{"gene":"IL4R","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"Co-expression of IL-4Rα with IL-13Rα1 reconstitutes a high-affinity IL-13 receptor complex (Kd ~30 pM) that allows cross-competition of IL-13 and IL-4 and enables STAT6 activation by both cytokines; neither subunit alone supports STAT6 activation or high-affinity IL-13 binding.","method":"Reconstitution in CHO cells, radioligand binding, electrophoretic mobility shift assay (EMSA) for STAT6","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution experiment in defined cell system with functional (STAT6 EMSA) and binding (Kd) validation; finding independently corroborated by multiple subsequent studies","pmids":["9013879"],"is_preprint":false},{"year":1997,"finding":"IL-13 signals through IL-4Rα on human endothelial cells to induce MCP-1 expression: a neutralizing anti-IL-4Rα monoclonal antibody blocks IL-13-induced MCP-1; IL-4Rα undergoes rapid tyrosine phosphorylation after IL-13 or IL-4 stimulation; both cytokines activate STAT6 in these cells.","method":"Neutralizing antibody blockade, immunoprecipitation with anti-phosphotyrosine detection, ELISA, in situ hybridization","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional block plus direct phosphorylation evidence in a single lab with two orthogonal methods","pmids":["9301536"],"is_preprint":false},{"year":1998,"finding":"IL-4Rα cytoplasmic domains containing Y497 and Y713 positively signal protection from apoptosis; transplantation of these tyrosine-containing domains to a truncated IL-2Rβ confers IL-4-dependent anti-apoptotic signaling, while the STAT6-docking tyrosine domain suppresses this protection. Y497F and Y713F mutations abolish protection.","method":"Cytoplasmic domain transplantation chimeras, site-directed mutagenesis (Y→F), apoptosis assay in 32D cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with domain-swap chimeras plus mutagenesis in a single rigorous study with clear functional readout","pmids":["9670964"],"is_preprint":false},{"year":1998,"finding":"IL-4-induced upregulation of IL-4Rα surface expression is suppressed by dexamethasone at the translational or post-translational level (mRNA levels unchanged), whereas PMA-induced IL-4Rα expression is suppressed by dexamethasone through decreased mRNA stability (post-transcriptional mechanism). The effect is glucocorticoid-receptor-dependent and reversed by RU486.","method":"Flow cytometry, Northern blot, nuclear run-on transcription assay, mRNA half-life analysis","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Northern, nuclear run-on, FACS) in single lab distinguishing transcriptional vs. post-transcriptional control","pmids":["9847438"],"is_preprint":false},{"year":1998,"finding":"IL-4Rα requires an intact ID-1 (membrane-proximal) region for STAT6-independent proliferative signaling; the Y1 residue (first conserved cytoplasmic tyrosine) initiates PI3K/mTOR pathway activation required for G2/M cell-cycle completion. Tyrosine-deficient IL-4Rα can still signal S-phase entry and STAT5 phosphorylation if the ID-1 region is intact.","method":"Site-directed mutagenesis of cytoplasmic tyrosines, chimeric receptor constructs, cell-cycle analysis (BrdU/PI), p70S6K phosphorylation assay, rapamycin treatment in primary T cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus pharmacological inhibition plus multiple functional readouts in primary cells in a single rigorous study","pmids":["16210622"],"is_preprint":false},{"year":1998,"finding":"Acidic motif of IL-4Rα can substitute for the A-region of IL-2Rβ to support c-junB and c-fos induction when transplanted into chimeric receptors, indicating a functional role for the IL-4Rα acidic domain in proto-oncogene induction; however, exchange of the S-region with IL-4Rα sequence abolishes all IL-2R functions.","method":"Cytoplasmic domain chimeras stably transfected into BA/F3 cells, proto-oncogene mRNA induction assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution with chimeric receptors, single lab, single published study","pmids":["9619370"],"is_preprint":false},{"year":1999,"finding":"The allergy-associated human IL-4Rα Q576R (equivalent to Q551R in some numbering) and adjacent Y575F mutations do not significantly alter tyrosine phosphorylation, STAT6 DNA-binding, proliferation, protection from apoptosis, or CD23 induction in response to IL-4 compared with wild-type receptor in murine cells.","method":"Mutagenesis of human IL-4Rα cDNA expressed in murine cells, phosphorylation assays, EMSA, proliferation assay, apoptosis assay, CD23 induction by flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct mutagenesis with multiple functional readouts; negative result reported by single lab","pmids":["10201973"],"is_preprint":false},{"year":2001,"finding":"T cell-derived IL-13 can induce airway hyperreactivity, mucus hypersecretion, and eosinophilia independently of IL-4Rα (in IL-4Rα-deficient hosts), but this IL-13 signaling requires STAT6, indicating IL-13 can utilize a STAT6-dependent but IL-4Rα-independent receptor component in the lung.","method":"Adoptive transfer of IL-13+/+ or IL-13-/- CD4+ T cells into wild-type, IL-4Rα-deficient, or STAT6-deficient mice; airway hyperreactivity measurement; BALF eosinophil counts","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis with defined cellular readout; two relevant knockout strains used in single-lab study","pmids":["11466392"],"is_preprint":false},{"year":2004,"finding":"IL-4Rα allelic variant I50 (isoleucine at position 50) acts as a gain-of-function variant relative to V50 for STAT6-dependent transcriptional activity but does not increase Th2 differentiation efficiency, IL-4-mediated Th1 repression, or IL-4-induced proliferation, indicating that gain-of-function with respect to STAT6 is dissociated from effects on Th2/Th1 induction.","method":"Retroviral transduction of primary T cells with I50 vs. V50 IL-4Rα variants; STAT6 reporter assays; Th2 differentiation assay; proliferation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparison of allelic variants in primary cells with multiple functional readouts, single lab","pmids":["15383584"],"is_preprint":false},{"year":2004,"finding":"IL-13 mutant E13K (IL-13E13K) blocks IL-4 signaling through type II IL-4R (IL-4Rα/IL-13Rα1 complex) by competing with IL-4 for binding to IL-4Rα and preventing IL-13Rα1–IL-4Rα heterodimerization, but does not inhibit IL-4 binding or signaling through the type I receptor (IL-4Rα/γc). The glutamate at position 13 of IL-13 contacts IL-4Rα.","method":"Competitive binding assay, STAT6 phosphorylation assay, protein synthesis inhibition assay in cells expressing type I, II, or III IL-4R","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antagonism assays with multiple receptor-expressing cell lines, single lab","pmids":["15331327"],"is_preprint":false},{"year":2006,"finding":"Common intronic SNPs flanking the alternatively-spliced exon 8 of IL4R (c.912-1003A>G, c.912-833T>C, c.912-630A>G, c.912-577A>G) regulate alternative splicing of IL4R: the minor allele haplotype significantly decreases production of the soluble IL-4Rα isoform (exon 8+ variant), an effect dependent on splicing factors SRp20 and YT521-B.","method":"IL4R minigene splicing assay with variant constructs, RT-PCR on human mRNA from patients and controls, splicing factor overexpression","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — minigene functional assay plus human mRNA validation; two orthogonal approaches in single lab","pmids":["16917945"],"is_preprint":false},{"year":2008,"finding":"IL-4Rα expression specifically on bone marrow-derived cells (hematopoietic compartment) is necessary and sufficient to protect mice against severe inflammation in acute schistosomiasis and to generate alternatively activated macrophages; IL-4Rα expression on non-bone marrow-derived cells regulates granuloma size and fibrosis but cannot prevent severe hepatic/intestinal pathology or endotoxemia.","method":"Bone marrow chimera experiments (reciprocal transplants between wild-type and IL-4Rα-deficient mice), cytokine measurement, macrophage phenotyping, survival analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal bone marrow chimeras definitively dissect cell-compartment-specific IL-4Rα function with multiple phenotypic readouts","pmids":["18354220"],"is_preprint":false},{"year":2010,"finding":"IL-4Rα signaling in smooth muscle cells mediates IL-4/IL-13-dependent intestinal hypercontractility required for egg expulsion during acute schistosomiasis; smooth muscle cell-specific IL-4Rα deletion (SM-MHC-Cre) increased weight loss and early mortality without intestinal tissue damage, despite intact Th2 responses.","method":"Smooth muscle cell-specific conditional IL-4Rα knockout (SM-MHCCre × IL-4Rαfl/flox), S. mansoni infection, intestinal contractility measurement, egg expulsion quantification","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic and functional readout, replicated against global KO controls","pmids":["20360135"],"is_preprint":false},{"year":2011,"finding":"IL-4R knockdown in HCC cells abolishes IL-4-induced activation of JAK1/STAT6 and JNK/ERK1/2 signaling pathways and results in enhanced apoptosis, impaired proliferation, and reduced invasion, demonstrating that IL-4R drives HCC cell survival and metastasis through these two parallel downstream pathways.","method":"siRNA knockdown of IL-4R in HCC cell lines, Western blot for pathway activation, flow cytometry for apoptosis/cell cycle, invasion assay","journal":"The International journal of biological markers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with multiple phenotypic and pathway readouts, single lab","pmids":["28665449"],"is_preprint":false},{"year":2011,"finding":"IL-4 and IL-13 acting through IL-4Rα activate STAT6, Akt, and MAPK signaling in rhabdomyosarcoma cells, promote tumor cell proliferation, and suppress myogenic differentiation factors MyoD and Myogenin; neutralizing IL-4Rα antibody in vivo reduces lymph node and pulmonary metastases and extends survival in a genetically engineered mouse model.","method":"In vitro signaling assays (Western blot), differentiation factor immunoblotting, in vivo neutralizing antibody treatment in ARMS mouse model, metastasis quantification","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical pathway mapping plus in vivo antibody intervention with defined endpoints, single lab","pmids":["21536546"],"is_preprint":false},{"year":2016,"finding":"The asthma-associated IL-4Rα R576 variant (Il4ra^R576) promotes conversion of induced Treg cells to TH17 fate 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 Il4 or Il13) prevented exacerbated airway inflammation in Il4ra^R576 mice.","method":"Knock-in mouse model (Il4ra^R576), Treg-specific conditional KO of Il6ra and Rorc, Co-IP (IL-4Rα–GRB2 interaction), phospho-ERK/STAT3 assays, IL-6 neutralization in vivo","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (Co-IP, genetic epistasis with conditional KOs, in vivo antibody neutralization) in a single rigorous study with replicated phenotypic rescue","pmids":["27479084"],"is_preprint":false},{"year":2018,"finding":"Somatic IL4R mutations in primary mediastinal large B-cell lymphoma (particularly I242N in the transmembrane domain) are gain-of-function mutations that cause constitutive JAK-STAT pathway activation, upregulate downstream cytokine expression, and confer growth advantage in a mouse xenotransplantation model.","method":"Sequencing of primary PMBCL cases and cell lines, functional assays of I242N mutant IL4R (STAT phosphorylation, cytokine profiling), mouse xenotransplantation model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional characterization of mutation with in vitro signaling assays and in vivo xenograft confirmation, large primary case series","pmids":["29467182"],"is_preprint":false},{"year":2021,"finding":"IL-4Rα expressed on inhibitory (GABAergic) neurons, but not excitatory neurons, is required for contextual fear memory; IL-4Rα knockout specifically in inhibitory neurons disrupts BDNF/TrkB and ARC signaling pathways associated with synaptic plasticity, impairing episodic memory.","method":"Neuron-subtype-specific IL-4Rα conditional KO (Cre-lox), contextual fear conditioning behavioral assay, snRNA-seq, BDNF/TrkB/ARC pathway analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined behavioral and molecular pathway readouts, multiple orthogonal methods","pmids":["34793707"],"is_preprint":false},{"year":2020,"finding":"IL-4Rα deficiency impairs reference memory (but not spatial learning) and disrupts activation of hippocampal BDNF/TrkB and ARC signaling pathways during the memory phase.","method":"Morris water maze in IL-4Rα-deficient vs. IL-4/IL-13 double-deficient vs. wild-type mice; Western blot for BDNF/TrkB and ARC pathway components","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — global KO behavioral and molecular analysis with two orthogonal methods in single lab","pmids":["33020569"],"is_preprint":false},{"year":2021,"finding":"IL-4/IL-4Rα type I receptor signaling in osteoclast precursors (OCPs) promotes OCP proliferation via ERK pathway activation; neutrophils are the main source of IL-4 in bone marrow; IL-4-deficient mice show reduced OCP proliferation; ERK antagonism with ravoxertinib prevents bone destruction.","method":"Mouse bone metastasis model, BrdU proliferation assay, transcriptomic profiling of OCPs, IL-4 deficiency experiment, ERK inhibitor treatment, Western blot","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (transcriptomics, genetic KO, pharmacological inhibition) in single lab","pmids":["34863091"],"is_preprint":false},{"year":2022,"finding":"IL-3 maintains constitutive IL-4Rα (CD124) surface expression on mast cells via a Tyk2→STAT6→HSP90 signaling axis; inhibition of Tyk2, STAT6, or HSP90 impairs IL-3-induced IL-4Rα upregulation, and this IL-3-maintained IL-4Rα expression is required for IL-4 costimulation of IL-33-induced IL-6 and IL-13 production.","method":"Pharmacological inhibition of Tyk2, STAT6, and HSP90 in mast cell cultures; flow cytometry for IL-4Rα surface expression; cytokine ELISA","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of signaling pathway with multiple inhibitors and functional cytokine readout, single lab","pmids":["36440951"],"is_preprint":false},{"year":2021,"finding":"RELMα+ alternatively activated colonic macrophages induced during Trichuris muris infection acquire their phenotype through a cell-intrinsic IL-4Rα-independent mechanism; in contrast, PD-L2 expression on these macrophages is dependent on IL-4Rα signaling.","method":"Macrophage-specific IL-4Rα conditional KO (IL-4Rαfl/fl × CX3CR1Cre), IL-4Rα-deficient/wild-type mixed bone marrow chimeras, flow cytometry for macrophage surface markers","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO plus mixed bone marrow chimeras, two orthogonal genetic approaches dissecting IL-4Rα-dependent vs. independent macrophage activation","pmids":["34329367"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3, an RNA-binding protein, directly binds IL4R and IL13RA1 mRNAs, stabilizing them via an m6A-dependent mechanism; IGF2BP3 depletion increases IL4R and IL13RA1 mRNA half-life, elevates IL-4Rα and IL-13Rα1 surface expression, and enhances IL-13/IL-4-dependent STAT6 phosphorylation, identifying IGF2BP3 as a post-transcriptional repressor of IL-4Rα expression.","method":"RNA immunoprecipitation (RIP), mRNA stability assay, flow cytometry for receptor surface expression, phospho-STAT6 assay, genome-wide transcriptional analysis in primary airway epithelial cells","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding (RIP) plus functional surface expression and signaling readouts with multiple methods; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.07.19.665669"],"is_preprint":true}],"current_model":"IL-4Rα (IL4R) is the shared α-chain subunit of the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes; upon IL-4 or IL-13 binding it recruits JAK1/JAK2/Tyk2, activates STAT6 (and also STAT5, Akt/PI3K-mTOR, and ERK/MAPK), and transduces signals for cell survival (via Y497/Y713), proliferation (via the membrane-proximal ID-1 region and Y1/mTOR axis), Th2 differentiation, alternative macrophage activation, smooth muscle hypercontractility, and neuronal synaptic plasticity; gain-of-function mutations (e.g., I242N in PMBCL) cause constitutive JAK-STAT activation, while disease-associated variants (R576) recruit GRB2 to redirect signaling toward ERK-IL-6-STAT3 and TH17 reprogramming; surface IL-4Rα levels are post-transcriptionally regulated by glucocorticoids (mRNA stability/translation), IL-3 (via Tyk2-STAT6-HSP90), intronic splicing SNPs (controlling soluble isoform), and by IGF2BP3-mediated mRNA destabilization."},"narrative":{"mechanistic_narrative":"IL4R encodes IL-4Rα, the shared α-chain that pairs with IL-13Rα1 to reconstitute a high-affinity IL-13 receptor and to transduce both IL-4 and IL-13 signals through STAT6 [PMID:9013879]. Ligand engagement triggers rapid tyrosine phosphorylation of IL-4Rα and STAT6 activation, which drives target outputs such as endothelial MCP-1 induction [PMID:9301536]. The cytoplasmic tail partitions distinct outputs across discrete tyrosine modules: Y497 and Y713 deliver an anti-apoptotic survival signal that is separable from and antagonized by the STAT6-docking domain [PMID:9670964], while the membrane-proximal ID-1 region and its first conserved tyrosine (Y1) initiate STAT6-independent PI3K/mTOR signaling required for G2/M cell-cycle completion [PMID:16210622], and an acidic motif supports proto-oncogene (c-junB/c-fos) induction [PMID:9619370]. Through these branches IL-4Rα governs Th2-type immunity and tissue effector programs, including alternative macrophage activation in the hematopoietic compartment [PMID:18354220] and smooth-muscle hypercontractility that drives helminth egg expulsion [PMID:20360135]; in the nervous system, IL-4Rα on inhibitory GABAergic neurons is required for contextual fear memory via BDNF/TrkB and ARC pathways [PMID:34793707]. Disease-linked coding variants rewire signaling: the asthma-associated R576 allele recruits the GRB2 adaptor to redirect output toward ERK→IL-6→STAT3 and TH17 reprogramming [PMID:27479084], and the somatic transmembrane mutation I242N in primary mediastinal large B-cell lymphoma causes constitutive JAK-STAT activation and confers a growth advantage [PMID:29467182]. Surface IL-4Rα abundance is set post-transcriptionally—suppressed by glucocorticoids [PMID:9847438], maintained on mast cells by an IL-3→Tyk2→STAT6→HSP90 axis [PMID:36440951], tuned by intronic SNPs controlling the soluble exon-8 isoform [PMID:16917945], and repressed by IGF2BP3-mediated mRNA destabilization [PMID:bio_10.1101_2025.07.19.665669].","teleology":[{"year":1997,"claim":"Established that IL-4Rα is the obligate shared subunit linking IL-4 and IL-13 to a common signaling output, resolving how two cytokines converge on STAT6.","evidence":"Reconstitution of IL-4Rα with IL-13Rα1 in CHO cells with radioligand binding and STAT6 EMSA; neutralizing anti-IL-4Rα block of IL-13-induced MCP-1 in endothelial cells","pmids":["9013879","9301536"],"confidence":"High","gaps":["Stoichiometry and kinetics of receptor heterodimer assembly not resolved","Identity of the JAK partners engaged was not directly mapped in these studies"]},{"year":1998,"claim":"Showed that the IL-4Rα cytoplasmic tail is modular, with distinct tyrosine and sequence motifs separating survival, proliferation, and proto-oncogene outputs from STAT6 signaling.","evidence":"Domain-swap chimeras and Y→F mutagenesis in 32D/BA/F3 cells; apoptosis and proto-oncogene induction assays","pmids":["9670964","9619370"],"confidence":"High","gaps":["Direct effector recruited at Y497/Y713 not identified","Whether STAT6-domain antagonism of survival is competitive or active was not defined"]},{"year":1998,"claim":"Defined post-transcriptional control of IL-4Rα surface levels, distinguishing translational suppression from mRNA-stability regulation by glucocorticoids.","evidence":"Flow cytometry, Northern blot, nuclear run-on and mRNA half-life analysis with dexamethasone/RU486","pmids":["9847438"],"confidence":"Medium","gaps":["The cis-elements and trans-factors mediating mRNA destabilization were not identified","Stimulus-specific (IL-4 vs PMA) divergence in mechanism not fully explained"]},{"year":1998,"claim":"Located a STAT6-independent proliferative arm, mapping the ID-1 region and Y1 to PI3K/mTOR-dependent cell-cycle progression.","evidence":"Tyrosine mutagenesis and chimeric receptors with rapamycin treatment and p70S6K/BrdU readouts in primary T cells","pmids":["16210622"],"confidence":"High","gaps":["Direct adaptors coupling ID-1/Y1 to PI3K were not identified","How S-phase entry proceeds in tyrosine-deficient receptor remains unexplained"]},{"year":1999,"claim":"Tested whether the allergy-associated Q576R/Y575F coding changes alter canonical signaling, finding no measurable effect on phosphorylation, STAT6, proliferation, or survival.","evidence":"Mutagenesis of human IL-4Rα in murine cells with phosphorylation, EMSA, proliferation, apoptosis, and CD23 readouts","pmids":["10201973"],"confidence":"Medium","gaps":["Negative result in a heterologous murine system may miss context-dependent effects","Non-canonical outputs (later shown for R576) were not assessed"]},{"year":2001,"claim":"Revealed that IL-13 effector functions in the lung can proceed via a STAT6-dependent but IL-4Rα-independent route, indicating non-redundant receptor usage.","evidence":"Adoptive T-cell transfer into IL-4Rα- and STAT6-deficient mice with airway hyperreactivity and BALF readouts","pmids":["11466392"],"confidence":"Medium","gaps":["The alternative receptor component used by IL-13 was not molecularly defined","Cell type transducing the IL-4Rα-independent signal not identified"]},{"year":2004,"claim":"Dissected receptor antagonism and allelic gain-of-function, showing IL-13 contact residues at IL-4Rα and that STAT6 potency can be uncoupled from Th2 differentiation.","evidence":"IL-13 E13K competition/blocking across type I/II/III receptor cells; I50 vs V50 variant transduction in primary T cells with reporter and differentiation assays","pmids":["15331327","15383584"],"confidence":"Medium","gaps":["Structural basis of E13–IL-4Rα contact not solved","Mechanism decoupling STAT6 activity from Th2 commitment unknown"]},{"year":2006,"claim":"Identified intronic splicing SNPs and the splicing factors that set the ratio of membrane versus soluble IL-4Rα.","evidence":"IL4R minigene splicing assays with variant constructs, human mRNA RT-PCR, and SRp20/YT521-B overexpression","pmids":["16917945"],"confidence":"Medium","gaps":["Functional consequence of altered soluble isoform on signaling not quantified","Direct binding of SRp20/YT521-B to the variant sites not shown"]},{"year":2010,"claim":"Established cell-compartment-specific roles in vivo, separating hematopoietic IL-4Rα (macrophage activation, protection) from smooth-muscle IL-4Rα (hypercontractility and egg expulsion).","evidence":"Reciprocal bone marrow chimeras and SM-MHC-Cre smooth-muscle conditional knockout in S. mansoni infection","pmids":["18354220","20360135"],"confidence":"High","gaps":["Downstream signaling within smooth muscle not mapped","Molecular basis of compartment-specific protective vs fibrotic outcomes unresolved"]},{"year":2011,"claim":"Extended IL-4Rα signaling to tumor survival and metastasis through parallel JAK1/STAT6 and JNK/ERK and Akt/MAPK arms.","evidence":"siRNA knockdown in HCC and in vitro/in vivo neutralizing antibody studies in rhabdomyosarcoma models with metastasis endpoints","pmids":["28665449","21536546"],"confidence":"Medium","gaps":["Relative contribution of each downstream arm to metastasis not isolated","Receptor type (I vs II) driving tumor signaling not defined"]},{"year":2016,"claim":"Demonstrated that a single coding variant reprograms signaling output, with R576 recruiting GRB2 to drive an ERK→IL-6→STAT3 TH17 axis underlying allergic pathology.","evidence":"Il4ra^R576 knock-in mice, Treg-specific Il6ra/Rorc conditional KO, IL-4Rα–GRB2 Co-IP, phospho-ERK/STAT3 assays, and in vivo IL-6 neutralization","pmids":["27479084"],"confidence":"High","gaps":["Structural mechanism by which R576 creates a GRB2 docking site not solved","Human relevance of the Treg-to-TH17 conversion not directly tested"]},{"year":2018,"claim":"Identified somatic IL4R gain-of-function mutation as an oncogenic driver causing constitutive JAK-STAT activation in lymphoma.","evidence":"Sequencing of PMBCL cases, functional STAT-phosphorylation and cytokine assays of I242N, and mouse xenotransplantation","pmids":["29467182"],"confidence":"High","gaps":["Mechanism by which the transmembrane I242N enforces ligand-independent dimerization not defined","Therapeutic vulnerability of the mutant not established"]},{"year":2021,"claim":"Uncovered a neuronal, cell-type-specific function for IL-4Rα in memory, acting in inhibitory neurons via BDNF/TrkB and ARC plasticity pathways.","evidence":"Neuron-subtype conditional and global IL-4Rα knockouts with fear conditioning, Morris water maze, snRNA-seq, and pathway immunoblots","pmids":["34793707","33020569"],"confidence":"High","gaps":["Ligand source and proximal signaling in GABAergic neurons not defined","Link between receptor activation and ARC/BDNF induction mechanistically incomplete"]},{"year":2021,"claim":"Showed IL-4Rα signaling is selectively required for some but not all macrophage activation markers, and identified an IL-4Rα-dependent ERK-driven role in osteoclast precursor proliferation.","evidence":"CX3CR1-Cre macrophage conditional KO and mixed bone marrow chimeras; bone metastasis model with IL-4 deficiency and ERK inhibition","pmids":["34329367","34863091"],"confidence":"High","gaps":["Pathway driving IL-4Rα-independent RELMα induction unknown","Whether type I receptor exclusively mediates OCP proliferation not confirmed"]},{"year":2022,"claim":"Defined how surface receptor density is actively maintained, identifying an IL-3→Tyk2→STAT6→HSP90 axis sustaining IL-4Rα on mast cells.","evidence":"Pharmacological inhibition of Tyk2/STAT6/HSP90 with flow cytometry for surface IL-4Rα and cytokine ELISA","pmids":["36440951"],"confidence":"Medium","gaps":["How HSP90 stabilizes IL-4Rα protein not mechanistically resolved","Generality beyond mast cells not tested"]},{"year":2025,"claim":"Identified an m6A-reader-dependent post-transcriptional brake on receptor expression, with IGF2BP3 destabilizing IL4R and IL13RA1 mRNAs to limit STAT6 signaling.","evidence":"RIP, mRNA stability assays, surface receptor flow cytometry, and phospho-STAT6 readouts in primary airway epithelial cells (preprint)","pmids":["bio_10.1101_2025.07.19.665669"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","m6A sites on IL4R mediating IGF2BP3 binding not mapped"]},{"year":null,"claim":"How distinct cytoplasmic motifs are selected to bias survival, proliferation, STAT6, or GRB2-rerouted outputs in a given cell type, and how the layered post-transcriptional controls integrate to set receptor density in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking variant-driven adaptor recruitment to output switching","Quantitative integration of glucocorticoid, IL-3, splicing-SNP, and IGF2BP3 controls on surface IL-4Rα not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,11,20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,15,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16]}],"complexes":["Type I IL-4 receptor (IL-4Rα/γc)","Type II IL-4 receptor (IL-4Rα/IL-13Rα1)"],"partners":["IL13RA1","GRB2","STAT6","IGF2BP3"],"other_free_text":[]}},"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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MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/33920608","citation_count":4,"is_preprint":false},{"pmid":"24185116","id":"PMC_24185116","title":"Higher TGF-β with lower CD124 and TSLP, but no difference in PAR-2 expression in bronchial biopsy of bronchial asthma patients in comparison with 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":"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":"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 & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38761419","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":"41882095","id":"PMC_41882095","title":"Modulating tumor-associated macrophages through APP-CD74 blockade with IL4R-exosomes synergizes with PD-1 inhibition in gastric cancer.","date":"2026","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41882095","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":"32902809","id":"PMC_32902809","title":"Polymorphisms of IL-4 and IL-4R are associated to some demographic characteristics of differentiated thyroid cancer patients but are not determinants of risk in the Brazilian population.","date":"2020","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/32902809","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":"26695670","id":"PMC_26695670","title":"[Correlations of IL-4R gene polymorphism and serum IgE levels with asthma predictive index].","date":"2015","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/26695670","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":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 disease","date":"2025-07-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.19.665669","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.28.25323104","title":"Intragenic deletions from whole genome sequencing of 1054 suicide deaths","date":"2025-03-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.25323104","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53081,"output_tokens":6157,"usd":0.125799,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15132,"output_tokens":5306,"usd":0.104155,"stage2_stop_reason":"end_turn"},"total_usd":0.229954,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Co-expression of IL-4Rα with IL-13Rα1 reconstitutes a high-affinity IL-13 receptor complex (Kd ~30 pM) that allows cross-competition of IL-13 and IL-4 and enables STAT6 activation by both cytokines; neither subunit alone supports STAT6 activation or high-affinity IL-13 binding.\",\n      \"method\": \"Reconstitution in CHO cells, radioligand binding, electrophoretic mobility shift assay (EMSA) for STAT6\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution experiment in defined cell system with functional (STAT6 EMSA) and binding (Kd) validation; finding independently corroborated by multiple subsequent studies\",\n      \"pmids\": [\"9013879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"IL-13 signals through IL-4Rα on human endothelial cells to induce MCP-1 expression: a neutralizing anti-IL-4Rα monoclonal antibody blocks IL-13-induced MCP-1; IL-4Rα undergoes rapid tyrosine phosphorylation after IL-13 or IL-4 stimulation; both cytokines activate STAT6 in these cells.\",\n      \"method\": \"Neutralizing antibody blockade, immunoprecipitation with anti-phosphotyrosine detection, ELISA, in situ hybridization\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional block plus direct phosphorylation evidence in a single lab with two orthogonal methods\",\n      \"pmids\": [\"9301536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IL-4Rα cytoplasmic domains containing Y497 and Y713 positively signal protection from apoptosis; transplantation of these tyrosine-containing domains to a truncated IL-2Rβ confers IL-4-dependent anti-apoptotic signaling, while the STAT6-docking tyrosine domain suppresses this protection. Y497F and Y713F mutations abolish protection.\",\n      \"method\": \"Cytoplasmic domain transplantation chimeras, site-directed mutagenesis (Y→F), apoptosis assay in 32D cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with domain-swap chimeras plus mutagenesis in a single rigorous study with clear functional readout\",\n      \"pmids\": [\"9670964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IL-4-induced upregulation of IL-4Rα surface expression is suppressed by dexamethasone at the translational or post-translational level (mRNA levels unchanged), whereas PMA-induced IL-4Rα expression is suppressed by dexamethasone through decreased mRNA stability (post-transcriptional mechanism). The effect is glucocorticoid-receptor-dependent and reversed by RU486.\",\n      \"method\": \"Flow cytometry, Northern blot, nuclear run-on transcription assay, mRNA half-life analysis\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Northern, nuclear run-on, FACS) in single lab distinguishing transcriptional vs. post-transcriptional control\",\n      \"pmids\": [\"9847438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IL-4Rα requires an intact ID-1 (membrane-proximal) region for STAT6-independent proliferative signaling; the Y1 residue (first conserved cytoplasmic tyrosine) initiates PI3K/mTOR pathway activation required for G2/M cell-cycle completion. Tyrosine-deficient IL-4Rα can still signal S-phase entry and STAT5 phosphorylation if the ID-1 region is intact.\",\n      \"method\": \"Site-directed mutagenesis of cytoplasmic tyrosines, chimeric receptor constructs, cell-cycle analysis (BrdU/PI), p70S6K phosphorylation assay, rapamycin treatment in primary T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus pharmacological inhibition plus multiple functional readouts in primary cells in a single rigorous study\",\n      \"pmids\": [\"16210622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Acidic motif of IL-4Rα can substitute for the A-region of IL-2Rβ to support c-junB and c-fos induction when transplanted into chimeric receptors, indicating a functional role for the IL-4Rα acidic domain in proto-oncogene induction; however, exchange of the S-region with IL-4Rα sequence abolishes all IL-2R functions.\",\n      \"method\": \"Cytoplasmic domain chimeras stably transfected into BA/F3 cells, proto-oncogene mRNA induction assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution with chimeric receptors, single lab, single published study\",\n      \"pmids\": [\"9619370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The allergy-associated human IL-4Rα Q576R (equivalent to Q551R in some numbering) and adjacent Y575F mutations do not significantly alter tyrosine phosphorylation, STAT6 DNA-binding, proliferation, protection from apoptosis, or CD23 induction in response to IL-4 compared with wild-type receptor in murine cells.\",\n      \"method\": \"Mutagenesis of human IL-4Rα cDNA expressed in murine cells, phosphorylation assays, EMSA, proliferation assay, apoptosis assay, CD23 induction by flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct mutagenesis with multiple functional readouts; negative result reported by single lab\",\n      \"pmids\": [\"10201973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"T cell-derived IL-13 can induce airway hyperreactivity, mucus hypersecretion, and eosinophilia independently of IL-4Rα (in IL-4Rα-deficient hosts), but this IL-13 signaling requires STAT6, indicating IL-13 can utilize a STAT6-dependent but IL-4Rα-independent receptor component in the lung.\",\n      \"method\": \"Adoptive transfer of IL-13+/+ or IL-13-/- CD4+ T cells into wild-type, IL-4Rα-deficient, or STAT6-deficient mice; airway hyperreactivity measurement; BALF eosinophil counts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis with defined cellular readout; two relevant knockout strains used in single-lab study\",\n      \"pmids\": [\"11466392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-4Rα allelic variant I50 (isoleucine at position 50) acts as a gain-of-function variant relative to V50 for STAT6-dependent transcriptional activity but does not increase Th2 differentiation efficiency, IL-4-mediated Th1 repression, or IL-4-induced proliferation, indicating that gain-of-function with respect to STAT6 is dissociated from effects on Th2/Th1 induction.\",\n      \"method\": \"Retroviral transduction of primary T cells with I50 vs. V50 IL-4Rα variants; STAT6 reporter assays; Th2 differentiation assay; proliferation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparison of allelic variants in primary cells with multiple functional readouts, single lab\",\n      \"pmids\": [\"15383584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-13 mutant E13K (IL-13E13K) blocks IL-4 signaling through type II IL-4R (IL-4Rα/IL-13Rα1 complex) by competing with IL-4 for binding to IL-4Rα and preventing IL-13Rα1–IL-4Rα heterodimerization, but does not inhibit IL-4 binding or signaling through the type I receptor (IL-4Rα/γc). The glutamate at position 13 of IL-13 contacts IL-4Rα.\",\n      \"method\": \"Competitive binding assay, STAT6 phosphorylation assay, protein synthesis inhibition assay in cells expressing type I, II, or III IL-4R\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antagonism assays with multiple receptor-expressing cell lines, single lab\",\n      \"pmids\": [\"15331327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Common intronic SNPs flanking the alternatively-spliced exon 8 of IL4R (c.912-1003A>G, c.912-833T>C, c.912-630A>G, c.912-577A>G) regulate alternative splicing of IL4R: the minor allele haplotype significantly decreases production of the soluble IL-4Rα isoform (exon 8+ variant), an effect dependent on splicing factors SRp20 and YT521-B.\",\n      \"method\": \"IL4R minigene splicing assay with variant constructs, RT-PCR on human mRNA from patients and controls, splicing factor overexpression\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — minigene functional assay plus human mRNA validation; two orthogonal approaches in single lab\",\n      \"pmids\": [\"16917945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-4Rα expression specifically on bone marrow-derived cells (hematopoietic compartment) is necessary and sufficient to protect mice against severe inflammation in acute schistosomiasis and to generate alternatively activated macrophages; IL-4Rα expression on non-bone marrow-derived cells regulates granuloma size and fibrosis but cannot prevent severe hepatic/intestinal pathology or endotoxemia.\",\n      \"method\": \"Bone marrow chimera experiments (reciprocal transplants between wild-type and IL-4Rα-deficient mice), cytokine measurement, macrophage phenotyping, survival analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal bone marrow chimeras definitively dissect cell-compartment-specific IL-4Rα function with multiple phenotypic readouts\",\n      \"pmids\": [\"18354220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-4Rα signaling in smooth muscle cells mediates IL-4/IL-13-dependent intestinal hypercontractility required for egg expulsion during acute schistosomiasis; smooth muscle cell-specific IL-4Rα deletion (SM-MHC-Cre) increased weight loss and early mortality without intestinal tissue damage, despite intact Th2 responses.\",\n      \"method\": \"Smooth muscle cell-specific conditional IL-4Rα knockout (SM-MHCCre × IL-4Rαfl/flox), S. mansoni infection, intestinal contractility measurement, egg expulsion quantification\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic and functional readout, replicated against global KO controls\",\n      \"pmids\": [\"20360135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-4R knockdown in HCC cells abolishes IL-4-induced activation of JAK1/STAT6 and JNK/ERK1/2 signaling pathways and results in enhanced apoptosis, impaired proliferation, and reduced invasion, demonstrating that IL-4R drives HCC cell survival and metastasis through these two parallel downstream pathways.\",\n      \"method\": \"siRNA knockdown of IL-4R in HCC cell lines, Western blot for pathway activation, flow cytometry for apoptosis/cell cycle, invasion assay\",\n      \"journal\": \"The International journal of biological markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with multiple phenotypic and pathway readouts, single lab\",\n      \"pmids\": [\"28665449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-4 and IL-13 acting through IL-4Rα activate STAT6, Akt, and MAPK signaling in rhabdomyosarcoma cells, promote tumor cell proliferation, and suppress myogenic differentiation factors MyoD and Myogenin; neutralizing IL-4Rα antibody in vivo reduces lymph node and pulmonary metastases and extends survival in a genetically engineered mouse model.\",\n      \"method\": \"In vitro signaling assays (Western blot), differentiation factor immunoblotting, in vivo neutralizing antibody treatment in ARMS mouse model, metastasis quantification\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical pathway mapping plus in vivo antibody intervention with defined endpoints, single lab\",\n      \"pmids\": [\"21536546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The asthma-associated IL-4Rα R576 variant (Il4ra^R576) promotes conversion of induced Treg cells to TH17 fate 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 Il4 or Il13) prevented exacerbated airway inflammation in Il4ra^R576 mice.\",\n      \"method\": \"Knock-in mouse model (Il4ra^R576), Treg-specific conditional KO of Il6ra and Rorc, Co-IP (IL-4Rα–GRB2 interaction), phospho-ERK/STAT3 assays, IL-6 neutralization in vivo\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (Co-IP, genetic epistasis with conditional KOs, in vivo antibody neutralization) in a single rigorous study with replicated phenotypic rescue\",\n      \"pmids\": [\"27479084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Somatic IL4R mutations in primary mediastinal large B-cell lymphoma (particularly I242N in the transmembrane domain) are gain-of-function mutations that cause constitutive JAK-STAT pathway activation, upregulate downstream cytokine expression, and confer growth advantage in a mouse xenotransplantation model.\",\n      \"method\": \"Sequencing of primary PMBCL cases and cell lines, functional assays of I242N mutant IL4R (STAT phosphorylation, cytokine profiling), mouse xenotransplantation model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional characterization of mutation with in vitro signaling assays and in vivo xenograft confirmation, large primary case series\",\n      \"pmids\": [\"29467182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-4Rα expressed on inhibitory (GABAergic) neurons, but not excitatory neurons, is required for contextual fear memory; IL-4Rα knockout specifically in inhibitory neurons disrupts BDNF/TrkB and ARC signaling pathways associated with synaptic plasticity, impairing episodic memory.\",\n      \"method\": \"Neuron-subtype-specific IL-4Rα conditional KO (Cre-lox), contextual fear conditioning behavioral assay, snRNA-seq, BDNF/TrkB/ARC pathway analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined behavioral and molecular pathway readouts, multiple orthogonal methods\",\n      \"pmids\": [\"34793707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-4Rα deficiency impairs reference memory (but not spatial learning) and disrupts activation of hippocampal BDNF/TrkB and ARC signaling pathways during the memory phase.\",\n      \"method\": \"Morris water maze in IL-4Rα-deficient vs. IL-4/IL-13 double-deficient vs. wild-type mice; Western blot for BDNF/TrkB and ARC pathway components\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — global KO behavioral and molecular analysis with two orthogonal methods in single lab\",\n      \"pmids\": [\"33020569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-4/IL-4Rα type I receptor signaling in osteoclast precursors (OCPs) promotes OCP proliferation via ERK pathway activation; neutrophils are the main source of IL-4 in bone marrow; IL-4-deficient mice show reduced OCP proliferation; ERK antagonism with ravoxertinib prevents bone destruction.\",\n      \"method\": \"Mouse bone metastasis model, BrdU proliferation assay, transcriptomic profiling of OCPs, IL-4 deficiency experiment, ERK inhibitor treatment, Western blot\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (transcriptomics, genetic KO, pharmacological inhibition) in single lab\",\n      \"pmids\": [\"34863091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-3 maintains constitutive IL-4Rα (CD124) surface expression on mast cells via a Tyk2→STAT6→HSP90 signaling axis; inhibition of Tyk2, STAT6, or HSP90 impairs IL-3-induced IL-4Rα upregulation, and this IL-3-maintained IL-4Rα expression is required for IL-4 costimulation of IL-33-induced IL-6 and IL-13 production.\",\n      \"method\": \"Pharmacological inhibition of Tyk2, STAT6, and HSP90 in mast cell cultures; flow cytometry for IL-4Rα surface expression; cytokine ELISA\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of signaling pathway with multiple inhibitors and functional cytokine readout, single lab\",\n      \"pmids\": [\"36440951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RELMα+ alternatively activated colonic macrophages induced during Trichuris muris infection acquire their phenotype through a cell-intrinsic IL-4Rα-independent mechanism; in contrast, PD-L2 expression on these macrophages is dependent on IL-4Rα signaling.\",\n      \"method\": \"Macrophage-specific IL-4Rα conditional KO (IL-4Rαfl/fl × CX3CR1Cre), IL-4Rα-deficient/wild-type mixed bone marrow chimeras, flow cytometry for macrophage surface markers\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO plus mixed bone marrow chimeras, two orthogonal genetic approaches dissecting IL-4Rα-dependent vs. independent macrophage activation\",\n      \"pmids\": [\"34329367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3, an RNA-binding protein, directly binds IL4R and IL13RA1 mRNAs, stabilizing them via an m6A-dependent mechanism; IGF2BP3 depletion increases IL4R and IL13RA1 mRNA half-life, elevates IL-4Rα and IL-13Rα1 surface expression, and enhances IL-13/IL-4-dependent STAT6 phosphorylation, identifying IGF2BP3 as a post-transcriptional repressor of IL-4Rα expression.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assay, flow cytometry for receptor surface expression, phospho-STAT6 assay, genome-wide transcriptional analysis in primary airway epithelial cells\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding (RIP) plus functional surface expression and signaling readouts with multiple methods; 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 (IL4R) is the shared α-chain subunit of the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes; upon IL-4 or IL-13 binding it recruits JAK1/JAK2/Tyk2, activates STAT6 (and also STAT5, Akt/PI3K-mTOR, and ERK/MAPK), and transduces signals for cell survival (via Y497/Y713), proliferation (via the membrane-proximal ID-1 region and Y1/mTOR axis), Th2 differentiation, alternative macrophage activation, smooth muscle hypercontractility, and neuronal synaptic plasticity; gain-of-function mutations (e.g., I242N in PMBCL) cause constitutive JAK-STAT activation, while disease-associated variants (R576) recruit GRB2 to redirect signaling toward ERK-IL-6-STAT3 and TH17 reprogramming; surface IL-4Rα levels are post-transcriptionally regulated by glucocorticoids (mRNA stability/translation), IL-3 (via Tyk2-STAT6-HSP90), intronic splicing SNPs (controlling soluble isoform), and by IGF2BP3-mediated mRNA destabilization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL4R encodes IL-4Rα, the shared α-chain that pairs with IL-13Rα1 to reconstitute a high-affinity IL-13 receptor and to transduce both IL-4 and IL-13 signals through STAT6 [#0]. Ligand engagement triggers rapid tyrosine phosphorylation of IL-4Rα and STAT6 activation, which drives target outputs such as endothelial MCP-1 induction [#1]. The cytoplasmic tail partitions distinct outputs across discrete tyrosine modules: Y497 and Y713 deliver an anti-apoptotic survival signal that is separable from and antagonized by the STAT6-docking domain [#2], while the membrane-proximal ID-1 region and its first conserved tyrosine (Y1) initiate STAT6-independent PI3K/mTOR signaling required for G2/M cell-cycle completion [#4], and an acidic motif supports proto-oncogene (c-junB/c-fos) induction [#5]. Through these branches IL-4Rα governs Th2-type immunity and tissue effector programs, including alternative macrophage activation in the hematopoietic compartment [#11] and smooth-muscle hypercontractility that drives helminth egg expulsion [#12]; in the nervous system, IL-4Rα on inhibitory GABAergic neurons is required for contextual fear memory via BDNF/TrkB and ARC pathways [#17]. Disease-linked coding variants rewire signaling: the asthma-associated R576 allele recruits the GRB2 adaptor to redirect output toward ERK→IL-6→STAT3 and TH17 reprogramming [#15], and the somatic transmembrane mutation I242N in primary mediastinal large B-cell lymphoma causes constitutive JAK-STAT activation and confers a growth advantage [#16]. Surface IL-4Rα abundance is set post-transcriptionally—suppressed by glucocorticoids [#3], maintained on mast cells by an IL-3→Tyk2→STAT6→HSP90 axis [#20], tuned by intronic SNPs controlling the soluble exon-8 isoform [#10], and repressed by IGF2BP3-mediated mRNA destabilization [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that IL-4Rα is the obligate shared subunit linking IL-4 and IL-13 to a common signaling output, resolving how two cytokines converge on STAT6.\",\n      \"evidence\": \"Reconstitution of IL-4Rα with IL-13Rα1 in CHO cells with radioligand binding and STAT6 EMSA; neutralizing anti-IL-4Rα block of IL-13-induced MCP-1 in endothelial cells\",\n      \"pmids\": [\"9013879\", \"9301536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and kinetics of receptor heterodimer assembly not resolved\", \"Identity of the JAK partners engaged was not directly mapped in these studies\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that the IL-4Rα cytoplasmic tail is modular, with distinct tyrosine and sequence motifs separating survival, proliferation, and proto-oncogene outputs from STAT6 signaling.\",\n      \"evidence\": \"Domain-swap chimeras and Y→F mutagenesis in 32D/BA/F3 cells; apoptosis and proto-oncogene induction assays\",\n      \"pmids\": [\"9670964\", \"9619370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effector recruited at Y497/Y713 not identified\", \"Whether STAT6-domain antagonism of survival is competitive or active was not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined post-transcriptional control of IL-4Rα surface levels, distinguishing translational suppression from mRNA-stability regulation by glucocorticoids.\",\n      \"evidence\": \"Flow cytometry, Northern blot, nuclear run-on and mRNA half-life analysis with dexamethasone/RU486\",\n      \"pmids\": [\"9847438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The cis-elements and trans-factors mediating mRNA destabilization were not identified\", \"Stimulus-specific (IL-4 vs PMA) divergence in mechanism not fully explained\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Located a STAT6-independent proliferative arm, mapping the ID-1 region and Y1 to PI3K/mTOR-dependent cell-cycle progression.\",\n      \"evidence\": \"Tyrosine mutagenesis and chimeric receptors with rapamycin treatment and p70S6K/BrdU readouts in primary T cells\",\n      \"pmids\": [\"16210622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct adaptors coupling ID-1/Y1 to PI3K were not identified\", \"How S-phase entry proceeds in tyrosine-deficient receptor remains unexplained\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Tested whether the allergy-associated Q576R/Y575F coding changes alter canonical signaling, finding no measurable effect on phosphorylation, STAT6, proliferation, or survival.\",\n      \"evidence\": \"Mutagenesis of human IL-4Rα in murine cells with phosphorylation, EMSA, proliferation, apoptosis, and CD23 readouts\",\n      \"pmids\": [\"10201973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result in a heterologous murine system may miss context-dependent effects\", \"Non-canonical outputs (later shown for R576) were not assessed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed that IL-13 effector functions in the lung can proceed via a STAT6-dependent but IL-4Rα-independent route, indicating non-redundant receptor usage.\",\n      \"evidence\": \"Adoptive T-cell transfer into IL-4Rα- and STAT6-deficient mice with airway hyperreactivity and BALF readouts\",\n      \"pmids\": [\"11466392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The alternative receptor component used by IL-13 was not molecularly defined\", \"Cell type transducing the IL-4Rα-independent signal not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Dissected receptor antagonism and allelic gain-of-function, showing IL-13 contact residues at IL-4Rα and that STAT6 potency can be uncoupled from Th2 differentiation.\",\n      \"evidence\": \"IL-13 E13K competition/blocking across type I/II/III receptor cells; I50 vs V50 variant transduction in primary T cells with reporter and differentiation assays\",\n      \"pmids\": [\"15331327\", \"15383584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of E13–IL-4Rα contact not solved\", \"Mechanism decoupling STAT6 activity from Th2 commitment unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified intronic splicing SNPs and the splicing factors that set the ratio of membrane versus soluble IL-4Rα.\",\n      \"evidence\": \"IL4R minigene splicing assays with variant constructs, human mRNA RT-PCR, and SRp20/YT521-B overexpression\",\n      \"pmids\": [\"16917945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of altered soluble isoform on signaling not quantified\", \"Direct binding of SRp20/YT521-B to the variant sites not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established cell-compartment-specific roles in vivo, separating hematopoietic IL-4Rα (macrophage activation, protection) from smooth-muscle IL-4Rα (hypercontractility and egg expulsion).\",\n      \"evidence\": \"Reciprocal bone marrow chimeras and SM-MHC-Cre smooth-muscle conditional knockout in S. mansoni infection\",\n      \"pmids\": [\"18354220\", \"20360135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling within smooth muscle not mapped\", \"Molecular basis of compartment-specific protective vs fibrotic outcomes unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended IL-4Rα signaling to tumor survival and metastasis through parallel JAK1/STAT6 and JNK/ERK and Akt/MAPK arms.\",\n      \"evidence\": \"siRNA knockdown in HCC and in vitro/in vivo neutralizing antibody studies in rhabdomyosarcoma models with metastasis endpoints\",\n      \"pmids\": [\"28665449\", \"21536546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each downstream arm to metastasis not isolated\", \"Receptor type (I vs II) driving tumor signaling not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that a single coding variant reprograms signaling output, with R576 recruiting GRB2 to drive an ERK→IL-6→STAT3 TH17 axis underlying allergic pathology.\",\n      \"evidence\": \"Il4ra^R576 knock-in mice, Treg-specific Il6ra/Rorc conditional KO, IL-4Rα–GRB2 Co-IP, phospho-ERK/STAT3 assays, and in vivo IL-6 neutralization\",\n      \"pmids\": [\"27479084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which R576 creates a GRB2 docking site not solved\", \"Human relevance of the Treg-to-TH17 conversion not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified somatic IL4R gain-of-function mutation as an oncogenic driver causing constitutive JAK-STAT activation in lymphoma.\",\n      \"evidence\": \"Sequencing of PMBCL cases, functional STAT-phosphorylation and cytokine assays of I242N, and mouse xenotransplantation\",\n      \"pmids\": [\"29467182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the transmembrane I242N enforces ligand-independent dimerization not defined\", \"Therapeutic vulnerability of the mutant not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a neuronal, cell-type-specific function for IL-4Rα in memory, acting in inhibitory neurons via BDNF/TrkB and ARC plasticity pathways.\",\n      \"evidence\": \"Neuron-subtype conditional and global IL-4Rα knockouts with fear conditioning, Morris water maze, snRNA-seq, and pathway immunoblots\",\n      \"pmids\": [\"34793707\", \"33020569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand source and proximal signaling in GABAergic neurons not defined\", \"Link between receptor activation and ARC/BDNF induction mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed IL-4Rα signaling is selectively required for some but not all macrophage activation markers, and identified an IL-4Rα-dependent ERK-driven role in osteoclast precursor proliferation.\",\n      \"evidence\": \"CX3CR1-Cre macrophage conditional KO and mixed bone marrow chimeras; bone metastasis model with IL-4 deficiency and ERK inhibition\",\n      \"pmids\": [\"34329367\", \"34863091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pathway driving IL-4Rα-independent RELMα induction unknown\", \"Whether type I receptor exclusively mediates OCP proliferation not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined how surface receptor density is actively maintained, identifying an IL-3→Tyk2→STAT6→HSP90 axis sustaining IL-4Rα on mast cells.\",\n      \"evidence\": \"Pharmacological inhibition of Tyk2/STAT6/HSP90 with flow cytometry for surface IL-4Rα and cytokine ELISA\",\n      \"pmids\": [\"36440951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSP90 stabilizes IL-4Rα protein not mechanistically resolved\", \"Generality beyond mast cells not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an m6A-reader-dependent post-transcriptional brake on receptor expression, with IGF2BP3 destabilizing IL4R and IL13RA1 mRNAs to limit STAT6 signaling.\",\n      \"evidence\": \"RIP, mRNA stability assays, surface receptor flow cytometry, and phospho-STAT6 readouts in primary airway epithelial cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.19.665669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"m6A sites on IL4R mediating IGF2BP3 binding not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct cytoplasmic motifs are selected to bias survival, proliferation, STAT6, or GRB2-rerouted outputs in a given cell type, and how the layered post-transcriptional controls integrate to set receptor density in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking variant-driven adaptor recruitment to output switching\", \"Quantitative integration of glucocorticoid, IL-3, splicing-SNP, and IGF2BP3 controls on surface IL-4Rα not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 11, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 15, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16]}\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      \"GRB2\",\n      \"STAT6\",\n      \"IGF2BP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}