Affinage

STAT6

Signal transducer and activator of transcription 6 · UniProt P42226

Length
847 aa
Mass
94.1 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT6 is a latent cytoplasmic transcription factor that serves as the central effector of IL-4 and IL-13 signaling, driving Th2-associated gene programs, alternative macrophage polarization, and humoral responses (PMID:8085155, PMID:8624821, PMID:8871614). It was cloned as an IL-4-induced tyrosine-phosphorylated DNA-binding protein whose intracellular receptor coupling and dimerization map to the same functional domain (PMID:8085155), and genetic ablation in mice abolishes IL-4/IL-13-driven CD23 and MHC class II upregulation, B-cell proliferation, IgE/IgG1 class switching, Th2 differentiation, and IL-13-mediated macrophage activation (PMID:8624821, PMID:8602263, PMID:8871614). Receptor-proximal activation requires JAK1, which is itself phosphorylated by upstream PKCζ, and is potentiated by Arg27 methylation that licenses optimal tyrosine phosphorylation, nuclear translocation, and DNA binding (PMID:15153491, PMID:15526032). Activated STAT6 dimerizes and engages N4-type GAS elements with preference over N3 sites through a discriminating H415 residue, as resolved by crystal structures showing a large DNA-binding conformational change (PMID:27803324). In the nucleus STAT6 recruits coactivators p300/CBP, NCOA1, the bridging p100–RNA helicase A complex, and the PARP-active cofactor CoaSt6/PARP14 to activate target genes, while it also represses inflammatory enhancers overlapping the NF-κB p65 cistrome in an HDAC3-dependent manner and directly blocks NF-κB DNA binding (PMID:10373589, PMID:16914450, PMID:17478423, PMID:29343442, PMID:11390419). Through these outputs STAT6 instructs Arg1- and Gas6-dependent macrophage efferocytosis, monocyte-to-DC demethylation, and Th9 differentiation (PMID:31619589, PMID:31363052, PMID:26758199, PMID:22180613). STAT6 abundance and activity are tuned by ubiquitination: the E3 ligase Grail targets it for degradation, whereas TRAF6 reduces K48-linked degradative ubiquitination and TRAF3 promotes activating K450 ubiquitination (PMID:25145352, PMID:33017719, PMID:37474750). Gain-of-function mutations in the SH2 and DNA-binding domains confer ligand-independent nuclear residency and constitutive transcription, causing germline allergic disease with eosinophilia and elevated IgE and driving follicular lymphomagenesis, with mutant activity sustained by a self-reinforcing STAT6–PARP14 circuit (PMID:10747856, PMID:25428220, PMID:36538978, PMID:36216080, PMID:35851155).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 High

    Established the molecular identity of the IL-4-induced DNA-binding activity, defining STAT6 as a receptor-coupled transcription factor and the entry point of the entire pathway.

    Evidence Protein purification, gene cloning, and phosphopeptide inhibition of receptor coupling

    PMID:8085155

    Open questions at the time
    • Did not identify activating kinases
    • No nuclear target genes defined at this stage
  2. 1996 High

    Defined STAT6 as genetically essential and non-redundant for IL-4 and IL-13 biology, converting a biochemical activity into a defined physiological pathway.

    Evidence Independent STAT6-knockout mice with B-cell, T-cell, IgE, Th2, and macrophage readouts

    PMID:8602263 PMID:8624821 PMID:8871614

    Open questions at the time
    • Knockouts did not resolve direct vs indirect target genes
    • Mechanism of IL-4/IL-13 pathway convergence not molecularly dissected
  3. 2000 Medium

    Showed STAT6 acts not only as an activator but as a repressor of STAT1/IFNγ and NF-κB transcription, and that gain-of-function SH2 mutants activate independently of IL-4/JAK1/JAK3, foreshadowing constitutive disease alleles.

    Evidence Mutant reconstitution in STAT6-deficient and JAK-deficient cells with reporter and EMSA assays

    PMID:10747856 PMID:10982806 PMID:11150515

    Open questions at the time
    • Identity of the non-JAK kinase phosphorylating STAT6VT not determined
    • Coactivator-sequestration model of repression not directly proven
  4. 2001 High

    Demonstrated direct STAT6–NF-κB cross-regulation, with STAT6 protein blocking NF-κB DNA binding and nuclear translocation to suppress osteoclastogenesis, extending STAT6 beyond Th2 gene induction.

    Evidence Reciprocal Co-IP, EMSA cooperativity/competition, and knockout rescue with exogenous STAT6

    PMID:11390419 PMID:9584180

    Open questions at the time
    • Structural basis of STAT6–NF-κB contact not resolved
    • In vivo balance of cooperative vs antagonistic NF-κB outcomes unclear
  5. 2004 High

    Mapped upstream and post-translational control of activation, placing PKCζ above JAK1 and identifying Arg27 methylation as a licensing modification for tyrosine phosphorylation and nuclear entry.

    Evidence PKCζ-knockout mice with kinase assays, and Arg27Ala mutagenesis with methylation inhibitors

    PMID:15153491 PMID:15526032

    Open questions at the time
    • Arg27 methyltransferase not identified
    • Quantitative ordering of methylation relative to receptor engagement not established
  6. 2006 Medium

    Resolved the composition of the STAT6 nuclear coactivator complex, showing RNA helicase A is recruited via the p100 bridge and enhances IgE promoter occupancy and transcription.

    Evidence Co-IP, in vitro pulldown, ChIP, RNAi, and reporter assays

    PMID:10373589 PMID:16914450

    Open questions at the time
    • Stoichiometry of the STAT6–p100–RHA complex undefined
    • Genome-wide scope of RHA dependence not established
  7. 2007 High

    Identified an enzymatic coactivator arm, CoaSt6/PARP14 ADP-ribosylation activity, required for STAT6-driven transcription, linking a catalytic modification to target gene output.

    Evidence PARP activity assay with catalytic-dead mutant, PARP inhibitors, reporter, and ChIP

    PMID:17478423

    Open questions at the time
    • Direct ADP-ribosylation targets within the complex beyond p100 not fully mapped
    • In vivo relevance to physiological Th2 genes only partially defined
  8. 2016 High

    Provided the structural mechanism of DNA-site selectivity, showing H415 discriminates N4 from N3 GAS elements through a major conformational change on binding.

    Evidence X-ray crystallography of phospho-STAT6 dimer with N3/N4 DNA, SAXS, MD, and H415 mutagenesis

    PMID:27803324

    Open questions at the time
    • Full-length STAT6 (with transactivation and N-domains) not crystallized
    • Structure of coactivator-bound complexes not solved
  9. 2018 High

    Established STAT6 as a genome-scale direct transcriptional repressor in alternatively activated macrophages, acting through HDAC3 and decommissioning NF-κB-overlapping inflammatory enhancers.

    Evidence ChIP-seq, ATAC-seq, eRNA profiling, HDAC3 inhibition, and STAT6-knockout macrophages

    PMID:29343442

    Open questions at the time
    • Mechanism of HDAC3 recruitment by STAT6 not defined
    • Determinants of activated vs repressed locus choice unresolved
  10. 2019 High

    Connected STAT6 transcriptional output to functional macrophage programs, showing Arg1- and Gas6-dependent efferocytosis that limits tissue injury.

    Evidence STAT6-knockout mice, bone marrow chimeras, adoptive transfer, gene knockdown, and co-culture efferocytosis

    PMID:22180613 PMID:26758199 PMID:31363052 PMID:31619589

    Open questions at the time
    • Direct vs indirect STAT6 control of Arg1/Gas6 loci not fully dissected in every tissue
    • Crosstalk with other AAM transcription factors incompletely mapped
  11. 2020 High

    Defined ubiquitin-based control of STAT6 stability and activity, with Grail driving degradation, TRAF6 antagonizing degradative K48 chains, and TRAF3 installing activating K450 ubiquitin.

    Evidence Co-IP, linkage-specific ubiquitination assays, site mutagenesis, and E3-ligase knockout macrophages/mice

    PMID:25145352 PMID:33017719 PMID:37474750

    Open questions at the time
    • Deubiquitinases counteracting these E3s not identified
    • Interplay/ordering of competing ubiquitin marks on the same molecule unresolved
  12. 2023 High

    Established gain-of-function STAT6 alleles as drivers of human disease, with SH2 and DNA-binding-domain mutations conferring ligand-independent nuclear residency and constitutive transcription in allergy and lymphoma, sustained by a STAT6–PARP14 feed-forward loop and reversible by JAK inhibition.

    Evidence Reporter assays, nuclear fractionation, EMSA, patient cells/organoids, knock-in mice, qChIP, PARP14 knockdown, and ruxolitinib treatment

    PMID:25428220 PMID:35851155 PMID:36216080 PMID:36538978 PMID:36758835

    Open questions at the time
    • Genotype-phenotype determinants separating allergic vs oncogenic outcomes unclear
    • Whether PARP14 circuit is therapeutically tractable in patients not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The kinase responsible for ligand-independent phosphorylation of STAT6 gain-of-function mutants and the identity of the Arg27 methyltransferase and STAT6-cleaving mast-cell protease remain undefined.
  • Non-JAK kinase acting on constitutive STAT6 mutants not identified
  • Physiological role of the truncated mast-cell STAT6 isoform unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 2 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
CBP/P300JAK1NCOA1NFKB1PARP14RBCK1TRAF3TRAF6
Complex memberships
STAT2–STAT6–p48 (ISGF3-like) complexSTAT6–p100–RNA helicase A complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 STAT6 (IL-4 Stat) was purified and cloned as an IL-4-induced tyrosine-phosphorylated DNA-binding protein; phosphotyrosine-containing peptides from the intracellular domain of the IL-4 receptor inhibited IL-4 Stat activation, indicating direct receptor coupling; the same functional domain mediates both receptor coupling and dimerization. Protein purification, gene cloning, inhibitory peptide assays Science High 8085155
1996 Stat6-deficient mice (gene targeting) completely lack IL-4-induced increases in MHC class II antigen and IL-4 receptor surface expression; lymphocytes fail to proliferate in response to IL-4; B cells do not produce IgE; T lymphocytes fail to differentiate into Th2 cells in response to IL-4 or IL-13, establishing Stat6 as essential for IL-4 signaling. Gene targeting/knockout mouse, cell proliferation assays, flow cytometry, immunization Immunity High 8624821
1996 Stat6-deficient mice fail to upregulate CD23 and MHC class II on B cells in response to IL-4; IL-4-induced B-cell proliferation and T-cell proliferative responses are abolished; IgE and IgG1 responses after nematode infection are profoundly reduced, confirming Stat6 as central mediator of IL-4 biological responses. Gene targeting/knockout mouse, flow cytometry, proliferation assays, parasite infection model Nature High 8602263
1996 IL-13-mediated macrophage functions (morphologic changes and MHC class II upregulation) are abolished in STAT6-deficient mice, demonstrating that IL-13 signals through the same STAT6 pathway as IL-4. STAT6-knockout mouse, macrophage functional assays, flow cytometry Journal of Immunology High 8871614
1998 STAT6 and NF-κB directly bind each other in vitro and in vivo (GST pulldown and co-immunoprecipitation); tyrosine-phosphorylated STAT6 and NF-κB bind cooperatively to DNA containing both cognate sites and synergistically activate IL-4-induced transcription. GST pulldown, co-immunoprecipitation, EMSA, luciferase reporter assay Molecular and Cellular Biology High 9584180
1999 p300/CBP is required for STAT6-mediated transcriptional induction by IL-4; the STAT6 transactivation domain interacts with a C-terminal region of CBP (aa 1850–2176); E1A represses IL-4-induced STAT6 transcription through p300/CBP sequestration; co-immunoprecipitation confirmed endogenous STAT6–CBP complex. Two-hybrid assay, co-immunoprecipitation, E1A repression, luciferase reporter, GAL4 fusion assay Nucleic Acids Research High 10373589
2000 STAT6 suppresses STAT1-dependent transcription by a mechanism that does not require STAT6 DNA-binding to N4 sites (a H415A mutation that reduces N4 affinity retains full suppression of STAT1/IFNγ-driven transcription); suppression of NF-κB-dependent transcription requires both the STAT6 transactivation domain and STAT6 DNA binding to N4 sites; both mechanisms require the transactivation domain and likely involve sequestration of distinct coactivators. Transient transfection of STAT6 deletion/point mutants in STAT6-deficient HEK293 cells, luciferase reporter assay Journal of Biological Chemistry Medium 10982806
2000 IL-4 induces phosphorylation of STAT6 on multiple serines within the transactivation domain (residues 719–789); serine phosphorylation does not require tyrosine 641 phosphorylation; PI3K, PKC, and MAPK pathways are not required, suggesting a novel kinase pathway. Phosphoamino acid analysis, 2D phosphopeptide mapping, STAT6 deletion/point mutants, kinase inhibitors Molecular Immunology Medium 11164892
2001 IL-4-induced STAT6 blocks NF-κB DNA binding and nuclear translocation, thereby inhibiting osteoclastogenesis; exogenously added STAT6 protein directly inhibits NF-κB/DNA interaction; IL-4 fails to block osteoclastogenesis in STAT6−/− mice but this is restored by exogenous STAT6. STAT6-knockout mouse osteoclast differentiation assay, EMSA competition, exogenous STAT6 protein addition Journal of Clinical Investigation High 11390419
2002 Protein phosphatase 2A (PP2A) inhibition induces serine phosphorylation of STAT6 and severely inhibits STAT6 DNA binding, acting downstream of JAK kinases in IL-4 signaling; PP2A does not affect IL-4-induced tyrosine phosphorylation of JAK1 or STAT6. PP2A inhibitor (okadaic acid), EMSA, Western blot for phospho-STAT6 Journal of Biological Chemistry Medium 12426308
2002 In mast cells, IL-4 induces nuclear translocation of full-length STAT6 followed by cleavage by a nuclear serine-family protease, generating a C-terminally truncated STAT6 isoform with preferential DNA-binding access; STAT6 chromatin immunoprecipitation identified IL-4-responsive target genes in mast cells including the IL-4 gene itself. Western blot, nuclear fractionation, serine protease inhibitors, chromatin immunoprecipitation Journal of Immunology Medium 12244176
2004 Methylation of STAT6 on Arg27 is required for optimal IL-4-dependent STAT6 tyrosine phosphorylation, nuclear translocation, and DNA-binding activity; Arg27Ala mutant STAT6 and methylation inhibitors markedly diminish all three activities. STAT6 point mutagenesis (Arg27Ala), methylation inhibitors, Western blot, EMSA, nuclear fractionation Journal of Immunology High 15153491
2004 PKCζ interacts with and phosphorylates JAK1; PKCζ deficiency ablates Stat6 tyrosine phosphorylation and JAK1 activation in IL-4-stimulated fibroblasts and liver, placing PKCζ upstream of JAK1 in the IL-4/Stat6 pathway. PKCζ-knockout mouse, co-immunoprecipitation, kinase assay, Western blot for phospho-STAT6/JAK1 EMBO Journal High 15526032
2005 IFN-γ suppresses STAT6 phosphorylation in differentiated Th1 cells by impairing STAT6 recruitment to the phosphorylated IL-4 receptor, without reducing IL-4R expression or JAK1/JAK3 phosphorylation; pulldown with phospho-IL-4R/GST fusion confirmed reduced STAT6 binding in WT vs. IFNGR−/− Th1 cells. IFNGR-knockout mouse T cells, GST pulldown of STAT6 to phospho-IL-4R, Western blot Journal of Immunology Medium 15661890
2006 RNA helicase A (RHA) is a component of the STAT6 transcription complex; RHA does not directly interact with STAT6 but is bridged through the coactivator p100, forming a ternary STAT6–p100–RHA complex; p100-mediated RHA recruitment enhances STAT6 binding to the IgE promoter and IL-4-induced transcription. Co-immunoprecipitation, in vitro pulldown, chromatin immunoprecipitation, RNAi knockdown, luciferase reporter Nucleic Acids Research Medium 16914450
2007 CoaSt6 (collaborator of STAT6) possesses PARP enzymatic activity that auto-ADP-ribosylates itself and modifies p100; a catalytically inactive CoaSt6 mutant fails to enhance STAT6-mediated transcription; chemical PARP inhibition blocks IL-4-dependent target gene transcription in vivo. PARP activity assay, CoaSt6 catalytic mutant, PARP inhibitors, luciferase reporter, chromatin immunoprecipitation Journal of Biological Chemistry High 17478423
2007 IL-4-Stat6 signaling induces expression of tristetraprolin (TTP), an ARE-binding mRNA destabilizing protein, in mast cells; TTP then promotes decay of TNF-α mRNA in an AU-rich element-dependent manner; RNAi depletion of TTP prevents IL-4-mediated TNF-α down-regulation; this effect is absent in Stat6-deficient mice. Stat6-knockout mouse, RNAi, TNF-α mRNA stability assay, ELISA, peritoneal injection model Journal of Experimental Medicine High 14638848
2000 A gain-of-function STAT6 mutant (STAT6VT) carrying two amino acid changes in the SH2 domain undergoes IL-4-independent tyrosine phosphorylation, dimerization, DNA binding, and transcriptional activation; phosphorylation is mediated by a non-IL-4/non-JAK1/JAK3 kinase in U4A fibroblasts. STAT6 mutagenesis, transfection in JAK1/JAK3-deficient U4A cells, EMSA, reporter assay, Western blot Journal of Biological Chemistry High 10747856
1999 IFN-α activates Stat6 in B cells and induces formation of novel Stat2:Stat6 complexes (including a STAT2–STAT6–p48 ISGF3-like complex); this activation is cell-type specific, occurring predominantly in B cells. Western blot for phospho-STAT6, co-immunoprecipitation of STAT2:STAT6 complexes, cell line comparison Journal of Immunology Medium 10490982
2000 The glucocorticoid receptor (GR) physically associates with STAT6 in T lymphocytes; GC suppress STAT6-dependent transcription without affecting STAT6 DNA binding; STAT6 overexpression enhances IL-4-mediated inhibition of GC-induced MMTV transactivation. Co-immunoprecipitation, luciferase reporter assay, EMSA in CTLL-2 cells FEBS Letters Medium 11150515
2014 The E3 ubiquitin ligase Grail interacts with STAT6, ubiquitinates it, and targets it for degradation, creating a negative feedback loop in Th2 cells; Grail deficiency results in increased STAT6 and IL-4 receptor α expression and enhanced Th2 effector cytokine production; Grail expression itself depends on IL-4/STAT6/GATA3 signaling. Co-immunoprecipitation, ubiquitination assay, Grail-knockout mouse, Western blot, allergy model Nature Communications High 25145352
2016 Crystal structures of phosphorylated STAT6 core fragment (homodimer) alone and bound to N3 and N4 DNA sites reveal a dramatic conformational change upon DNA binding; H415 in the DNA-binding domain discriminates N4 from N3 sites; H415N mutation decreases N4 affinity and increases N3 affinity both in vitro and in vivo. X-ray crystallography, molecular dynamics simulation, SAXS, point mutagenesis, DNA binding assay PNAS High 27803324
2014 Follicular lymphoma-associated STAT6 mutations (hotspot D419) are activating; they increase transactivation in reporter assays, enhance IL-4-induced target gene expression, and facilitate nuclear residency of STAT6 independently of IL-4-induced Y641 phosphorylation; structural modeling places most mutations at the STAT6–DNA interface. Luciferase reporter assay, stable STAT6 transfection in lymphoma cell lines, nuclear fractionation, whole-exome sequencing, structural modeling Blood High 25428220
2016 IL-4-activated STAT6 is required for direct transcriptional repression of a large set of genes during alternative macrophage polarization; repression is associated with decreased lineage-determining TF, p300, and RNA Pol II binding, reduced enhancer RNA, H3K27ac, and chromatin accessibility; STAT6 repressor function is HDAC3-dependent on a subset of genes; STAT6-repressed enhancers overlap the NF-κB p65 cistrome and show decreased LPS responsiveness after IL-4 stimulus. ChIP-seq, ATAC-seq, enhancer RNA profiling, HDAC3 inhibition, STAT6-knockout macrophages, in vivo polarization Immunity High 29343442
2016 JAK3-STAT6 pathway activation downstream of IL-4 is required for TET2-dependent DNA demethylation at dendritic-cell-specific loci during monocyte-to-DC differentiation; a constitutively active STAT6 bypasses upstream IL-4 signaling and instructs DC-specific demethylation. DNA methylome profiling, TET2 knockdown, JAK3 inhibitor, constitutively active STAT6 expression Genome Biology High 26758199
2019 STAT6 deficiency in microglia/macrophages reduces efferocytosis of dead neurons, increases inflammatory gene expression, and enlarges infarct volume after experimental stroke; decreased Arginase 1 (Arg1) expression in STAT6−/− microglia/macrophages is responsible for impaired efferocytosis; adoptive transfer of WT macrophages rescues efferocytosis in STAT6-KO mice. STAT6-knockout mouse, bone marrow chimeras, microglia/macrophage-neuron co-culture, adoptive macrophage transfer, flow cytometry JCI Insight High 31619589
2019 STAT6 activation downstream of IL-4 or TSG6 signaling drives Gas6 expression in alveolar macrophages; Gas6 expression is required for efferocytosis of apoptotic neutrophils; Gas6-depleted macrophages fail to clear PMNs in LPS-challenged lungs. In vitro macrophage priming, adoptive macrophage transfer, Gas6 knockdown, STAT6 inhibition, co-culture efferocytosis assay PNAS High 31363052
2017 A stapled helical peptide targeting NCOA1 disrupts the NCOA1/STAT6 protein-protein interaction and represses STAT6-mediated transcription; crystal structure of stapled peptide bound to NCOA1 was solved. Crystal structure of NCOA1–stapled peptide complex, co-immunoprecipitation, luciferase reporter assay Journal of the American Chemical Society High 29090910
2020 TRAF6 stabilizes STAT6 protein by binding STAT6 via its TRAF6 C domain and reducing K48-linked (degradative) ubiquitination of STAT6; TRAF6 promotes K63-linked ubiquitination of STAT6; TRAF6 E3 ligase activity is dispensable for STAT6 stabilization. Co-immunoprecipitation, ubiquitination assay with K48/K63 linkage-specific antibodies, TRAF6 overexpression/knockout, Western blot Molecular Immunology Medium 33017719
2023 TRAF3 promotes STAT6 ubiquitination (at K450 and K129 residues) and transcriptional activity; site mutation of K450 abolishes TRAF3-mediated STAT6 activation; TRAF3 deficiency reduces K450 ubiquitination and impairs IL-4-induced M2 macrophage polarization. Quantitative ubiquitomics, ubiquitination assay, luciferase reporter, STAT6 site mutagenesis, TRAF3-knockout macrophages Cell Death and Differentiation High 37474750
2022 STAT6 competitively binds CREB-binding protein (CBP), inhibiting CBP-mediated P53 acetylation; reduced P53 acetylation transcriptionally restores SLC7A11 expression, thereby suppressing ferroptosis in lung epithelial cells; lung-specific STAT6 depletion exacerbates ferroptosis and ALI. Co-immunoprecipitation (STAT6–CBP), P53 acetylation assay, ChIP for P53 on SLC7A11 promoter, lung-specific STAT6 knockout mouse, ferrostatin-1 rescue Cell Death & Disease Medium 35668064
2022 STAT6 transcriptionally inhibits PPARα expression through a SIE (sis-inducible element) in the PPARα promoter, reducing fatty acid oxidation-related gene expression and promoting lipid accumulation in renal tubular cells; STAT6 inhibition or tubular-specific depletion restores FAO and attenuates renal fibrosis. ChIP assay of STAT6 on PPARα promoter, tubular-specific STAT6-knockout mouse, STAT6 inhibitor, gene expression profiling Cell Death & Disease Medium 35046382
2022 A gain-of-function STAT6 missense variant (p.D419N) increases transcriptional activity independent of IL-4 stimulation, promotes nuclear localization of STAT6 without phosphorylation at baseline, and causes hyperphosphorylation upon IL-4 stimulation; knock-in mice develop spontaneous dermatitis with eosinophil infiltration and elevated IgE. Luciferase reporter, nuclear fractionation, knock-in mouse model, Western blot Journal of Allergy and Clinical Immunology High 36538978
2023 A gain-of-function STAT6 mutation (p.E372K in the DNA-binding domain) augments both basal and cytokine-induced STAT6 phosphorylation without altering dephosphorylation kinetics; JAK1/2 inhibitor ruxolitinib reverses the STAT6 hyperresponsiveness, demonstrating the mutation acts upstream of or at the JAK-STAT6 interface. Western blot of patient lymphocytes, EMSA, immunofluorescence, luciferase assay, JAK inhibitor treatment Journal of Allergy and Clinical Immunology High 36758835
2012 IL-4 inhibits melanogenesis in normal human melanocytes through JAK2-STAT6 signaling; IL-4 increases STAT6 phosphorylation and downregulates MITF and dopachrome tautomerase; JAK2 inhibitor AG490 or STAT6 siRNA blocks IL-4-induced melanogenesis suppression. JAK2 inhibitor, STAT6 siRNA knockdown, Western blot for pSTAT6, gene expression analysis Journal of Investigative Dermatology Medium 22992805
2011 IL-4-activated STAT6 is required for Th9 development by repressing T-bet and Foxp3 expression and inducing IRF4; STAT6 activation is independent of TGF-β-induced PU.1 (Sfpi1); these mechanisms define the transcription factor network balancing IL-9 production. STAT6-knockout mouse Th differentiation assay, retroviral STAT6/IRF4 expression, intracellular cytokine staining Journal of Immunology High 22180613
2012 STAT6-STAT1 axis regulates OC-STAMP and DC-STAMP expression governing macrophage cell-cell fusion (FBGC formation); STAT6 deficiency increases STAT1 activation and inhibits fusion; STAT1 deficiency or co-expression of OC-STAMP/DC-STAMP is sufficient to induce fusion independently of IL-4. STAT6-knockout and STAT1-knockout mouse macrophage fusion assay, OC-STAMP/DC-STAMP co-expression, Western blot Journal of Biological Chemistry Medium 22865856
2022 A germline STAT6 gain-of-function variant (p.Glu377Lys, DNA-binding domain) displays strong nuclear localization preference, increased DNA-binding affinity, and spontaneous transcriptional activity without cytokine stimulation; gastric organoids from the patient show constitutive STAT6 downstream signaling. EMSA, immunofluorescence, luciferase assay, Western blot, patient-derived gastric organoids Journal of Allergy and Clinical Immunology High 36216080
2022 PARP14 is a transcriptional co-activator and direct target of STAT6; activating STAT6 mutations (within the DNA-binding domain) bind the PARP14 promoter (shown by qChIP), increase IL-4-induced transactivation at the PARP14 promoter, and create a self-reinforcing STAT6–PARP14 regulatory circuit; PARP14 knockdown or PARP inhibition abrogates STAT6-mutant gain-of-function. qChIP of STAT6 on PARP14 promoter, luciferase reporter, PARP14 siRNA, PARP inhibitor, RNA sequencing Leukemia High 35851155

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1274 8624821
1996 Essential role of Stat6 in IL-4 signalling. Nature 1240 8602263
1994 An interleukin-4-induced transcription factor: IL-4 Stat. Science (New York, N.Y.) 776 8085155
2000 Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 528 10661403
2007 Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clinical immunology (Orlando, Fla.) 416 18166499
2019 STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice. JCI insight 261 31619589
2006 Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine & growth factor reviews 248 16540365
2000 The biology of Stat4 and Stat6. Oncogene 232 10851056
2010 IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 213 21149710
2018 The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages. Immunity 207 29343442
2011 STAT6-dependent regulation of Th9 development. Journal of immunology (Baltimore, Md. : 1950) 190 22180613
1996 Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 183 8871614
1998 Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription. Molecular and cellular biology 169 9584180
2022 STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway. Cell death & disease 164 35668064
2001 IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB. The Journal of clinical investigation 157 11390419
2015 Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. Journal of immunology (Baltimore, Md. : 1950) 154 25934862
2017 STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis. Medical science monitor basic research 146 28615615
2013 STAT6 and lung inflammation. JAK-STAT 123 24416647
2019 STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation. Proceedings of the National Academy of Sciences of the United States of America 116 31363052
2014 Activating STAT6 mutations in follicular lymphoma. Blood 111 25428220
2006 PKCzeta at the crossroad of NF-kappaB and Jak1/Stat6 signaling pathways. Cell death and differentiation 108 16322752
1999 p300/CBP is required for transcriptional induction by interleukin-4 and interacts with Stat6. Nucleic acids research 107 10373589
2016 IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome biology 101 26758199
2015 JAK3/STAT6 Stimulates Bone Marrow-Derived Fibroblast Activation in Renal Fibrosis. Journal of the American Society of Nephrology : JASN 99 26032813
2001 STAT6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts. Journal of immunology (Baltimore, Md. : 1950) 97 11254707
1997 STAT6: its role in interleukin 4-mediated biological functions. Journal of molecular medicine (Berlin, Germany) 97 9181473
2004 Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma. Journal of immunology (Baltimore, Md. : 1950) 92 15585884
2000 Interleukin-4/STAT6 represses STAT1 and NF-kappa B-dependent transcription through distinct mechanisms. The Journal of biological chemistry 91 10982806
2003 Identification of novel IL-4/Stat6-regulated genes in T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 86 14500660
2021 STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. Pathology, research and practice 84 33991851
2007 Collaborator of Stat6 (CoaSt6)-associated poly(ADP-ribose) polymerase activity modulates Stat6-dependent gene transcription. The Journal of biological chemistry 79 17478423
2012 IL-4 inhibits the melanogenesis of normal human melanocytes through the JAK2-STAT6 signaling pathway. The Journal of investigative dermatology 78 22992805
2006 IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites. European journal of immunology 77 16810739
2016 IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics. Scientific reports 73 27113293
2015 Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis. Breast cancer research : BCR 72 26208975
1999 IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells. Journal of immunology (Baltimore, Md. : 1950) 72 10490982
2008 IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochemical and biophysical research communications 71 18294957
2023 TRAF3/STAT6 axis regulates macrophage polarization and tumor progression. Cell death and differentiation 70 37474750
2002 STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. Neoplasia (New York, N.Y.) 63 12082548
2009 Small interfering RNA against transcription factor STAT6 inhibits allergic airway inflammation and hyperreactivity in mice. Journal of immunology (Baltimore, Md. : 1950) 62 19494273
2014 B-cell-intrinsic STAT6 signaling controls germinal center formation. European journal of immunology 61 24777733
2011 Cisplatin ototoxicity involves cytokines and STAT6 signaling network. Cell research 61 21321603
2007 Kaempferol inhibits IL-4-induced STAT6 activation by specifically targeting JAK3. Journal of immunology (Baltimore, Md. : 1950) 60 17785825
2003 IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells. The Journal of experimental medicine 60 14638848
2005 The role of constitutively active Stat6 in leukemia and lymphoma. Critical reviews in oncology/hematology 58 16213149
2016 NAB2-STAT6 Gene Fusion in Meningeal Hemangiopericytoma and Solitary Fibrous Tumor. Journal of neuropathology and experimental neurology 57 26883114
2016 Structural basis for DNA recognition by STAT6. Proceedings of the National Academy of Sciences of the United States of America 57 27803324
2022 STAT6 gain-of-function variant exacerbates multiple allergic symptoms. The Journal of allergy and clinical immunology 54 36538978
2004 Methylation of STAT6 modulates STAT6 phosphorylation, nuclear translocation, and DNA-binding activity. Journal of immunology (Baltimore, Md. : 1950) 53 15153491
2000 A gain-of-function mutation in STAT6. The Journal of biological chemistry 53 10747856
2023 Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6. The Journal of allergy and clinical immunology 52 36758835
2021 Clinical and molecular implications of NAB2-STAT6 fusion variants in solitary fibrous tumour. Pathology 49 33745702
2023 IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation. JCI insight 48 36757802
2022 STAT6 contributes to renal fibrosis by modulating PPARα-mediated tubular fatty acid oxidation. Cell death & disease 48 35046382
2022 A germline STAT6 gain-of-function variant is associated with early-onset allergies. The Journal of allergy and clinical immunology 48 36216080
2014 Grail controls Th2 cell development by targeting STAT6 for degradation. Nature communications 48 25145352
2000 IL-4 induces serine phosphorylation of the STAT6 transactivation domain in B lymphocytes. Molecular immunology 48 11164892
2013 TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway. PloS one 47 23844087
1998 STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production. International immunology 47 9796920
2004 Crosstalk between PKCzeta and the IL4/Stat6 pathway during T-cell-mediated hepatitis. The EMBO journal 46 15526032
2000 The glucocorticoid receptor and STAT6 physically and functionally interact in T-lymphocytes. FEBS letters 46 11150515
1999 Stat6-dependent and -independent pathways for IL-4 production. Journal of immunology (Baltimore, Md. : 1950) 46 10586046
2019 Analysis of IL-4/STAT6 Signaling in Macrophages. Methods in molecular biology (Clifton, N.J.) 42 31041750
2015 Th2 Cytokines Augment IL-31/IL-31RA Interactions via STAT6-dependent IL-31RA Expression. The Journal of biological chemistry 40 25847241
2007 CCL23 expression is induced by IL-4 in a STAT6-dependent fashion. Journal of immunology (Baltimore, Md. : 1950) 39 17371990
2011 Interleukin-4 inhibits RANKL-induced NFATc1 expression via STAT6: a novel mechanism mediating its blockade of osteoclastogenesis. Journal of cellular biochemistry 38 21751242
2023 Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma. Journal of clinical immunology 36 37316763
2019 IL-37 attenuates allergic process via STAT6/STAT3 pathways in murine allergic rhinitis. International immunopharmacology 36 30665041
2012 An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion. The Journal of biological chemistry 36 22865856
2011 STAT6 expression in glioblastoma promotes invasive growth. BMC cancer 36 21595984
1998 Stat6 inhibits human interleukin-4 promoter activity in T cells. Blood 36 9845517
2004 STAT6-dependent differentiation and production of IL-5 and IL-13 in murine NK2 cells. Journal of immunology (Baltimore, Md. : 1950) 35 15470039
2002 Corticosteroid inhibits IL-4 signaling through down-regulation of IL-4 receptor and STAT6 activity. FEBS letters 34 11997017
2000 Activation of the IL-4 STAT pathway in rheumatoid synovium. Journal of immunology (Baltimore, Md. : 1950) 34 10725752
1999 STAT6-independent production of IL-4 by mast cells. European journal of immunology 34 10229091
2023 Efferocytosis is restricted by axon guidance molecule EphA4 via ERK/Stat6/MERTK signaling following brain injury. Journal of neuroinflammation 33 37941008
2000 Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance. Journal of immunology (Baltimore, Md. : 1950) 33 11067913
2021 STAT6 Signaling Mediates PPARγ Activation and Resolution of Acute Sterile Inflammation in Mice. Cells 31 33652833
2020 TRPM7 modulates macrophage polarization by STAT1/STAT6 pathways in RAW264.7 cells. Biochemical and biophysical research communications 30 33153718
2006 Characterization of RNA helicase A as component of STAT6-dependent enhanceosome. Nucleic acids research 29 16914450
2002 Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated STAT6 signaling. The Journal of biological chemistry 29 12426308
2024 STAT4 and STAT6, their role in cellular and humoral immunity and in diverse human diseases. International reviews of immunology 27 39188021
2020 TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6. Molecular immunology 27 33017719
2017 Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction. Journal of the American Chemical Society 27 29090910
2011 Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis. Allergy 27 20608912
2003 Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. Cancer immunology, immunotherapy : CII 27 14593499
2002 IL-4 induces the proteolytic processing of mast cell STAT6. Journal of immunology (Baltimore, Md. : 1950) 27 12244176
2005 IFN-gamma suppresses STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor. Journal of immunology (Baltimore, Md. : 1950) 26 15661890
2004 IL-4-dependent CD86 expression requires JAK/STAT6 activation and is negatively regulated by PKCdelta. Cellular signalling 26 14636897
2024 S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke. CNS neuroscience & therapeutics 25 39107960
2021 Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6. American journal of respiratory cell and molecular biology 25 33264064
2021 The roles of STAT6 in regulating B cell fate, activation, and function. Immunology letters 25 33662403
2020 Interleukin-4 stimulates lipogenesis in meibocytes by activating the STAT6/PPARγ signaling pathway. The ocular surface 25 32360783
2011 Transcriptional activation of the IL31 gene by NFAT and STAT6. Journal of leukocyte biology 24 22045870
2024 Irisin reprograms microglia through activation of STAT6 and prevents cognitive dysfunction after surgery in mice. Brain, behavior, and immunity 23 39701329
2022 Inhibition of STAT6 Activation by AS1517499 Inhibits Expression and Activity of PPARγ in Macrophages to Resolve Acute Inflammation in Mice. Biomolecules 23 35327639
2022 PARP14 is a novel target in STAT6 mutant follicular lymphoma. Leukemia 22 35851155
2023 Electroacupuncture Alleviates Neuroinflammation by Regulating Microglia Polarization via STAT6/PPARγ in Ischemic Stroke Rats. Neuroscience 21 37741355
2019 Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 21 31822802
2002 Phytochemical inhibition of interleukin-4-activated Stat6 and expression of VCAM-1. Biochemical and biophysical research communications 21 11944890

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