Affinage

STAT6

Signal transducer and activator of transcription 6 · UniProt P42226

Length
847 aa
Mass
94.1 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT6 is a latent transcription factor that serves as the central mediator of IL-4 and IL-13 signaling, governing Th2 immunity, alternative macrophage activation, and allergic inflammation. Upon cytokine stimulation, JAK3-mediated tyrosine phosphorylation at Y641 promotes SH2-domain-dependent homodimerization and DNA binding to N4-spaced GAS elements — a specificity conferred by H415 in the DNA-binding domain — while STAT6 continuously shuttles into the nucleus via importin-α/β through its coiled-coil domain independently of phosphorylation, with nuclear accumulation driven by DNA retention (PMID:8602263, PMID:9651359, PMID:27803324, PMID:20498360). Nuclear STAT6 recruits a multicomponent coactivator assembly (p300/CBP, p100, RNA helicase A, NCOA1, and the PARP-family protein CoaSt6) to activate target genes including arginase I, Ym1, Gas6, and MUC5AC, while simultaneously repressing inflammatory enhancers through HDAC3-dependent chromatin deacetylation and inhibition of NF-κB DNA binding via IκBα stabilization and CBP sequestration (PMID:10373589, PMID:12234934, PMID:16914450, PMID:29090910, PMID:29343442, PMID:10982806). STAT6 protein levels and activity are tuned by suppressive acetylation at K383 by CBP (promoted by Trim24-mediated CBP ubiquitination), activating ubiquitination at K450 by TRAF3, stabilization by TRAF6 through blockade of K48-linked ubiquitination, and proteasomal degradation directed by the E3 ligase Grail (PMID:31554795, PMID:37474750, PMID:33017719, PMID:25145352). Germline gain-of-function mutations in the STAT6 DNA-binding domain (E372K, E377K) cause constitutive nuclear localization and transcriptional activation, resulting in severe early-onset allergic disease (PMID:36758835, PMID:36216080).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 High

    Establishing STAT6 as the non-redundant mediator of IL-4 and IL-13 biological responses resolved which STAT family member transduces these cytokine signals in vivo.

    Evidence Stat6-knockout mice showing abolished IL-4-induced B-cell proliferation, CD23/MHC II upregulation, and IL-13-induced macrophage responses

    PMID:8602263 PMID:8871614

    Open questions at the time
    • Relative contribution of STAT6 to IL-4 versus IL-13 signaling in individual cell types not fully dissected
    • Downstream transcriptional targets not yet identified at this stage
  2. 1997 High

    Mapping the STAT6 domain architecture — a C-terminal proline-rich transactivation domain and an SH2 domain with separable receptor-binding and dimerization functions — defined the structural basis for signal transduction from receptor to DNA.

    Evidence Gal4 fusion/deletion mutant reporter assays and systematic alanine-scanning mutagenesis of the SH2 domain

    PMID:9233621 PMID:9651359

    Open questions at the time
    • Three-dimensional structure not yet available
    • Serine phosphorylation contributions to transactivation unknown
  3. 1999 High

    Identification of p300/CBP as a STAT6 coactivator and discovery that IFN-α can activate STAT6 in B cells via STAT2:STAT6 heterodimers expanded the mechanistic picture beyond the IL-4/IL-13 paradigm.

    Evidence Co-IP and mammalian two-hybrid mapping CBP interaction to STAT6 TAD; EMSA and Co-IP showing STAT2:STAT6 heterodimers in IFN-α-treated B cells

    PMID:10373589 PMID:10490982

    Open questions at the time
    • Structural basis of CBP-STAT6 interaction not resolved
    • Physiological relevance of STAT2:STAT6 in IFN signaling not confirmed in vivo
  4. 2000 High

    Dissection of how STAT6 represses NF-κB (via DNA-binding-dependent CBP competition and IκBα stabilization) and STAT1 (via TAD-dependent, DNA-binding-independent mechanisms) revealed STAT6 as an active transcriptional repressor, not merely an activator.

    Evidence STAT6 point mutants (H415A) in STAT6-null HEK293 reconstitution, live-cell NF-κB reporter imaging, IκBα phosphorylation assays

    PMID:10982806 PMID:12734399

    Open questions at the time
    • Genome-wide repression targets unknown
    • Whether repression requires new protein synthesis or is direct was unresolved
  5. 2000 High

    Identification of serine phosphorylation within the STAT6 TAD (residues 719–789) occurring independently of Y641 and the IRS/PI3K/MAPK pathways, plus the observation that PP2A regulates DNA binding via serine dephosphorylation, revealed a second layer of post-translational regulation.

    Evidence 2D phosphopeptide mapping with STAT6 deletion mutants; PP2A inhibitor treatment separating serine from tyrosine phosphorylation effects

    PMID:11164892 PMID:12426308

    Open questions at the time
    • Identity of the serine kinase unknown
    • Specific serine residues not pinpointed
    • Physiological role of serine phosphorylation in vivo not tested
  6. 2001 High

    Downstream of STAT6, identification of arginase I as the effector suppressing NO production in macrophages, and demonstration of STAT6 requirement for goblet cell hyperplasia during nematode infection, linked STAT6 to defined anti-inflammatory and mucosal defense programs.

    Evidence STAT6-KO macrophages with arginine supplementation rescue; STAT6-KO mice in nematode infection model

    PMID:11136476 PMID:11160269

    Open questions at the time
    • Full repertoire of STAT6-dependent target genes not catalogued
    • Direct versus indirect transcriptional effects not distinguished genome-wide
  7. 2002 High

    Discovery of p100 as a STAT6 coactivator bridging STAT6 to RNA Pol II, and identification of STAT6-dependent Ym1 promoter elements, began to define the transcription complex architecture at target genes.

    Evidence Reciprocal Co-IP and in vitro pulldown for p100-STAT6 and p100-Pol II; EMSA with STAT6-null nuclear extracts on Ym1 promoter

    PMID:12215441 PMID:12234934

    Open questions at the time
    • Whether p100 is constitutive or stimulus-recruited was unclear
    • Genome-wide occupancy of the STAT6-p100 complex not mapped
  8. 2006 High

    Assembly of a ternary STAT6–p100–RNA helicase A complex on IL-4-responsive promoters, and discovery that the PARP-family protein CoaSt6 enhances STAT6 transcription through poly(ADP-ribosyl)ation activity, revealed enzymatic cofactors within the STAT6 transactivation machinery.

    Evidence ChIP plus RNAi for RHA; in vitro PARP assay with catalytically inactive CoaSt6 mutant and pharmacological PARP inhibition

    PMID:16914450 PMID:17478423

    Open questions at the time
    • ADP-ribosylation substrates beyond p100 not identified
    • Whether RHA helicase activity is required was not tested
  9. 2010 High

    Live-cell imaging demonstrated that STAT6 constitutively shuttles into the nucleus via the coiled-coil domain and importin-α/β, with cytokine-induced nuclear accumulation resulting from phosphorylation-dependent DNA retention rather than increased import, resolving the mechanism of signal-dependent nuclear concentration.

    Evidence FRAP and photobleaching with importin pathway inhibition and domain deletions

    PMID:20498360

    Open questions at the time
    • Nuclear export pathway not characterized
    • Whether other nuclear factors contribute to retention beyond DNA binding was unclear
  10. 2014 High

    Identification of Grail as an E3 ligase mediating STAT6 proteasomal degradation, and demonstration of B-cell-intrinsic STAT6 requirement for germinal center formation via Gpr183/Ebi2 regulation, expanded understanding of both STAT6 turnover and its cell-type-specific functions.

    Evidence Co-IP and ubiquitination assay with Grail-KO Th2 cells; conditional B-cell STAT6 KO in helminth infection model with Gpr183 expression analysis

    PMID:24777733 PMID:25145352

    Open questions at the time
    • Ubiquitin chain linkage type for Grail-mediated degradation not determined
    • Whether Gpr183 is a direct STAT6 transcriptional target not shown
  11. 2016 High

    The crystal structure of phosphorylated STAT6 homodimer bound to DNA revealed the structural basis for N4-site selectivity through H415 and a dramatic conformational rearrangement upon DNA binding, providing the first atomic-resolution view of STAT6 target recognition.

    Evidence X-ray crystallography, SAXS, molecular dynamics, and H415N mutagenesis with in vitro/in vivo DNA binding

    PMID:27803324

    Open questions at the time
    • Structure of full-length STAT6 (including TAD) not solved
    • How coactivators dock onto the DNA-bound dimer not structurally defined
  12. 2017 High

    Structural and functional characterization of the NCOA1–STAT6 interaction, and identification of a stapled peptide that disrupts it and blocks STAT6-dependent transcription, validated NCOA1 as an essential STAT6 coactivator and demonstrated therapeutic targetability.

    Evidence Crystal structure of stapled peptide–NCOA1 complex, reporter assay, Co-IP disruption

    PMID:29090910

    Open questions at the time
    • Whether NCOA1 is required at all STAT6 target genes or a subset was not determined
    • In vivo efficacy of the stapled peptide not tested
  13. 2018 High

    Genome-wide epigenomic profiling revealed that STAT6 actively represses inflammatory enhancers through HDAC3-dependent deacetylation — reducing p300, Pol II, eRNA, H3K27ac, and chromatin accessibility at NF-κB-co-occupied sites — establishing enhancer-level repression as a primary anti-inflammatory mechanism.

    Evidence ChIP-seq, ATAC-seq, RNA-seq in WT and STAT6-KO macrophages with HDAC3 inhibition

    PMID:29343442

    Open questions at the time
    • How STAT6 recruits HDAC3 (direct interaction or adaptor-mediated) not established
    • Whether repression is reversible upon STAT6 removal not kinetically resolved
  14. 2019 High

    Discovery that CBP acetylates STAT6 at K383 to suppress M2 polarization (promoted by Trim24-mediated CBP ubiquitination), and that STAT6 induces Gas6 for efferocytosis, revealed acetylation as a suppressive modification and identified a physiological output linking STAT6 to apoptotic cell clearance.

    Evidence MS identification of K383 acetylation, Trim24-KO macrophages; STAT6-KO adoptive transfer rescuing efferocytosis with Gas6-expressing macrophages

    PMID:31363052 PMID:31554795

    Open questions at the time
    • Deacetylase responsible for removing K383 acetylation not identified
    • Whether Gas6 induction is a direct or indirect STAT6 target not determined
  15. 2020 High

    TRAF6 was shown to stabilize STAT6 by blocking K48-linked ubiquitination, while STAT6 was also found to inhibit ferroptosis by competing with p53 for CBP binding to restore SLC7A11, revealing non-canonical STAT6 functions in protein stability and cell death pathways.

    Evidence TRAF6-KD macrophages with K48/K63 ubiquitin linkage discrimination; STAT6 conditional KO mice with p53 acetylation and SLC7A11 expression assays

    PMID:33017719 PMID:35668064

    Open questions at the time
    • Whether TRAF6-STAT6 stabilization is cytokine-dependent or constitutive not fully resolved
    • Generality of STAT6 anti-ferroptotic function beyond lung epithelium unknown
  16. 2022 High

    Identification of germline gain-of-function STAT6 mutations (E377K, E372K) in the DNA-binding domain causing constitutive nuclear localization, enhanced DNA binding, and severe early-onset allergic disease — reversible by JAK inhibition — established STAT6 as a Mendelian disease gene and validated the clinical relevance of its structural biology.

    Evidence Whole-exome sequencing in patients, EMSA, luciferase assays, immunofluorescence, gastric organoids, ruxolitinib rescue

    PMID:36216080 PMID:36758835

    Open questions at the time
    • Full phenotypic spectrum of STAT6 gain-of-function in humans not delineated
    • Structural mechanism by which DNA-binding domain mutations cause constitutive activation not crystallographically resolved
  17. 2023 High

    TRAF3 was identified as an E3 ligase ubiquitinating STAT6 at K450 to enhance its transcriptional activity and M2 polarization, while somatic STAT6 gain-of-function mutations in follicular lymphoma were shown to create a self-reinforcing STAT6–PARP14 circuit, linking STAT6 regulation to both innate immunity and lymphomagenesis.

    Evidence Quantitative ubiquitomics with K450 mutagenesis and TRAF3-KO mice; ChIP showing STAT6MUT-specific PARP14 promoter binding with PARP inhibitor rescue in pre-B CFU assay

    PMID:35851155 PMID:37474750

    Open questions at the time
    • Ubiquitin chain type at K450 not fully characterized
    • Whether PARP14 circuit operates in human follicular lymphoma patients in vivo not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the kinase responsible for STAT6 serine phosphorylation in the TAD, the structural basis of full-length STAT6 interaction with its coactivator complex, the mechanism of HDAC3 recruitment to STAT6-repressed enhancers, and the physiological significance of constitutive STAT6 mitochondrial association.
  • Serine kinase for TAD phosphorylation unidentified
  • Full-length STAT6 structure including TAD and coactivator contacts not solved
  • HDAC3 recruitment mechanism to STAT6 at enhancers not defined
  • Functional role of STAT6 at mitochondria uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 6 R-HSA-4839726 Chromatin organization 2
Partners
CBPDHX9NCOA1RNF128TIPARPTRAF3TRAF6TSN
Complex memberships
STAT2:STAT6 heterodimerSTAT6-p100-RHA ternary complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 STAT6 is essential for IL-4 signaling: Stat6-deficient mice show abolished IL-4-induced B-cell proliferation, impaired T-cell proliferative responses, and loss of CD23/MHC class II upregulation, demonstrating STAT6 is the central mediator of IL-4-mediated biological responses. Gene targeting (knockout mice), functional immune assays Nature High 8602263
1996 STAT6 is also required for IL-13 signaling in macrophages: STAT6-deficient mice show impaired IL-13-induced morphological changes, MHC class II upregulation, and failure to decrease nitric oxide production, indicating IL-4 and IL-13 share the STAT6 signaling pathway. STAT6 knockout mice, macrophage functional assays Journal of immunology High 8871614
1997 The carboxyl terminus of STAT6 contains a 140-amino-acid proline-rich transcriptional activation domain required for IL-4-induced gene expression; truncation mutants lacking this domain cannot activate transcription and act as dominant negatives. Gal4 fusion constructs, deletion mutant analysis, reporter gene assays Journal of immunology High 9233621
1998 The STAT6 SH2 domain mediates both receptor binding (to tyrosine-phosphorylated IL-4Rα) and dimerization; mutational analysis identified residues specifically required for each function, and the SH2 domain structure resembles but differs from Src SH2 at C-terminal ends. Alanine-scanning mutagenesis, phosphopeptide binding assays, DNA binding assays, expression in mammalian and insect cells Journal of biological chemistry High 9651359
1998 A conditionally active STAT6 fusion protein (STAT6:ER*) activates STAT6-regulated gene expression (CD23 induction, reporter activation) independently of detectable tyrosine phosphorylation, suggesting STAT6 can signal through phosphorylation-independent mechanisms. Conditional fusion protein (hormone-binding domain), reporter assays, flow cytometry Journal of immunology Medium 9686563
1999 STAT6 interacts with the coactivator p300/CBP through its C-terminal transactivation domain; this interaction is required for IL-4-induced transcription, as E1A (which sequesters p300/CBP) blocks IL-4 responses, and CBP interaction domain maps to CBP aa 1850–2176. Co-immunoprecipitation, mammalian two-hybrid assay, E1A repression assay, reporter gene assays Nucleic acids research High 10373589
1999 IFN-α activates STAT6 in B cells in a cell-type-specific manner, leading to formation of novel STAT2:STAT6 heterodimeric complexes (including an ISGF3-like complex with STAT2, STAT6, and p48) that can target IFN-responsive elements. Tyrosine phosphorylation assays, EMSA, co-immunoprecipitation Journal of immunology Medium 10490982
2000 STAT6 mediates IL-4-induced repression of NF-κB- and STAT1-dependent transcription via distinct mechanisms: NF-κB repression requires STAT6 DNA binding (H415A mutation abolishes it) and involves CBP sequestration; STAT1 repression requires STAT6 transactivation domain but is DNA-binding-independent. Transient transfection in STAT6-deficient HEK293 cells, STAT6 point and deletion mutants, reporter assays Journal of biological chemistry High 10982806
2000 IL-4 induces serine phosphorylation of STAT6 specifically within its transactivation domain (residues 719–789), independently of tyrosine phosphorylation at Y641 and independently of the IRS/PI3K, PKC, or MAPK pathways. Phosphoamino acid analysis, 2D phosphopeptide mapping, STAT6 deletion and point mutants in B cells Molecular immunology High 11164892
2000 A gain-of-function STAT6 mutant (STAT6VT) with two SH2 domain amino acid changes undergoes constitutive tyrosine phosphorylation, DNA binding, and transcriptional activation independently of IL-4, via an IL-4-independent kinase. Site-directed mutagenesis, expression in JAK1/JAK3-deficient cells, DNA binding assay, reporter assay Journal of biological chemistry High 10747856
2001 IL-4 and IL-13 inhibit NO production in macrophages via STAT6-dependent upregulation of arginase I, which depletes arginine (the iNOS substrate), rather than by directly inhibiting iNOS expression or activity. STAT6-knockout macrophages, arginase activity assay, arginine supplementation rescue, NO production assay, Toxoplasma killing assay Journal of immunology High 11160269
2001 IL-4-induced STAT6 blocks osteoclastogenesis by inhibiting NF-κB DNA binding; exogenous STAT6 protein directly inhibits NF-κB/DNA interaction, and this blockade is absent in STAT6-/- mice but rescued by exogenous STAT6 addition. STAT6 KO mice, EMSA with unlabeled STAT6 competitor, exogenous protein addition, osteoclastogenesis assay Journal of clinical investigation High 11390419
2001 STAT6 is required for IL-4-induced cytoskeletal changes in B cells (spreading, polarization, microvilli formation) but is less critical for adhesion, indicating STAT6-dependent gene expression regulates cytoskeletal remodeling. STAT6-KO B cells, light and electron microscopy, adhesion assays International immunology Medium 10882411
2002 p100 protein (SN-like/tudor domain) is a coactivator for STAT6 that interacts with STAT6's transactivation domain, enhances STAT6-mediated transcription, and bridges STAT6 to RNA polymerase II. In vitro pulldown, Co-IP in vivo, reporter assays, RNA pol II co-immunoprecipitation EMBO journal High 12234934
2002 Ym1 gene expression in macrophages is induced by IL-4 through STAT6-binding response elements in its promoter; STAT6 participates as an obligate component of protein complexes binding to these sites, confirmed by nuclear extracts from STAT6-deficient macrophages. Microarray, promoter reporter assays, EMSA with STAT6-null nuclear extracts, in vivo allergic peritonitis model Journal of biological chemistry High 12215441
2002 Protein phosphatase 2A (PP2A) regulates STAT6 function: PP2A inhibition induces serine phosphorylation of STAT6 and severely inhibits its DNA binding without affecting JAK1 or tyrosine phosphorylation, placing PP2A downstream of JAKs. PP2A inhibitor treatment, phosphorylation assays, EMSA Journal of biological chemistry Medium 12426308
2006 RNA helicase A (RHA) is a component of the STAT6 transcription complex; it does not directly interact with STAT6 but is recruited via p100 to form a STAT6-p100-RHA ternary complex on IL-4-responsive promoters and enhances IL-4-induced transcription. In vitro and in vivo binding assays, chromatin immunoprecipitation, RNAi knockdown, reporter assay Nucleic acids research High 16914450
2007 CoaSt6 (collaborator of Stat6), a PARP-like protein, associates with STAT6 and possesses poly(ADP-ribosyl)ation activity; its catalytic activity is required for enhancement of STAT6-mediated transcription, and PARP inhibition blocks IL-4-dependent transcription. PARP enzymatic assay, catalytically inactive mutant, PARP chemical inhibitor, reporter assay, ADP-ribosylation of p100 Journal of biological chemistry High 17478423
2007 Kaempferol inhibits IL-4-induced STAT6 activation by specifically blocking the kinase activity of JAK3 (not JAK1), and has no effect in non-hematopoietic cell lines lacking JAK3, confirming JAK3 as the specific target. In vitro kinase assay, phosphorylation analysis, cell lines lacking JAK3 Journal of immunology High 17785825
2010 STAT6 continuously shuttles into the nucleus independently of tyrosine phosphorylation via the coiled-coil domain and the classical importin-α/importin-β1 system; nuclear accumulation occurs after cytokine stimulation due to phosphorylation-dependent DNA binding rather than increased import. Live-cell imaging, FRAP, photobleaching, importin pathway inhibition, domain deletion analysis Journal of immunology High 20498360
2013 STAT6 constitutively associates with mitochondria independently of tyrosine phosphorylation (SH2 domain and Y641); a truncated STAT6 lacking the SH2 domain still accumulates in MitoTracker-positive mitochondria. Live-cell imaging, immunofluorescence, electron microscopy, GFP fusion constructs, digitonin fractionation PLoS ONE Medium 23383189
2014 Grail (an E3 ubiquitin ligase) interacts with STAT6 and targets it for ubiquitination and proteasomal degradation, forming a negative feedback loop in Th2 cells that limits IL-4 receptor α and STAT6 levels. Co-IP, ubiquitination assay, Grail-KO mice, Th2 cell functional assays Nature communications High 25145352
2016 Crystal structure of phosphorylated STAT6 core fragment homodimer bound to N3 and N4 DNA reveals a dramatic conformational change upon DNA binding; H415 in the DNA-binding domain discriminates N4 from N3 sites, and H415N mutation decreases N4 affinity and increases N3 affinity both in vitro and in vivo. X-ray crystallography, molecular dynamics simulation, SAXS, mutagenesis, in vitro and in vivo DNA binding assays PNAS High 27803324
2017 NCOA1 (nuclear receptor coactivator 1) is required for STAT6 transcriptional activity; a stapled helical peptide disrupts the NCOA1/STAT6 protein-protein interaction and represses STAT6-mediated transcription, with first crystal structure of stapled peptide-NCOA1 complex solved. Stapled peptide design, crystal structure of peptide-NCOA1 complex, reporter assay, Co-IP disruption Journal of the American Chemical Society High 29090910
2018 IL-4-activated STAT6 directly represses inflammatory enhancers through an HDAC3-dependent mechanism on a subset of genes, reducing p300 and RNA Pol II binding, enhancer RNA expression, H3K27ac, and chromatin accessibility; STAT6-repressed enhancers overlap with the NF-κB p65 cistrome and exhibit decreased LPS responsiveness. ChIP-seq, ATAC-seq, RNA-seq in macrophages, HDAC3 inhibition, STAT6-KO mice, in vitro/in vivo IL-4 polarization Immunity High 29343442
2019 STAT6 is acetylated at Lys383 by CBP during macrophage activation; Trim24 (a CBP-associated E3 ligase) promotes STAT6 acetylation by ubiquitinating CBP at Lys119 to facilitate CBP recruitment to STAT6. Acetylation of STAT6 suppresses M2 polarization; Trim24 loss inhibits acetylation and promotes M2 polarization. Mass spectrometry identification of acetylation site, Co-IP, ubiquitination assay, Trim24 KO mice, human/mouse macrophage assays Nature communications High 31554795
2019 STAT6 activation in macrophages induces expression of the efferocytic ligand Gas6, which mediates clearance of apoptotic neutrophils; Gas6-depleted macrophages fail to clear apoptotic cells, and adoptive transfer of Gas6-expressing macrophages rescues efferocytosis in STAT6-KO mice. STAT6-KO mice, adoptive transfer, in vitro efferocytosis assay, bone marrow-derived macrophage priming PNAS High 31363052
2020 TRAF6 stabilizes STAT6 protein by reducing K48-linked ubiquitination that would otherwise lead to proteasomal degradation; TRAF6 promotes K63-linked ubiquitination of STAT6 but this E3 ligase activity is dispensable for STAT6 stabilization, while TRAF6-STAT6 interaction requires the TRAF6 C domain. Co-IP, ubiquitination assay, TRAF6 KO/KD macrophages, STAT6 protein stability assay Molecular immunology High 33017719
2023 TRAF3 promotes STAT6 ubiquitination at K450 (and K129) to enhance its transcriptional activity and M2 macrophage polarization; TRAF3 deficiency decreases STAT6 ubiquitination and abolishes IL-4-induced M2 polarization. Quantitative ubiquitomics (MS), site-directed mutagenesis (K450 mutation), ubiquitination assay, luciferase assay, TRAF3-KO mice melanoma model Cell death and differentiation High 37474750
2022 STAT6 inhibits ferroptosis in lung epithelial cells by competitively binding to CBP, thereby inhibiting CBP-mediated acetylation of p53 and transcriptionally restoring SLC7A11 (a ferroptosis suppressor) expression. STAT6 conditional KO mice, STAT6 overexpression, Co-IP (STAT6-CBP), p53 acetylation assay, SLC7A11 expression analysis Cell death and disease High 35668064
2001 Stat6 is required for Th2-mediated intestinal goblet cell hyperplasia during nematode infection; STAT6-deficient mice fail to generate infection-induced goblet cell hyperplasia, correlating with impaired IL-4/IL-13 production and reduced parasite expulsion. STAT6-KO mice, parasite infection model, goblet cell quantification Parasite immunology Medium 11136476
2001 A peptide derived from the STAT6-binding region of IL-4Rα, when delivered intracellularly, completely inhibits IL-4-dependent tyrosine phosphorylation of STAT6 and STAT6-dependent transcription, without affecting STAT5 phosphorylation. Cell-permeable peptide delivery, phosphorylation assay, reporter gene assay European journal of biochemistry Medium 11532018
2016 STAT3 and STAT6 synergize to upregulate cathepsin secretion by macrophages via engagement of IRE1α (UPR sensor); pharmacological inhibition of IRE1α blocks cathepsin secretion and macrophage-mediated cancer cell invasion. Whole-genome expression analysis, IRE1α pharmacological inhibition, STAT3/STAT6 genetic deletion, invasion assay Cell reports High 27626662
2014 B-cell-intrinsic STAT6 signaling is required for germinal center formation; STAT6 deficiency in B cells results in failure to downregulate the chemotactic receptor Gpr183/Ebi2, which is essential for proper GC B-cell positioning and differentiation. Conditional B-cell STAT6 deficiency (BM chimeras), helminth infection model, flow cytometry, GC B-cell analysis European journal of immunology High 24777733
2007 STAT6 mediates IL-4/IL-13-induced downregulation of skin barrier proteins loricrin and involucrin in keratinocytes; STAT6 transgenic mice are deficient in loricrin and involucrin expression. Primary keratinocyte cultures, siRNA/transgenic mouse model, gene/protein expression analysis Clinical immunology Medium 18166499
2023 Germline gain-of-function STAT6 mutation (E372K in DNA-binding domain) augments both basal and cytokine-induced STAT6 phosphorylation, causes preferential nuclear localization, and drives severe allergic disease; JAK1/2 inhibitor ruxolitinib reverses STAT6 hyperresponsiveness. Whole-exome sequencing, EMSA, luciferase assay, Western blot, immunofluorescence, JAK inhibitor treatment, gastric organoids Journal of allergy and clinical immunology High 36758835
2022 Germline STAT6 gain-of-function variant (E377K in DNA-binding domain) results in spontaneous STAT6 transcriptional activity, strong preference for nuclear localization, increased DNA binding affinity, and constitutive activation of downstream signaling in gastric organoids. Exome sequencing, EMSA, luciferase assay, immunofluorescence, gastric organoids, Western blot Journal of allergy and clinical immunology High 36216080
2015 IL-4-induced STAT6 and KLF4 implement M2 macrophage polarization via induction of MCPIP, which inhibits NF-κB activation (deubiquitinase activity) and drives M2 polarization through its RNase activity causing sequential ROS, ER stress, and autophagy induction. Murine macrophages, myeloid-specific MCPIP overexpression/KO mice, M1/M2 polarization assays Journal of immunology High 25934862
2000 STAT6 NF-κB inhibition involves inhibition of IκBα phosphorylation and degradation (blocking NF-κB nuclear import), while glucocorticoid receptor acts by increasing p65 nuclear export rate; STAT6 and GR thus inhibit NF-κB by distinct mechanisms. Fluorescent fusion protein live imaging, NF-κB reporter assay, IκBα phosphorylation assay Journal of cell science High 12734399
2017 Lyn kinase negatively regulates IL-4/IL-13-induced STAT6 activation and MUC5AC expression; Lyn overexpression decreases STAT6 phosphorylation and chromatin binding to the MUC5AC promoter, while Lyn knockdown increases STAT6 and MUC5AC levels. Chromatin immunoprecipitation, overexpression/knockdown in cells and OVA-challenged mice, STAT6 phosphorylation assay Scientific reports Medium 28205598
2020 IL-4 stimulates lipogenesis in meibomian gland epithelial cells through a STAT6/PPARγ signaling pathway; STAT6 phosphorylation inhibition suppresses IL-4-mediated lipid synthesis and PPARγ/SREBP-1 expression. IL-4 treatment with STAT6 inhibitor, Western blot, lipid staining, HGMEC culture Ocular surface Medium 32360783
2022 Gain-of-function STAT6 mutations in follicular lymphoma (DNA-binding domain) enhance IL-4-induced transcription at the PARP14 promoter; STAT6MUT binds PARP14 promoter (not STAT6WT by ChIP), creating a self-reinforcing circuit; PARP14 knockdown or PARP inhibition abrogates the STAT6MUT gain-of-function phenotype. qChIP, reporter assay, RNA-seq, CRISPR KD, PARP inhibitor treatment, pre-B CFU assay Leukemia High 35851155

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Essential role of Stat6 in IL-4 signalling. Nature 1237 8602263
2013 Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 568 24030747
2007 Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clinical immunology (Orlando, Fla.) 415 18166499
2019 Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24. Nature communications 293 31554795
2006 Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine & growth factor reviews 248 16540365
2019 STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice. JCI insight 244 31619589
2001 Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. Journal of immunology (Baltimore, Md. : 1950) 238 11160269
2000 The biology of Stat4 and Stat6. Oncogene 231 10851056
2018 The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages. Immunity 203 29343442
1996 Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 183 8871614
2002 TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. The Journal of biological chemistry 179 12215441
2022 STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway. Cell death & disease 158 35668064
2001 IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB. The Journal of clinical investigation 157 11390419
2016 STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation. Cell reports 156 27626662
2015 Extensive survey of STAT6 expression in a large series of mesenchymal tumors. American journal of clinical pathology 156 25873501
2015 Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. Journal of immunology (Baltimore, Md. : 1950) 154 25934862
2002 Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II. The EMBO journal 146 12234934
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 113 31363052
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 106 10373589
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
2001 Stat6 dependent goblet cell hyperplasia during intestinal nematode infection. Parasite immunology 91 11136476
2000 Interleukin-4/STAT6 represses STAT1 and NF-kappa B-dependent transcription through distinct mechanisms. The Journal of biological chemistry 90 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 80 33991851
2007 Collaborator of Stat6 (CoaSt6)-associated poly(ADP-ribose) polymerase activity modulates Stat6-dependent gene transcription. The Journal of biological chemistry 77 17478423
2016 IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics. Scientific reports 72 27113293
2013 STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines. Journal of immunology (Baltimore, Md. : 1950) 72 23303670
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
2015 Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis. Breast cancer research : BCR 71 26208975
2014 Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infection and immunity 70 25287927
2023 TRAF3/STAT6 axis regulates macrophage polarization and tumor progression. Cell death and differentiation 67 37474750
2017 PVT1-derived miR-1207-5p promotes breast cancer cell growth by targeting STAT6. Cancer science 66 28235236
2003 NF-kappaB signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms. Journal of cell science 66 12734399
2009 Small interfering RNA against transcription factor STAT6 inhibits allergic airway inflammation and hyperreactivity in mice. Journal of immunology (Baltimore, Md. : 1950) 62 19494273
2002 STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. Neoplasia (New York, N.Y.) 62 12082548
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
2005 The role of constitutively active Stat6 in leukemia and lymphoma. Critical reviews in oncology/hematology 58 16213149
1999 IL-13 activates STAT6 and inhibits liver injury induced by ischemia/reperfusion. The American journal of pathology 58 10514388
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
1998 Mice with STAT6-targeted gene disruption develop a Th1 response and control cutaneous leishmaniasis. Journal of immunology (Baltimore, Md. : 1950) 56 9834104
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 51 36758835
1998 Mutational analysis of the STAT6 SH2 domain. The Journal of biological chemistry 49 9651359
1997 Identification of a STAT6 domain required for IL-4-induced activation of transcription. Journal of immunology (Baltimore, Md. : 1950) 49 9233621
2021 Clinical and molecular implications of NAB2-STAT6 fusion variants in solitary fibrous tumour. Pathology 48 33745702
2000 IL-4 induces serine phosphorylation of the STAT6 transactivation domain in B lymphocytes. Molecular immunology 48 11164892
2014 Grail controls Th2 cell development by targeting STAT6 for degradation. Nature communications 47 25145352
2013 TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway. PloS one 47 23844087
2001 STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia. The Journal of clinical investigation 47 11714739
2022 A germline STAT6 gain-of-function variant is associated with early-onset allergies. The Journal of allergy and clinical immunology 46 36216080
2008 IL-4 is a critical determinant in the generation of allergic inflammation initiated by a constitutively active Stat6. Journal of immunology (Baltimore, Md. : 1950) 46 18292582
2023 IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation. JCI insight 42 36757802
2017 Lyn regulates mucus secretion and MUC5AC via the STAT6 signaling pathway during allergic airway inflammation. Scientific reports 42 28205598
2017 Lack of STAT6 Attenuates Inflammation and Drives Protection against Early Steps of Colitis-Associated Colon Cancer. Cancer immunology research 42 28385737
2017 Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner. Leukemia 42 28819278
2019 Analysis of IL-4/STAT6 Signaling in Macrophages. Methods in molecular biology (Clifton, N.J.) 41 31041750
2009 Polymorphisms in the STAT6 gene and their association with carcass traits in feedlot cattle. Animal genetics 41 19519791
2001 Binding of BAZF and Bc16 to STAT6-binding DNA sequences. Biochemical and biophysical research communications 39 11374866
2011 Interleukin-4 inhibits RANKL-induced NFATc1 expression via STAT6: a novel mechanism mediating its blockade of osteoclastogenesis. Journal of cellular biochemistry 37 21751242
2019 IL-37 attenuates allergic process via STAT6/STAT3 pathways in murine allergic rhinitis. International immunopharmacology 36 30665041
2011 STAT6 expression in multiple cell types mediates the cooperative development of allergic airway disease. Journal of immunology (Baltimore, Md. : 1950) 36 21242523
1998 Stat6 inhibits human interleukin-4 promoter activity in T cells. Blood 36 9845517
2023 Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma. Journal of clinical immunology 34 37316763
1999 STAT6-independent production of IL-4 by mast cells. European journal of immunology 34 10229091
2000 Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance. Journal of immunology (Baltimore, Md. : 1950) 33 11067913
2023 Efferocytosis is restricted by axon guidance molecule EphA4 via ERK/Stat6/MERTK signaling following brain injury. Journal of neuroinflammation 30 37941008
2021 STAT6 Signaling Mediates PPARγ Activation and Resolution of Acute Sterile Inflammation in Mice. Cells 30 33652833
2010 Live cell imaging reveals continuous STAT6 nuclear trafficking. Journal of immunology (Baltimore, Md. : 1950) 30 20498360
2020 TRPM7 modulates macrophage polarization by STAT1/STAT6 pathways in RAW264.7 cells. Biochemical and biophysical research communications 29 33153718
2008 IL-13 attenuates vascular tube formation via JAK2-STAT6 pathway. Circulation journal : official journal of the Japanese Circulation Society 29 18296848
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
1999 IL-4 preferentially activates a novel STAT6 isoform in mast cells. Journal of immunology (Baltimore, Md. : 1950) 29 10072514
2018 Hierarchical control of interleukin 13 (IL-13) signals in lung fibroblasts by STAT6 and SOX11. The Journal of biological chemistry 28 30076218
2022 Curcumin Reprograms TAMs from a Protumor Phenotype towards an Antitumor Phenotype via Inhibiting MAO-A/STAT6 Pathway. Cells 27 36359867
2011 Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis. Allergy 27 20608912
2020 TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6. Molecular immunology 26 33017719
2018 MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6. Oncology letters 26 30675252
2004 Interleukin-4 elicits apoptosis of developing mast cells via a Stat6-dependent mitochondrial pathway. Experimental hematology 26 14725901
2024 STAT4 and STAT6, their role in cellular and humoral immunity and in diverse human diseases. International reviews of immunology 25 39188021
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
2017 Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction. Journal of the American Chemical Society 25 29090910
2021 Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6. American journal of respiratory cell and molecular biology 24 33264064
2011 Transcriptional activation of the IL31 gene by NFAT and STAT6. Journal of leukocyte biology 24 22045870
2016 Zebrafish STAT6 negatively regulates IFNφ1 production by attenuating the kinase activity of TANK-binding kinase 1. Developmental and comparative immunology 23 27743998
2011 Association of ORMDL3, STAT6 and TBXA2R gene polymorphisms with asthma. International journal of immunogenetics 23 22017802
2000 STAT6 is required for the regulation of IL-4-induced cytoskeletal events in B cells. International immunology 23 10882411
2024 S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke. CNS neuroscience & therapeutics 22 39107960
2024 Irisin reprograms microglia through activation of STAT6 and prevents cognitive dysfunction after surgery in mice. Brain, behavior, and immunity 22 39701329
2013 Live-cell imaging of the association of STAT6-GFP with mitochondria. PloS one 22 23383189
2018 Inhibition of STAT6/Anoctamin-1 Activation Suppresses Proliferation and Invasion of Gastric Cancer Cells. Cancer biotherapy & radiopharmaceuticals 21 29466035
2001 Specific inhibition of interleukin-4-dependent Stat6 activation by an intracellularly delivered peptide. European journal of biochemistry 21 11532018
1998 A conditionally active form of STAT6 can mimic certain effects of IL-4. Journal of immunology (Baltimore, Md. : 1950) 21 9686563
2022 PARP14 is a novel target in STAT6 mutant follicular lymphoma. Leukemia 20 35851155