine mutant constructs in primary activated T cells, BrdU incorporation, rapamycin sensitivity, p70S6K phosphorylation","pmids":["16210622"],"confidence":"High","gaps":["Direct binding partner linking ID-1 to STAT5 not identified","Whether mTOR-dependent G2/M regulation operates in non-T cells unknown"]},{"year":2006,"claim":"Bone marrow chimera and splicing studies collectively showed that IL-4Rα function is partitioned by cell type (hematopoietic for macrophage polarization and survival vs. non-hematopoietic for granuloma/fibrosis) and that soluble IL-4Rα levels are governed by intronic SNP-dependent alternative splicing.","evidence":"Reciprocal BM chimeras in IL-4Rα−/− mice with S. mansoni infection; minigene splicing assays and human mRNA quantification for intronic SNPs; IL-4Rα−/− Nippostrongylus model for IL-10/Th2 dependence","pmids":["18354220","16917945","16940042"],"confidence":"High","gaps":["How splicing factor SRp20/YT521-B are themselves regulated in disease contexts not known","Quantitative contribution of soluble vs. membrane IL-4Rα to pathway output in vivo not measured"]},{"year":2010,"claim":"Cell-type-specific conditional knockout in smooth muscle cells demonstrated that IL-4Rα directly controls intestinal hypercontractility needed for helminth expulsion, extending IL-4Rα function beyond immune cells.","evidence":"SM-MHC-Cre × IL-4Rαfl/flox mice with S. mansoni infection, intestinal contractility assays, egg counts, survival","pmids":["20360135"],"confidence":"High","gaps":["Downstream contractile effectors activated by IL-4Rα in smooth muscle not characterized","Whether type I or type II receptor mediates the smooth muscle response not determined"]},{"year":2011,"claim":"Establishing that IL-4Rα activates STAT6/Akt/MAPK in rhabdomyosarcoma to promote proliferation and suppress myogenic differentiation, with anti-IL-4Rα antibody reducing metastases in vivo, linked IL-4Rα signaling to solid tumor biology.","evidence":"IL-4/IL-13 stimulation of RMS lines with Western blot for STAT6/Akt/MAPK/MyoD; anti-IL-4Rα antibody in genetically engineered mouse ARMS model","pmids":["21536546"],"confidence":"High","gaps":["Relative contributions of STAT6 versus Akt versus MAPK to metastatic phenotype not dissected","Whether IL-4Rα signals cell-autonomously versus through tumor microenvironment not fully resolved"]},{"year":2016,"claim":"Identifying that the R576 variant recruits GRB2→ERK→IL-6→STAT3 to reprogram Tregs toward TH17 provided the first mechanistic explanation for how a coding variant in IL-4Rα exacerbates asthma through a non-canonical signaling axis.","evidence":"R576 knock-in mice with Treg-specific conditional KOs of IL6ra and Rorc; GRB2 co-IP with IL-4Rα R576; anti-IL-6 rescue","pmids":["27479084"],"confidence":"High","gaps":["Whether GRB2 recruitment occurs at a specific phosphotyrosine or non-tyrosine motif not mapped","Generalizability to human Treg cells not directly shown"]},{"year":2018,"claim":"Discovery that somatic I242N transmembrane mutations constitutively activate JAK-STAT in primary mediastinal large B-cell lymphoma established IL-4Rα as a bona fide oncogenic driver when mutated in its transmembrane domain.","evidence":"PMBCL sequencing, functional assays of I242N mutant, JAK-STAT signaling, xenotransplantation growth advantage","pmids":["29467182"],"confidence":"High","gaps":["Structural mechanism by which I242N causes ligand-independent dimerization/activation not solved","Whether other transmembrane mutations have similar effects not systematically tested"]},{"year":2021,"claim":"Conditional knockout of IL-4Rα on inhibitory neurons impaired episodic memory and long-term potentiation, revealing an unexpected neuroimmune role for IL-4Rα in synaptic plasticity independent of peripheral immunity.","evidence":"Vgat-Cre × IL-4Rαfl/flox mice, contextual fear conditioning, LTP recordings, snRNA-seq, T-cell adoptive transfer","pmids":["34793707"],"confidence":"High","gaps":["Downstream signaling pathway in neurons (STAT6 vs. other) not fully characterized","Whether IL-4Rα signals through type I or type II receptor in GABAergic neurons not determined"]},{"year":2022,"claim":"Showing that IL-3 maintains surface IL-4Rα via Tyk2/STAT6/HSP90 on mast cells identified a cytokine-driven feedforward loop that primes IL-4 responsiveness on effector cells.","evidence":"Pharmacological inhibition of Tyk2, STAT6, and HSP90 in mast cells with surface IL-4Rα flow cytometry","pmids":["36440951"],"confidence":"Medium","gaps":["Whether HSP90 acts on IL-4Rα protein folding/stability or transcription not resolved","Single lab finding with pharmacological inhibitors only"]},{"year":null,"claim":"Major unresolved questions include the structural basis for ligand-independent activation by transmembrane mutations, the identity of the IL-4Rα-independent IL-13/STAT6 pathway component, and the signaling logic by which IL-4Rα in neurons regulates synaptic gene programs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of full-length IL-4Rα in a signaling-competent complex","IL-4Rα-independent IL-13 receptor component never identified","Neuronal downstream signaling cascade not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,8,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,7,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,8,13,14,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,9,10,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,15,18]}],"complexes":["Type I IL-4 receptor (IL-4Rα/γc)","Type II IL-4 receptor (IL-4Rα/IL-13Rα1)"],"partners":["IL13RA1","IL2RG","STAT6","JAK1","GRB2","STAT5","IGF2BP3"],"other_free_text":[]},"mechanistic_narrative":"IL4R encodes the IL-4Rα chain, the shared ligand-binding subunit of the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes that transduce IL-4 and IL-13 signals across hematopoietic and non-hematopoietic cell types [PMID:9013879, PMID:9301536, PMID:15331327]. Discrete cytoplasmic domains couple to distinct downstream pathways: Y497 and Y713 mediate anti-apoptotic signaling, the first conserved tyrosine (Y1) activates PI3K/mTOR to drive G2/M cell-cycle progression, and the ID-1 region signals through STAT5 for S-phase entry independent of cytoplasmic tyrosines, while the canonical output is JAK1-dependent STAT6 phosphorylation [PMID:9670964, PMID:16210622]. Disease-associated coding variants alter pathway output—the R576 gain-of-function variant recruits GRB2 to activate ERK→IL-6→STAT3 signaling, reprogramming Tregs toward a TH17 fate in asthma, while the somatic I242N transmembrane mutation drives constitutive JAK-STAT activation in primary mediastinal large B-cell lymphoma [PMID:27479084, PMID:29467182]. Beyond canonical immunity, IL-4Rα on smooth muscle cells controls intestinal contractility during helminth infection, on inhibitory neurons mediates T-cell-derived IL-4 effects on synaptic plasticity and episodic memory, and its surface expression is regulated post-transcriptionally by glucocorticoids, intronic SNP-dependent alternative splicing, and IGF2BP3-mediated mRNA destabilization [PMID:20360135, PMID:34793707, PMID:9847438, PMID:16917945]."},"prefetch_data":{"uniprot":{"accession":"P24394","full_name":"Interleukin-4 receptor subunit alpha","aliases":[],"length_aa":825,"mass_kda":89.7,"function":"Receptor for both interleukin 4 and interleukin 13 (PubMed:17030238). Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regulating IgE production and, chemokine and mucus production at sites of allergic inflammation. In certain cell types, can signal through activation of insulin receptor substrates, IRS1/IRS2 Soluble IL4R (sIL4R) inhibits IL4-mediated cell proliferation and IL5 up-regulation by T-cells","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P24394/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL4R","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL4R","total_profiled":1310},"omim":[{"mim_id":"620532","title":"HYPER-IgE SYNDROME 6, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES6","url":"https://www.omim.org/entry/620532"},{"mim_id":"616085","title":"ZINC FINGER PROTEIN 37A; 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COPD patients.","date":"2014","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/24185116","citation_count":3,"is_preprint":false},{"pmid":"36910341","id":"PMC_36910341","title":"Association of the IL-4R Q576R Polymorphism with Pediatric Asthma: a meta-analysis.","date":"2022","source":"African health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36910341","citation_count":3,"is_preprint":false},{"pmid":"24510574","id":"PMC_24510574","title":"[Association study of bronchial asthma with polymorphisms of IL-4 and IL-4R receptor genes].","date":"2014","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24510574","citation_count":3,"is_preprint":false},{"pmid":"16538488","id":"PMC_16538488","title":"Lack of association of type 1 diabetes with the IL4R gene.","date":"2006","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/16538488","citation_count":2,"is_preprint":false},{"pmid":"30472377","id":"PMC_30472377","title":"Polymorphism rs4787951 in IL-4R contributes to the increased risk of renal cell carcinoma in a Chinese population.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30472377","citation_count":2,"is_preprint":false},{"pmid":"38279420","id":"PMC_38279420","title":"Anti-cancer activity of microbubble conjugated with Sorafenib containing liposome and IL4R-targeting peptide in kidney cancer cells.","date":"2023","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/38279420","citation_count":1,"is_preprint":false},{"pmid":"23363793","id":"PMC_23363793","title":"[Relationship of TGF-β and IL-4R gene polymorphisms with risk of classical Hodgkin lymphoma].","date":"2012","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/23363793","citation_count":1,"is_preprint":false},{"pmid":"19712222","id":"PMC_19712222","title":"Interleukin 4 receptor alpha (IL4R) and calcium-activated chloride channel 1 (CLCA1) genes map to donkey chromosome.","date":"2009","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/19712222","citation_count":1,"is_preprint":false},{"pmid":"40656893","id":"PMC_40656893","title":"Recognition of pivotal immune genes NR1H4 and IL4R as diagnostic biomarkers in distinguishing ovarian clear cell cancer from high-grade serous cancer.","date":"2025","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/40656893","citation_count":0,"is_preprint":false},{"pmid":"38761419","id":"PMC_38761419","title":"A multifunctional antibody fusion protein 57103 targeting CD24, IL-4R, and αvβ3 for treating cancer and regulating the tumor microenvironment.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & 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journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/26695670","citation_count":0,"is_preprint":false},{"pmid":"39767651","id":"PMC_39767651","title":"IL-4R and CXCR2 Contribute to Downregulating Neutrophil-Mediated Response in the Early Stage of Fungal Extract-Induced Allergic Airway Inflammation.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39767651","citation_count":0,"is_preprint":false},{"pmid":"9619370","id":"PMC_9619370","title":"Function of the human interleukin 4 receptor (IL-4R)-derived acidic motif revealed by cytoplasmic domain chimeras of the IL-4R alpha chain and the IL-2R beta chain.","date":"1998","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/9619370","citation_count":0,"is_preprint":false},{"pmid":"12968637","id":"PMC_12968637","title":"Coordinated regulation of the promoter and enhancer regions of human CD23 gene by signal through IL-4R and CD40, and the role of Ku70/80 in the enhancer activity.","date":"2003","source":"Journal of medical and dental sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12968637","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.13.688267","title":"Interdependent Dynamics of mRNA Expression and HIV-1 Viral Load: Insights from Transcriptomics and Mendelian Randomization","date":"2025-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.13.688267","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.26.25336729","title":"Type-2 immune skewing in patients with disseminated coccidioidomycosis","date":"2025-09-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.26.25336729","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.19.665669","title":"IGF2BP3 inhibits IL-13 and IL-4 effects in human airway epithelium and is dysregulated in type 2 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chains bound IL-13 with Kd ~30 pM and allowed cross-competition of IL-13 and IL-4, whereas each chain alone could not activate STAT6; IL-4Rα alone did not bind IL-13.\",\n      \"method\": \"Receptor reconstitution in CHO cells (co-expression), radioligand binding, electrophoretic mobility shift assay (EMSA) for STAT6 activation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of heterodimeric receptor complex with functional validation (STAT6 EMSA) and binding data\",\n      \"pmids\": [\"9013879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"IL-13 signals through IL-4Rα in human endothelial cells: a neutralizing anti-IL-4Rα monoclonal antibody blocked IL-13-induced MCP-1 expression; IL-13 and IL-4 both caused rapid tyrosine phosphorylation of immunoprecipitated IL-4Rα and activated STAT6.\",\n      \"method\": \"Neutralizing antibody blockade, immunoprecipitation with phosphotyrosine detection, EMSA for STAT6\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods (antibody blockade, Co-IP/phosphorylation, STAT6 EMSA) in a single study\",\n      \"pmids\": [\"9301536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tyrosine residues Y497 and Y713 within the cytoplasmic tail of IL-4Rα are required for IL-4-mediated protection from apoptosis; the domain containing the STAT6-docking tyrosines suppresses this protection. Transplantation of Y497 or Y713 domains to a truncated IL-2Rβ partially conferred protection, and Y→F mutation abolished it.\",\n      \"method\": \"Cytoplasmic domain transplant chimeras, site-directed mutagenesis (Y→F), apoptosis assays in 32D cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with domain transplants plus mutagenesis, functional readout (apoptosis protection)\",\n      \"pmids\": [\"9670964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Glucocorticoids (dexamethasone) down-regulate IL-4Rα expression by two distinct posttranscriptional mechanisms: (1) PMA-induced IL-4Rα expression is suppressed by decreasing mRNA half-life; (2) IL-4-induced IL-4Rα expression is suppressed at the translational or posttranslational level without changing mRNA stability or transcription rate. The effect is glucocorticoid-receptor-dependent (reversed by RU486).\",\n      \"method\": \"Northern blot, nuclear run-on transcription assay, flow cytometry, mRNA stability assay, GR antagonist (RU486)\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods (run-on, Northern, FACS, RU486 reversal) in one study\",\n      \"pmids\": [\"9847438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The allergy-associated IL-4Rα mutation Q576R (Q551R in some numbering) does not significantly alter IL-4-induced tyrosine phosphorylation, STAT6 DNA-binding, proliferation, apoptosis protection, or CD23 induction compared to wild-type receptor in murine cells expressing human IL-4Rα cDNA, indicating this variant does not directly enhance IL-4 signal transduction.\",\n      \"method\": \"Transfection of WT and mutant (Q576R, Y575F) human IL-4Rα cDNA in murine cells, phosphorylation assays, EMSA, proliferation and apoptosis assays, CD23 induction\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional testing of variant receptor with multiple readouts\",\n      \"pmids\": [\"10201973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-13-induced airway hyperreactivity and eosinophilia can occur independently of IL-4Rα but requires STAT6, revealing a novel IL-13 signaling pathway through a different receptor component that involves STAT6 without IL-4Rα.\",\n      \"method\": \"Adoptive transfer of IL-13+/+ or IL-13−/− CD4+ T cells into WT and IL-4Rα−/− or STAT6−/− mice, airway hyperreactivity and eosinophilia readouts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple knockout models and clear functional phenotype\",\n      \"pmids\": [\"11466392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The IL-4Rα variant encoding isoleucine at position 50 (I50) acts as a gain-of-function allele relative to V50 for STAT6-dependent transcriptional activity, but this enhanced STAT6 signaling does not increase Th2 differentiation efficiency or IL-4-mediated repression of Th1 development.\",\n      \"method\": \"Transfection of I50 vs V50 variant IL-4Rα in primary T cells, STAT6 reporter assays, Th2 differentiation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct comparison of variant receptors with multiple readouts, single lab\",\n      \"pmids\": [\"15383584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-13E13K (an IL-13 mutant antagonist) inhibits IL-4 binding and STAT6 phosphorylation in cells expressing the type II IL-4R (IL-4Rα/IL-13Rα1 heterodimer) but not type I IL-4R (IL-4Rα/γc), because Glu13 of IL-13 contacts IL-4Rα and its mutation to lysine prevents IL-13Rα1/IL-4Rα heterodimerization.\",\n      \"method\": \"Receptor-specific cell lines, competitive binding assay, STAT6 phosphorylation assay, protein synthesis inhibition assay\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mechanistic dissection of receptor subunit contributions with multiple functional readouts\",\n      \"pmids\": [\"15331327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In primary T cells, IL-4Rα lacking all cytoplasmic tyrosines can still signal for STAT5 phosphorylation and S-phase entry via an intact ID-1 region; Y1 (first conserved tyrosine) activates the PI3K/mTOR pathway to promote G2/M progression, and rapamycin blocks cell-cycle completion but not S-phase entry downstream of IL-4Rα.\",\n      \"method\": \"Cytoplasmic tyrosine mutant IL-4Rα constructs in primary activated T cells, BrdU incorporation, rapamycin treatment, p70S6K phosphorylation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with multiple mutants plus pharmacological inhibition in primary cells\",\n      \"pmids\": [\"16210622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-4Rα/STAT6 signaling in bone marrow-derived (hematopoietic) cells is both necessary and sufficient for protection against acute schistosomiasis by enabling alternatively activated macrophage generation and suppressing IL-12/TNF/IFN-γ-driven inflammation; IL-4Rα signaling in non-hematopoietic cells governs granuloma size and fibrosis but not survival.\",\n      \"method\": \"Bone marrow chimera experiments with IL-4Rα−/− and WT donors/recipients, cytokine measurements, pathology scoring\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using reciprocal bone marrow chimeras with clear cell-type-specific functional dissection\",\n      \"pmids\": [\"18354220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-4Rα signaling is required for IL-10 production by an IL-10+ Th2 subpopulation, and IL-10 is the key IL-4Rα-dependent factor that suppresses Th1 responses to maintain Th2 dominance during nematode infection.\",\n      \"method\": \"IL-4Rα−/− mice infected with Nippostrongylus brasiliensis, cytokine profiling, Th1 neutralization rescue experiments\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with defined cellular and cytokine readouts, single lab\",\n      \"pmids\": [\"16940042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Common intronic SNPs in IL4R (c.912-1003A>G, c.912-833T>C, c.912-630A>G, c.912-577A>G) affect alternative splicing of IL4R: minor alleles at these linked SNPs reduce exon 8 inclusion, decreasing expression of the soluble IL-4Rα isoform. This was demonstrated with an IL4R minigene construct and confirmed in human mRNA samples; splicing factors SRp20 and YT521-B modulate this.\",\n      \"method\": \"Minigene splicing assay, mRNA quantification in human samples, splicing factor overexpression\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — minigene reconstitution plus validation in endogenous human mRNA, multiple SNPs tested\",\n      \"pmids\": [\"16917945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-4Rα responsiveness in smooth muscle cells (non-hematopoietic) is required for IL-4/IL-13-mediated intestinal hypercontractility, which in turn promotes S. mansoni egg expulsion and host survival during acute schistosomiasis; smooth muscle cell-specific IL-4Rα deletion increased susceptibility independently of Th2 cytokine levels.\",\n      \"method\": \"Conditional knockout mice (SM-MHC-Cre × IL-4Rαfl/flox), S. mansoni infection, intestinal contractility assay, egg counts, survival\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined physiological phenotype\",\n      \"pmids\": [\"20360135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-4Rα signaling in rhabdomyosarcoma activates STAT6, Akt, and MAPK pathways; IL-4 and IL-13 stimulation promotes tumor cell proliferation and downregulates MyoD and Myogenin (myogenic differentiation factors); neutralizing anti-IL-4Rα antibody in a mouse ARMS model significantly reduced lymph node and pulmonary metastases.\",\n      \"method\": \"In vitro IL-4/IL-13 stimulation of human RMS lines (RD, Rh30) and primary mouse ARMS cells; Western blotting for STAT6, Akt, MAPK, MyoD, Myogenin; in vivo neutralizing antibody in genetically engineered mouse model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro signaling, protein expression, in vivo antibody blockade with survival/metastasis readout)\",\n      \"pmids\": [\"21536546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An asthma-associated IL-4Rα variant (R576) promotes conversion of induced Treg cells to TH17-like cells by recruiting the GRB2 adaptor protein, which activates ERK → IL-6 → STAT3 signaling to drive IL-17 expression. Treg-specific deletion of IL6ra or Rorc (but not IL-4 or IL-13) prevented exacerbated airway inflammation in Il4ra(R576) knock-in mice.\",\n      \"method\": \"R576 knock-in mice, Treg-specific conditional knockouts (IL6ra, Rorc, IL-4, IL-13), GRB2 co-immunoprecipitation, ERK/STAT3 pathway analysis, anti-IL-6 antibody treatment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — Co-IP of GRB2/IL-4Rα R576, epistasis via multiple conditional KOs, neutralization rescue, mechanistic signaling data in one study\",\n      \"pmids\": [\"27479084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Somatic IL4R mutations (most commonly I242N in the transmembrane domain) in primary mediastinal large B-cell lymphoma (PMBCL) are gain-of-function, causing constitutive JAK-STAT pathway activation, upregulation of downstream cytokine expression, and growth advantage in vivo in a mouse xenotransplantation model.\",\n      \"method\": \"Sequencing of primary PMBCL cases and cell lines, functional assays of I242N mutant IL4R, JAK-STAT signaling assays, xenotransplantation mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function mutation characterized with signaling assays and in vivo xenograft model\",\n      \"pmids\": [\"29467182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-4Rα on GABAergic (inhibitory) neurons mediates T cell (via IL-4) effects on synaptic plasticity and episodic memory: IL-4Rα knockout specifically in inhibitory neurons impaired contextual fear memory, and snRNA-seq implicated IL-4-driven regulation of synaptic function and plasticity pathways.\",\n      \"method\": \"Inhibitory neuron-specific IL-4Rα conditional knockout (Vgat-Cre), contextual fear memory assay, long-term potentiation recording, snRNA-seq, T-cell adoptive transfer in SCID and IL-4 KO backgrounds\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined behavioral and electrophysiological phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"34793707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The IL4R gene was mapped to human chromosome 16p11.2–16p12.1 by in situ hybridization and mouse-human somatic cell hybrid Southern blotting, and the mouse homolog was positioned in the distal region of chromosome 7.\",\n      \"method\": \"In situ hybridization, Southern blot of somatic cell hybrid panel, interspecific backcross analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal mapping methods, foundational chromosomal localization\",\n      \"pmids\": [\"1679753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-4Rα knockdown in hepatocellular carcinoma cell lines abolishes IL-4-induced activation of JAK1/STAT6 and JNK/ERK1/2 signaling pathways and results in enhanced apoptosis, impaired proliferation, and reduced invasion.\",\n      \"method\": \"siRNA knockdown of IL-4R in HCC cell lines, Western blot for JAK1/STAT6 and JNK/ERK1/2, flow cytometry for apoptosis and cell cycle, invasion assays\",\n      \"journal\": \"The International journal of biological markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined signaling and cellular phenotype readouts, single lab\",\n      \"pmids\": [\"28665449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-4/IL-4Rα type I receptor signaling in osteoclast precursors (OCPs) activates ERK pathway to promote OCP proliferation during early bone metastasis of colorectal cancer; IL-4 is supplied by neutrophils in bone marrow. ERK antagonist Ravoxertinib inhibited OCP proliferation and prevented bone destruction.\",\n      \"method\": \"BrdU assay for OCP proliferation, IL-4 deficiency mice, tumor conditioned medium stimulation, ERK pathway Western blot, ERK inhibitor Ravoxertinib in vivo\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway identified with KO model and pharmacological inhibition, single lab\",\n      \"pmids\": [\"34863091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The acidic motif of IL-4Rα cytoplasmic domain can functionally substitute for the acidic region (A-region) of IL-2Rβ to support c-junB and c-fos induction, while the haematopoietin box1 (S-region equivalent) of IL-4Rα cannot substitute for the S-region of IL-2Rβ for growth signaling; demonstrated by cytoplasmic domain chimeras.\",\n      \"method\": \"Chimeric receptor construction (IL-2Rβ/IL-4Rα domain swaps), stable transfection in BA/F3 cells, proto-oncogene induction assays, IL-2-driven proliferation assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — domain transplant chimera reconstitution, single lab\",\n      \"pmids\": [\"9619370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-3 maintains surface IL-4Rα (CD124) expression on mast cells through a Tyk2/STAT6/HSP90-dependent mechanism; inhibition of Tyk2, STAT6, or HSP90 impaired IL-3-induced IL-4Rα upregulation. Mast cells in this context do not express IL-13Rα1.\",\n      \"method\": \"Pharmacological inhibition of Tyk2, STAT6, HSP90 in mast cells; surface IL-4Rα flow cytometry; Western blot for signaling molecules\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple inhibitors with defined receptor expression readout, single lab\",\n      \"pmids\": [\"36440951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 (an RNA-binding protein) directly binds IL4R and IL13RA1 mRNAs, decreasing their stability; depletion of IGF2BP3 increased IL4R and IL13RA1 mRNA half-life, elevated IL-4Rα and IL-13Rα1 surface expression, and enhanced IL-13/IL-4-induced STAT6 phosphorylation in airway epithelial cells.\",\n      \"method\": \"RNA-binding protein immunoprecipitation (RIP), mRNA stability (half-life) assay, surface receptor flow cytometry after IGF2BP3 knockdown, STAT6 phosphorylation assay, RNA-seq\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct mRNA-binding demonstrated by RIP plus functional validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.19.665669\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL-4Rα is the shared ligand-binding subunit of two distinct receptor complexes—the type I receptor (IL-4Rα/γc on hematopoietic cells) and the type II receptor (IL-4Rα/IL-13Rα1 on non-hematopoietic cells)—that upon IL-4 or IL-13 binding activate JAK1/JAK2/Tyk2 to phosphorylate STAT6 and also signal through IRS-1, PI3K/mTOR, Akt, ERK, and STAT5 via discrete cytoplasmic tyrosine-containing domains (Y497 and Y713 for anti-apoptosis; Y1/first tyrosine for PI3K/mTOR-driven cell-cycle G2/M; the ID-1 region for STAT5/proliferation); disease-associated variants (e.g., I242N transmembrane mutation causing constitutive JAK-STAT activation in lymphoma; R576 recruiting GRB2→ERK→IL-6→STAT3 to reprogram Tregs toward TH17) alter specific downstream pathway outputs, and the soluble isoform is regulated at the splicing level by intronic SNPs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL4R encodes the IL-4Rα chain, the shared ligand-binding subunit of the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes that transduce IL-4 and IL-13 signals across hematopoietic and non-hematopoietic cell types [PMID:9013879, PMID:9301536, PMID:15331327]. Discrete cytoplasmic domains couple to distinct downstream pathways: Y497 and Y713 mediate anti-apoptotic signaling, the first conserved tyrosine (Y1) activates PI3K/mTOR to drive G2/M cell-cycle progression, and the ID-1 region signals through STAT5 for S-phase entry independent of cytoplasmic tyrosines, while the canonical output is JAK1-dependent STAT6 phosphorylation [PMID:9670964, PMID:16210622]. Disease-associated coding variants alter pathway output—the R576 gain-of-function variant recruits GRB2 to activate ERK→IL-6→STAT3 signaling, reprogramming Tregs toward a TH17 fate in asthma, while the somatic I242N transmembrane mutation drives constitutive JAK-STAT activation in primary mediastinal large B-cell lymphoma [PMID:27479084, PMID:29467182]. Beyond canonical immunity, IL-4Rα on smooth muscle cells controls intestinal contractility during helminth infection, on inhibitory neurons mediates T-cell-derived IL-4 effects on synaptic plasticity and episodic memory, and its surface expression is regulated post-transcriptionally by glucocorticoids, intronic SNP-dependent alternative splicing, and IGF2BP3-mediated mRNA destabilization [PMID:20360135, PMID:34793707, PMID:9847438, PMID:16917945].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the chromosomal location of IL4R (16p11.2–12.1) provided the foundation for subsequent genetic and functional studies of the receptor.\",\n      \"evidence\": \"In situ hybridization and somatic cell hybrid Southern blotting in human and interspecific backcross in mouse\",\n      \"pmids\": [\"1679753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No protein-level characterization or signaling data at this stage\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that IL-4Rα and IL-13Rα1 co-expression reconstitutes a high-affinity IL-4/IL-13 receptor resolved how IL-13 and IL-4 share a common signaling chain and compete for receptor binding.\",\n      \"evidence\": \"Receptor reconstitution in CHO cells with radioligand binding (Kd ~30 pM for IL-13) and STAT6 EMSA; antibody blockade and phosphorylation assays in endothelial cells\",\n      \"pmids\": [\"9013879\", \"9301536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the heterodimer not determined\", \"Contribution of γc versus IL-13Rα1 chains to differential signaling not yet dissected\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping individual cytoplasmic tyrosines to discrete functions (Y497/Y713 for anti-apoptosis; acidic domain for proto-oncogene induction) established that the IL-4Rα tail is a modular signaling scaffold rather than a single-output transducer.\",\n      \"evidence\": \"Domain transplant chimeras and Y→F mutagenesis in 32D cells; IL-2Rβ/IL-4Rα domain-swap chimeras in BA/F3 cells\",\n      \"pmids\": [\"9670964\", \"9619370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) directly phosphorylating Y497 and Y713 not identified\", \"Downstream effectors coupling these tyrosines to survival signals not mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Discovering that glucocorticoids downregulate IL-4Rα through two distinct posttranscriptional mechanisms revealed that receptor abundance is actively controlled beyond transcription.\",\n      \"evidence\": \"Nuclear run-on, Northern blot, mRNA stability assays, and GR antagonist (RU486) reversal in PMA- and IL-4-stimulated cells\",\n      \"pmids\": [\"9847438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the mRNA destabilizing factor(s) recruited by GR unknown\", \"Translational/posttranslational mechanism for IL-4-induced receptor regulation not molecularly defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Testing the atopy-associated Q576R variant and finding no enhanced IL-4 signaling in multiple assays challenged the assumption that this variant is a direct gain-of-function for canonical STAT6 output.\",\n      \"evidence\": \"WT versus Q576R IL-4Rα cDNA expressed in murine cells, with phosphorylation, EMSA, proliferation, apoptosis, and CD23 readouts\",\n      \"pmids\": [\"10201973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test non-canonical pathways (e.g., ERK, IL-6) that were later implicated\", \"Murine cellular context may not capture human-specific signaling differences\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that IL-13 can drive airway hyperreactivity through STAT6 independently of IL-4Rα revealed an alternative IL-13 signaling route, refining the model that all IL-13 effects require IL-4Rα.\",\n      \"evidence\": \"Adoptive T-cell transfer into IL-4Rα−/− versus STAT6−/− mice with airway hyperreactivity and eosinophilia readouts\",\n      \"pmids\": [\"11466392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the IL-4Rα-independent receptor complex mediating IL-13/STAT6 signaling not established\", \"Whether this pathway operates outside the lung not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discriminating type I (IL-4Rα/γc) from type II (IL-4Rα/IL-13Rα1) receptor function using an IL-13 mutant antagonist and showing that the I50V variant alters STAT6 transcriptional amplitude without changing Th2 differentiation revealed selective modularity of receptor-complex outputs.\",\n      \"evidence\": \"Receptor-specific cell lines with competitive binding and STAT6 phosphorylation; I50 vs V50 variant comparison with STAT6 reporters and Th2 assays\",\n      \"pmids\": [\"15331327\", \"15383584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how I50V variant augments STAT6 activation not solved\", \"Whether type II-selective antagonism has distinct downstream transcriptional consequences not profiled\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that a tyrosine-less IL-4Rα tail still drives S-phase entry via the ID-1/STAT5 axis, while Y1 engages PI3K/mTOR for G2/M completion, resolved how IL-4 couples receptor domains to distinct cell-cycle checkpoints.\",\n      \"evidence\": \"Multiple cytoplasmic tyrosine mutant constructs in primary activated T cells, BrdU incorporation, rapamycin sensitivity, p70S6K phosphorylation\",\n      \"pmids\": [\"16210622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner linking ID-1 to STAT5 not identified\", \"Whether mTOR-dependent G2/M regulation operates in non-T cells unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Bone marrow chimera and splicing studies collectively showed that IL-4Rα function is partitioned by cell type (hematopoietic for macrophage polarization and survival vs. non-hematopoietic for granuloma/fibrosis) and that soluble IL-4Rα levels are governed by intronic SNP-dependent alternative splicing.\",\n      \"evidence\": \"Reciprocal BM chimeras in IL-4Rα−/− mice with S. mansoni infection; minigene splicing assays and human mRNA quantification for intronic SNPs; IL-4Rα−/− Nippostrongylus model for IL-10/Th2 dependence\",\n      \"pmids\": [\"18354220\", \"16917945\", \"16940042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How splicing factor SRp20/YT521-B are themselves regulated in disease contexts not known\", \"Quantitative contribution of soluble vs. membrane IL-4Rα to pathway output in vivo not measured\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Cell-type-specific conditional knockout in smooth muscle cells demonstrated that IL-4Rα directly controls intestinal hypercontractility needed for helminth expulsion, extending IL-4Rα function beyond immune cells.\",\n      \"evidence\": \"SM-MHC-Cre × IL-4Rαfl/flox mice with S. mansoni infection, intestinal contractility assays, egg counts, survival\",\n      \"pmids\": [\"20360135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream contractile effectors activated by IL-4Rα in smooth muscle not characterized\", \"Whether type I or type II receptor mediates the smooth muscle response not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that IL-4Rα activates STAT6/Akt/MAPK in rhabdomyosarcoma to promote proliferation and suppress myogenic differentiation, with anti-IL-4Rα antibody reducing metastases in vivo, linked IL-4Rα signaling to solid tumor biology.\",\n      \"evidence\": \"IL-4/IL-13 stimulation of RMS lines with Western blot for STAT6/Akt/MAPK/MyoD; anti-IL-4Rα antibody in genetically engineered mouse ARMS model\",\n      \"pmids\": [\"21536546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of STAT6 versus Akt versus MAPK to metastatic phenotype not dissected\", \"Whether IL-4Rα signals cell-autonomously versus through tumor microenvironment not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying that the R576 variant recruits GRB2→ERK→IL-6→STAT3 to reprogram Tregs toward TH17 provided the first mechanistic explanation for how a coding variant in IL-4Rα exacerbates asthma through a non-canonical signaling axis.\",\n      \"evidence\": \"R576 knock-in mice with Treg-specific conditional KOs of IL6ra and Rorc; GRB2 co-IP with IL-4Rα R576; anti-IL-6 rescue\",\n      \"pmids\": [\"27479084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRB2 recruitment occurs at a specific phosphotyrosine or non-tyrosine motif not mapped\", \"Generalizability to human Treg cells not directly shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that somatic I242N transmembrane mutations constitutively activate JAK-STAT in primary mediastinal large B-cell lymphoma established IL-4Rα as a bona fide oncogenic driver when mutated in its transmembrane domain.\",\n      \"evidence\": \"PMBCL sequencing, functional assays of I242N mutant, JAK-STAT signaling, xenotransplantation growth advantage\",\n      \"pmids\": [\"29467182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which I242N causes ligand-independent dimerization/activation not solved\", \"Whether other transmembrane mutations have similar effects not systematically tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Conditional knockout of IL-4Rα on inhibitory neurons impaired episodic memory and long-term potentiation, revealing an unexpected neuroimmune role for IL-4Rα in synaptic plasticity independent of peripheral immunity.\",\n      \"evidence\": \"Vgat-Cre × IL-4Rαfl/flox mice, contextual fear conditioning, LTP recordings, snRNA-seq, T-cell adoptive transfer\",\n      \"pmids\": [\"34793707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway in neurons (STAT6 vs. other) not fully characterized\", \"Whether IL-4Rα signals through type I or type II receptor in GABAergic neurons not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that IL-3 maintains surface IL-4Rα via Tyk2/STAT6/HSP90 on mast cells identified a cytokine-driven feedforward loop that primes IL-4 responsiveness on effector cells.\",\n      \"evidence\": \"Pharmacological inhibition of Tyk2, STAT6, and HSP90 in mast cells with surface IL-4Rα flow cytometry\",\n      \"pmids\": [\"36440951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HSP90 acts on IL-4Rα protein folding/stability or transcription not resolved\", \"Single lab finding with pharmacological inhibitors only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis for ligand-independent activation by transmembrane mutations, the identity of the IL-4Rα-independent IL-13/STAT6 pathway component, and the signaling logic by which IL-4Rα in neurons regulates synaptic gene programs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of full-length IL-4Rα in a signaling-competent complex\", \"IL-4Rα-independent IL-13 receptor component never identified\", \"Neuronal downstream signaling cascade not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 8, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 8, 13, 14, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 9, 10, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 15, 18]}\n    ],\n    \"complexes\": [\n      \"Type I IL-4 receptor (IL-4Rα/γc)\",\n      \"Type II IL-4 receptor (IL-4Rα/IL-13Rα1)\"\n    ],\n    \"partners\": [\n      \"IL13RA1\",\n      \"IL2RG\",\n      \"STAT6\",\n      \"JAK1\",\n      \"GRB2\",\n      \"STAT5\",\n      \"IGF2BP3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}