Affinage

STAT3

Signal transducer and activator of transcription 3 · UniProt P40763

Round 2 corrected
Length
770 aa
Mass
88.1 kDa
Annotated
2026-04-28
130 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT3 is a latent cytoplasmic transcription factor that integrates signals from diverse cytokine and growth factor receptors to regulate gene expression programs controlling cell growth, differentiation, immune homeostasis, and metabolism. It is activated by JAK-mediated tyrosine phosphorylation at Y705 downstream of gp130-family cytokines (IL-6, LIF, OSM, CNTF), growth hormone, EGF, TPO/c-Mpl, TrkA, and the PI3K/BMX axis; upon activation it dimerizes, transits through an endocytic-pathway-dependent route to the nucleus, and directly binds promoters of target genes including VEGF, p53, hepcidin, S1PR1, and OPA1, while its nuclear residence is dynamically regulated by multiple CRM1-dependent nuclear export signals (PMID:7512451, PMID:8140422, PMID:16407171, PMID:12588893, PMID:11960372, PMID:16107692, PMID:16835372, PMID:21102457, PMID:28637784). Beyond canonical tyrosine-phosphorylation-dependent transcription, STAT3 activity is tuned by serine/threonine phosphorylation (GSK-3α/β at Thr714/Ser727; Cdk2), lysine acetylation by p300 enabling supercomplex formation with NF-κB/RelA, S-glutathionylation at Cys328/Cys542 that impairs JAK2-mediated activation, and deacetylation by HDAC7, as well as by transcriptional co-regulators including KAP1, KLF4, PIAS3, Daxx, and TRIM59 (PMID:24615012, PMID:24941337, PMID:28637784, PMID:29126425, PMID:24129709, PMID:29386185). STAT3 also functions outside the nucleus: unphosphorylated cytoplasmic STAT3 promotes microtubule polymerization and cell migration via stathmin, and mitochondrial STAT3 (imported via GRIM-19) associates with TFAM to regulate mitochondrial gene expression and oxidative phosphorylation (PMID:16835434, PMID:32165236). Dominant-negative loss-of-function mutations in STAT3 cause autosomal-dominant hyper-IgE syndrome (Job's syndrome), whereas constitutive STAT3 activation—achieved by engineered SH2-domain cysteine substitutions or via a S1PR1-JAK2 positive feedback loop—is sufficient to drive cellular transformation and tumor angiogenesis (PMID:17881745, PMID:10458605, PMID:21102457).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Identification of STAT3 as a distinct STAT family member activated specifically by gp130-utilizing cytokines and EGF—but not IFN-γ—established the principle that differential STAT activation encodes cytokine signaling specificity.

    Evidence Molecular cloning, tyrosine phosphorylation assays, EMSA, and receptor stimulation experiments in multiple cell types

    PMID:7512451 PMID:8140422

    Open questions at the time
    • Mechanism by which receptor selectivity is achieved at the molecular level was not resolved
    • Physiological gene targets were unknown
  2. 1994 High

    Demonstration that JAK kinases (Jak1, Jak2, Tyk2) constitutively associate with gp130/LIFR and are activated upon receptor dimerization placed JAKs as the obligate upstream kinases for STAT3 tyrosine phosphorylation.

    Evidence Co-immunoprecipitation and kinase activation assays with gp130/LIFR receptor components

    PMID:8272873

    Open questions at the time
    • Whether additional non-JAK kinases could phosphorylate STAT3 Y705 was unresolved
    • Direct JAK-STAT3 substrate relationship not yet shown by in vitro kinase assay
  3. 1995 Medium

    Discovery that IL-6 induces a delayed serine phosphorylation of STAT3 required for full transcriptional activity, and that GH and TPO also activate STAT3, broadened the receptor repertoire and established dual phosphorylation (tyrosine + serine) as necessary for maximal STAT3 function.

    Evidence Phosphatase treatment, kinase inhibitor studies, promoter-reporter assays (IL-6); IP/EMSA (GH, TPO)

    PMID:7533107 PMID:7544303 PMID:7876144

    Open questions at the time
    • Identity of the serine kinase was unknown
    • Functional contribution of serine phosphorylation versus tyrosine phosphorylation was not dissected in vivo
  4. 1999 High

    Engineering of constitutively active Stat3-C (SH2-domain cysteine substitutions) proved that persistent STAT3 dimerization and DNA binding are sufficient for oncogenic transformation, establishing STAT3 as a bona fide oncoprotein.

    Evidence Site-directed mutagenesis, soft agar colony formation, nude mouse tumor assays

    PMID:10458605

    Open questions at the time
    • Which endogenous target genes mediate transformation was unknown
    • Whether constitutive STAT3 activation occurs in human cancers was not yet shown in this study
  5. 2002 High

    ChIP demonstration that STAT3 directly binds the VEGF promoter to drive tumor angiogenesis provided the first identified direct transcriptional target linking STAT3 to tumor vascularization.

    Evidence Chromatin immunoprecipitation, site-specific promoter mutagenesis, dominant-negative STAT3

    PMID:11960372

    Open questions at the time
    • Whether VEGF is the primary angiogenic mediator of STAT3 or one of many was unclear
    • Relative contribution of STAT3-driven VEGF versus other pro-angiogenic pathways not dissected
  6. 2003 High

    Mapping of multiple CRM1-dependent nuclear export signals in STAT3 and the discovery of a tyrosine-phosphorylation-independent 'basal' nuclear signaling pathway revealed that STAT3 nuclear-cytoplasmic trafficking is not a simple on/off switch but a continuously regulated process.

    Evidence NES mutagenesis, leptomycin B treatment, nuclear/cytoplasmic fractionation, immunofluorescence

    PMID:12588893

    Open questions at the time
    • Nuclear import mechanism for unphosphorylated STAT3 was not identified
    • Functional consequences of basal nuclear STAT3 on specific gene targets were not defined
  7. 2003 Medium

    Identification of Tip60/HDAC7 as a STAT3 co-repressor complex, and Cdk2 as a negative regulator of STAT3 phosphorylation, revealed that STAT3 transcriptional output is modulated by chromatin-modifying and cell-cycle machinery.

    Evidence Co-immunoprecipitation, reporter assays, Cdk2 pharmacological/genetic inhibition, EMSA

    PMID:12551922 PMID:12789269

    Open questions at the time
    • Direct deacetylation of STAT3 by the Tip60/HDAC7 complex was not biochemically demonstrated at this time
    • Whether Cdk2 directly phosphorylates STAT3 or acts indirectly was unresolved
  8. 2005 High

    STAT3 was shown to directly repress the p53 promoter and to require an endocytic pathway for productive signaling, expanding the functional repertoire of STAT3 to include tumor suppressor gene silencing and revealing an unexpected requirement for membrane trafficking.

    Evidence ChIP and promoter mutagenesis (p53); cell fractionation, electron microscopy, dominant-negative dynamin/epsin (endocytic pathway)

    PMID:16107692 PMID:16407171

    Open questions at the time
    • How endosomal association facilitates STAT3 nuclear import was mechanistically undefined
    • Relative contribution of p53 repression versus oncogene activation in STAT3-driven tumors was not established
  9. 2006 Medium

    Discovery that unphosphorylated cytoplasmic STAT3 promotes microtubule polymerization through stathmin binding, and that STAT3 is activated by NGF/TrkA via Ser727 phosphorylation for neuronal function, demonstrated non-canonical, non-transcriptional STAT3 roles.

    Evidence Co-immunoprecipitation, microtubule polymerization and migration assays (stathmin); RNAi, neurite outgrowth assays (TrkA/NGF)

    PMID:16611639 PMID:16835434

    Open questions at the time
    • Structural basis of STAT3-stathmin interaction was not resolved
    • Whether cytoplasmic STAT3-stathmin function is relevant in vivo remained untested
  10. 2006 High

    Identification of hepcidin as a direct STAT3 transcriptional target established STAT3 as the obligate mediator of inflammation-induced iron homeostasis regulation.

    Evidence ChIP, gain/loss-of-function STAT3 constructs, promoter-reporter assays

    PMID:16835372

    Open questions at the time
    • Whether STAT3-independent pathways contribute to IL-6-driven hepcidin induction was not excluded
  11. 2007 High

    Identification of dominant-negative STAT3 mutations as the cause of hyper-IgE syndrome (Job's syndrome) established STAT3 as essential for human immune function and linked its loss of function to a primary immunodeficiency.

    Evidence Patient mutation sequencing, cytokine stimulation assays, gene expression profiling in patient cells across a large cohort

    PMID:17881745

    Open questions at the time
    • Which specific STAT3 target genes account for the immunological phenotype was not delineated
    • Genotype-phenotype correlation across different mutation classes was incomplete
  12. 2010 High

    The S1PR1-STAT3 positive feedback loop (STAT3 transcribes S1PR1; S1PR1 reactivates STAT3 via JAK2) explained how STAT3 activation persists in tumors and the tumor microenvironment, while STAT3 was also shown to reprogram cell metabolism toward aerobic glycolysis via HIF-1α.

    Evidence ChIP, siRNA, kinase assays, in vivo tumor models (S1PR1 loop); metabolic flux assays, HIF-1α manipulation (metabolism)

    PMID:21084727 PMID:21102457

    Open questions at the time
    • Whether the S1PR1 loop operates in all STAT3-activated cancers was unknown
    • Direct mitochondrial versus transcriptional mechanism for STAT3-mediated metabolic reprogramming was not fully dissected
  13. 2013 High

    KLF4 was identified as a phospho-STAT3-specific inhibitor whose deletion in vivo activates JAK-STAT3 signaling and promotes axon regeneration, while C/EBPβ and STAT3 were identified as synergistic master regulators of mesenchymal transformation in glioma.

    Evidence Co-IP, DNA-binding assays, conditional KLF4 knockout with axon regeneration (KLF4); transcriptional network inference, gain/loss-of-function, in vivo tumor models (C/EBPβ-STAT3)

    PMID:20032975 PMID:24129709

    Open questions at the time
    • How KLF4 selectively targets phospho-STAT3 structurally was not resolved
    • Whether STAT3/C/EBPβ co-regulation generalizes beyond glioma mesenchymal subtype was unknown
  14. 2014 High

    Discovery of GSK-3α/β-mediated dual Thr714/Ser727 phosphorylation (a Y705-independent phosphoform) and S-glutathionylation at Cys328/Cys542 revealed that STAT3 integrates metabolic kinase and redox signals through noncanonical post-translational modifications.

    Evidence Quantitative LC-MS/MS, site-directed mutagenesis, GSK-3 depletion, reporter assays (GSK-3); recombinant biochemistry, mass spectrometry, in vitro kinase assays (glutathionylation)

    PMID:24615012 PMID:24941337

    Open questions at the time
    • In vivo significance of the Thr714/Ser727 phosphoform beyond renal cell carcinoma was not established
    • Whether S-glutathionylation is reversible in cells under physiological oxidative stress was not shown
  15. 2017 High

    HDAC7 was shown to directly deacetylate STAT3, inhibiting its tyrosine phosphorylation and lung tumorigenesis, while p300-mediated acetylation at Lys370/383 enables a STAT3/RelA supercomplex that transcribes OPA1 to promote mitochondrial fusion, together demonstrating that lysine acetylation is a master switch toggling STAT3 between transcriptional programs.

    Evidence Pull-down, Co-IP, acetylation assays, dnStat3 rescue, in vivo lung cancer model (HDAC7); Co-IP, ChIP, mutagenesis, in vivo cardiac model (p300/RelA)

    PMID:28637784 PMID:29126425

    Open questions at the time
    • The full acetylation-dependent STAT3 interactome was not mapped
    • Whether HDAC7 and p300 act on the same pool of STAT3 or distinct subcellular pools was unresolved
  16. 2018 High

    ZNF341 was identified as a transcription factor controlling STAT3 expression itself, with loss-of-function ZNF341 mutations causing a hyper-IgE-like immunodeficiency by reducing STAT3 levels; concurrently, TRIM59 was shown to maintain nuclear STAT3 phosphorylation by shielding it from TC45 phosphatase.

    Evidence Promoter binding/reporter assays, patient genetics, functional complementation (ZNF341); Co-IP, phosphatase assays, xenograft models (TRIM59)

    PMID:29386185 PMID:29907690

    Open questions at the time
    • Whether other transcription factors cooperate with ZNF341 at the STAT3 promoter was unknown
    • Specificity of TRIM59 for STAT3 versus other STATs was not addressed
  17. 2020 Medium

    Mitochondrial STAT3 (imported via GRIM-19) was shown to bind TFAM and mitochondrial DNA, negatively regulating mitochondrial-encoded gene expression and oxidative phosphorylation, defining a direct transcriptional role for STAT3 in the mitochondrial compartment.

    Evidence GRIM-19 knockout, Co-IP of mitoSTAT3/TFAM, mitochondrial respiratory assays, xenograft models

    PMID:32165236

    Open questions at the time
    • Whether mitoSTAT3 has sequence-specific DNA-binding activity on mtDNA was not demonstrated
    • Stoichiometry and dynamics of mitochondrial import of STAT3 under physiological conditions were not characterized
  18. 2023 High

    A STAT3 Y705F knockin mouse model demonstrated that early virus-triggered STAT3 Y705 phosphorylation (via RIG-I/MAVS/Syk, independent of IL-6) restrains excessive type I/III IFN production; genetic epistasis with IFNAR1/IFNLR1 knockout confirmed STAT3 as a critical negative regulator of antiviral interferon responses.

    Evidence STAT3 Y705F knockin mice, multiple viral infection models, genetic epistasis, gene expression profiling

    PMID:37440406

    Open questions at the time
    • Direct transcriptional targets of STAT3 that suppress IFN production were not identified
    • Whether this IL-6-independent STAT3 activation mechanism operates in non-pulmonary tissues was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for STAT3's differential engagement with its many co-regulators, the full scope and regulation of mitochondrial STAT3 function, and how the multiple noncanonical post-translational modifications (acetylation, glutathionylation, Thr714 phosphorylation) are integrated in single cells to determine transcriptional output.
  • No high-resolution structure of full-length STAT3 in complex with co-regulators or on DNA
  • Quantitative integration of concurrent PTMs on the same STAT3 molecule has not been achieved
  • In vivo relevance of cytoplasmic STAT3-stathmin axis remains untested with genetic models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 8 GO:0140110 transcription regulator activity 8
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 1
Partners
GRIM19HDAC7JAK1JAK2KLF4RELASTMN1TRIM59
Complex memberships
STAT3/RelA supercomplexTip60/HDAC7/STAT3 co-repressor complexVDR/pSTAT3/TET2 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Stat3 (originally called APRF) is tyrosine-phosphorylated and translocated to the nucleus in response to IL-6, LIF, OSM, and CNTF (gp130-utilizing cytokines), but not IFN-γ; it shares ~52.5% homology with p91/STAT1 and represents a distinct STAT family member activated by the gp130 signaling pathway. Molecular cloning, tyrosine phosphorylation assays, nuclear translocation experiments, DNA-binding assays Cell High 7512451
1994 Stat3 becomes activated (tyrosine-phosphorylated, DNA-binding) in response to EGF and IL-6 but not IFN-γ; it likely forms homodimers and heterodimers with Stat1α, establishing differential STAT activation as a mechanism of signaling specificity. In vitro phosphorylation assays, electrophoretic mobility shift assay (EMSA), receptor stimulation experiments Science High 8140422
1994 JAK family kinases (Jak1, Jak2, Tyk2) constitutively associate with the beta receptor components gp130 and LIFR, and are activated upon ligand-induced dimerization of these receptors, placing JAKs upstream of STAT3 activation in the IL-6/CNTF/LIF/OSM pathway. Co-immunoprecipitation, kinase activation assays, receptor dimerization experiments Science High 8272873
1995 Growth hormone (GH) promotes tyrosine phosphorylation of Stat3 and induces Stat3 DNA-binding to the SIE element of c-fos promoter and the acute phase response element of the α2-macroglobulin promoter, demonstrating that GH activates Stat3 in addition to Stat1. Immunoprecipitation with anti-Stat3 antibodies, tyrosine phosphorylation assays, EMSA with specific promoter elements The Journal of biological chemistry High 7876144
1995 IL-6 induces a delayed serine phosphorylation of STAT3/APRF (reversible by protein phosphatase 2A, blocked by H7) in addition to tyrosine phosphorylation, and this serine phosphorylation is required for IL-6 target gene induction including α2-macroglobulin, Jun-B, and ICAM-1 promoters. Phosphatase treatment, kinase inhibitor studies, promoter-reporter assays FEBS letters Medium 7533107
1995 Thrombopoietin (TPO) induces tyrosine phosphorylation and DNA-binding activity of STAT3 (and STAT5) via its receptor c-Mpl, identifying STAT3 as a downstream effector of TPO signaling in megakaryocyte biology. EMSA, immunoprecipitation, tyrosine phosphorylation assays FEBS letters Medium 7544303
1999 Substitution of two cysteine residues in the SH2 domain C-terminal loop of Stat3 generates a constitutively dimerizing, DNA-binding, transcriptionally active molecule (Stat3-C) that transforms immortalized fibroblasts (soft agar colony formation, tumor formation in nude mice), proving that activated Stat3 alone is sufficient for cellular transformation. Site-directed mutagenesis, soft agar colony assay, nude mouse tumor formation, DNA-binding assays, transcriptional reporter assays Cell High 10458605
2002 Constitutively active Stat3 directly binds to the VEGF promoter in vivo (ChIP assay) and upregulates VEGF expression, stimulating tumor angiogenesis; mutation of the Stat3-binding site in the VEGF promoter abrogates this upregulation, establishing VEGF as a direct Stat3 transcriptional target. Chromatin immunoprecipitation (ChIP), promoter-reporter assays with site-specific mutation, antisense oligonucleotides, dominant-negative Stat3 Oncogene High 11960372
2003 Stat3 nuclear export is regulated by multiple nuclear export signal (NES) elements: NES(306-318) mediates post-stimulation export, while NES(404-414) and NES(524-535) regulate basal nuclear export. LMB treatment reveals a tyrosine-phosphorylation-independent 'basal' signaling pathway that maintains Stat3 nuclear accumulation in resting cells. Leptomycin B treatment, mutagenesis of NES elements, nuclear/cytoplasmic fractionation, immunofluorescence The Journal of clinical investigation High 12588893
2003 Tip60 (histone acetyltransferase) acts as a co-repressor of STAT3 by forming a complex with STAT3 and HDAC7; overexpression of Tip60 represses STAT3-driven transcription in a manner potentiated by HDAC7, and endogenous Tip60 interacts with endogenous STAT3. Co-immunoprecipitation, reporter gene assay (Gal4-fusion), siRNA, overexpression experiments The Journal of biological chemistry Medium 12551922
2003 Cdk2 negatively regulates Stat3 phosphorylation and DNA-binding activity; interference with cdk2 activity upregulates Stat3 phosphorylation, and Stat3 is activated at high cell density (confluence) in a ligand-independent manner that is associated with anti-proliferative conditions. Cdk2 inhibition, EMSA, phosphorylation assays, cell density experiments Oncogene Medium 12789269
2004 ERp57 (protein disulfide isomerase isoform) is a component of STAT3-DNA complexes; anti-ERp57 antibody prevents STAT3 binding to its consensus DNA sequence, indicating ERp57 is a necessary component of DNA-bound STAT3 complexes in melanoma and IL-6-stimulated hepatoma cells. EMSA, DNA affinity experiments, chromatin immunoprecipitation, antibody blocking Biochemical and biophysical research communications Medium 15451439
2004 STRA13 (a bHLH transcription factor) binds preferentially to phosphorylated (active) STAT3α and β isoforms via its HLH and C-terminal regions; STRA13 co-expression with STAT3 modulates transcription of STAT3-target genes including the Fas promoter, with STAT3β co-expression alleviating STRA13-induced apoptosis. Yeast two-hybrid, co-immunoprecipitation, reporter assays, apoptosis assays Journal of molecular biology Medium 15223310
2004 MITF phosphorylation at S409 (via gp130 receptor) causes PIAS3 to dissociate from MITF and associate with STAT3, establishing a regulatory switch where cytokine signaling mobilizes PIAS3 from MITF to STAT3, modulating STAT3-dependent gene expression in mast cells and melanocytes. Co-immunoprecipitation, phosphorylation mapping, receptor stimulation, gene expression analysis in MITF-mutant cells Molecular and cellular biology Medium 15572665
2005 Oncogenic Stat3 binds to the p53 gene promoter in vitro and in vivo, repressing p53 transcription; site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates this repression, and blocking Stat3 in cancer cells upregulates p53 expression and leads to p53-mediated apoptosis. ChIP, promoter-reporter assay with site-specific mutation, antisense oligonucleotides, apoptosis assays Molecular and cellular biology High 16107692
2005 STAT3 associates with early endosomes after IL-6 treatment (up to two-thirds of cytoplasmic tyrosine-phosphorylated STAT3 is endosome-associated within 15–30 min); dominant-negative dynamin, epsin 2a, and amphiphysin A1 inhibit STAT3-driven transcription, implicating the endocytic pathway as necessary for productive IL-6/STAT3 signaling. Cell fractionation, electron microscopy, immunofluorescence, detergent dissection, transcriptional reporter assays with dominant-negative endocytic regulators The Journal of biological chemistry High 16407171
2006 STAT3 is activated downstream of TrkA (NGF receptor) via Ser-727 phosphorylation; knockdown of STAT3 attenuates NGF-induced immediate early gene transcription, suppresses NGF-induced cyclin D1 expression and growth arrest in PC12 cells, and decreases BDNF-promoted neurite outgrowth in hippocampal neurons. RNA interference, phosphorylation assays, gene expression analysis, neurite outgrowth assays The Journal of biological chemistry Medium 16611639
2006 IL-6 directly induces hepcidin expression via STAT3; STAT3 binds to the hepcidin promoter and is necessary and sufficient for IL-6 responsiveness of the hepcidin promoter, establishing STAT3 as the direct mediator of inflammation-induced hepcidin regulation. STAT3 promoter binding assays, dominant-negative and constitutively active STAT3 constructs, promoter-reporter assays, ChIP Blood High 16835372
2006 Non-tyrosine-phosphorylated cytoplasmic STAT3 mediates cell migration by disrupting the interaction between microtubules and stathmin; STAT3 association with stathmin potentiates microtubule polymerization and cell movement. Co-immunoprecipitation, microtubule polymerization assays, cell migration assays Science's STKE Medium 16835434
2007 KAP1/TIF1β physically associates with endogenous STAT3 in vivo; siRNA-mediated reduction of KAP1 enhances IL-6-induced STAT3-dependent transcription and causes marked nuclear accumulation of Ser727-phosphorylated STAT3, identifying KAP1 as a negative transcriptional regulator of the IL-6/STAT3 pathway. Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, siRNA, nuclear fractionation, gene expression analysis Oncogene Medium 18037959
2008 A JAK2/STAT2/STAT3 pathway is required for early myogenic differentiation; interference by small molecule inhibitors or siRNA targeting JAK2, STAT2, or STAT3 inhibits myogenic differentiation; the pro-differentiation effect is partially mediated via MyoD and MEF2, and through regulation of IGF2 and HGF gene expression. siRNA knockdown, small molecule inhibitors, myogenic differentiation assays, gene expression analysis The Journal of biological chemistry Medium 18835816
2009 IκB-ζ (a nuclear protein) physically interacts with STAT3 through its coiled-coil domain (STAT3) and C-terminal region (IκB-ζ); overexpression of IκB-ζ inhibits STAT3 transcriptional activity and suppresses growth/induces apoptosis in Src-stimulated cells, partly by downregulating the STAT3 target MCL1. Yeast two-hybrid, co-immunoprecipitation, domain mapping, reporter assays, apoptosis assays Biochemical and biophysical research communications Medium 19595668
2010 STAT3 is a transcription factor for the S1PR1 (sphingosine-1-phosphate receptor 1) gene; S1PR1 reciprocally activates STAT3 (partly by upregulating JAK2 activity) and upregulates IL-6, creating a positive feedback loop that maintains persistent STAT3 activation in tumor cells and the tumor microenvironment. ChIP, luciferase reporter assays, siRNA silencing, kinase activity assays, in vivo tumor models Nature medicine High 21102457
2010 Constitutively active STAT3 acts as a master regulator of cell metabolism, inducing aerobic glycolysis (via HIF-1α upregulation) and downregulating mitochondrial activity (HIF-1α-independently via downregulation of mitochondrial proteins); inhibition of STAT3 tyrosine phosphorylation downregulates glycolysis prior to causing growth arrest and cell death. Metabolic flux assays, HIF-1α knockdown/overexpression, STAT3 inhibition (in vitro and in vivo xenografts), mitochondrial activity measurements Aging Medium 21084727
2011 STAT3 is phosphorylated on Y705 and activated in a PI3K-dependent manner in PI3K-transformed cells; this phosphorylation is mediated by the TEC kinase BMX; dominant-negative STAT3 interferes with PI3K-induced oncogenic transformation, linking PI3K and STAT3 pathways. Phospho-proteomics, dominant-negative constructs, kinase assays, transformation assays Cancer discovery Medium 22348200
2013 KLF4 physically interacts with STAT3 upon cytokine-induced Y705 phosphorylation, suppressing STAT3-dependent gene expression by blocking its DNA-binding activity; deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells via JAK-STAT3 signaling. Co-immunoprecipitation, DNA-binding assays, in vivo conditional knockout, axon regeneration assays, cytokine treatment Nature communications High 24129709
2013 C/EBPβ and STAT3 are identified as synergistic master regulators of mesenchymal transformation in glioma; ectopic co-expression of C/EBPβ and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage, while elimination of both factors in glioma cells collapses the mesenchymal signature. Transcriptional network reverse-engineering, ectopic co-expression, shRNA knockdown, neural stem cell differentiation assays, in vivo tumor models Nature High 20032975
2014 GSK-3α/β phosphorylates STAT3 simultaneously at Thr714 and Ser727 to create a novel noncanonical phosphoform (independent of Tyr705) that positively regulates target gene expression in response to combined EGFR and PAR-1 signaling in endothelial cells; this doubly phosphorylated STAT3 is markedly elevated in clear-cell renal-cell carcinoma. Quantitative LC-MS/MS, site-directed mutagenesis, GSK-3α/β depletion, transcriptional reporter assays, clinical tissue analysis Molecular and cellular biology High 24615012
2014 S-glutathionylation of STAT3 at Cys328 (DNA-binding domain) and Cys542 (linker domain) under oxidative conditions impairs JAK2-mediated STAT3 tyrosine phosphorylation; site-directed mutagenesis of these cysteines and in vitro kinase assays confirm their role in redox regulation of STAT3. Recombinant protein biochemistry, GSH/diamide treatment, mass spectrometry (mass mapping), site-directed mutagenesis, in vitro kinase assay, DTT reversal ACS chemical biology High 24941337
2017 HDAC7 directly interacts with STAT3, deacetylates it, and thereby inhibits Stat3 tyrosine phosphorylation; HDAC7 mutation/depletion leads to enhanced STAT3 acetylation and tyrosine phosphorylation, promoting lung tumorigenesis; dnStat3 expression reverses the tumor-suppressive effects of HDAC7 loss. Pull-down assay, co-immunoprecipitation, acetylation assays, Western blotting, dnStat3 rescue experiments, in vivo mouse lung cancer model Molecular cancer Medium 29126425
2017 p300-mediated acetylation of Stat3 at Lys370 or Lys383 enables Stat3 to form a supercomplex with RelA (NF-κB); this Stat3/RelA complex synergistically binds the OPA1 promoter to upregulate OPA1 expression at the transcriptional level downstream of TNFR2 activation, promoting mitochondrial fusion in cardiac myocytes. Co-immunoprecipitation, promoter ChIP, luciferase reporter assay, siRNA knockdown, site-directed mutagenesis (Lys370/383), in vivo transverse aortic constriction model Circulation research High 28637784
2018 ZNF341, a zinc finger transcription factor, binds to and activates the STAT3 promoter; loss-of-function mutations in ZNF341 cause reduced STAT3 expression and an autosomal-recessive hyper-IgE-like syndrome, identifying ZNF341 as a transcriptional regulator that controls STAT3 expression levels. Promoter binding assays, luciferase reporter assays, nuclear translocation experiments, patient genetics, functional complementation Science immunology High 29907690
2018 TRIM59 interacts with nuclear STAT3 and prevents its dephosphorylation by the nuclear phosphatase TC45, thereby maintaining STAT3 transcriptional activation and promoting glioblastoma tumorigenesis downstream of EGFR/SOX9 signaling. Co-immunoprecipitation, phosphatase assays, siRNA knockdown, orthotopic xenograft tumor models Cancer research Medium 29386185
2019 PCBP1 binds to an exonic splicing suppressor (ESS) in STAT3 exon 23, promoting alternative splicing that shifts the ratio from oncogenic STAT3α to tumor-suppressive STAT3β isoform; PCBP1 overexpression reduces STAT3α protein expression and inhibits cancer cell growth. Splicing reporter assays, RNA-binding assays, overexpression/knockdown, cell proliferation assays International journal of biological sciences Medium 31223278
2016 HSP110 directly binds to STAT3 and facilitates its phosphorylation by JAK2; HSP110 knockdown reduces STAT3 phosphorylation and nuclear translocation, and STAT3 inhibition blocks the proliferative effect of HSP110 in colorectal cancer cells. Co-immunoprecipitation (direct binding), Western blotting, nuclear translocation assays, STAT3 inhibitor experiments, patient tissue correlation Oncogene Medium 27819670
2022 Vitamin D receptor (VDR) and JAK2-mediated phosphorylated STAT3 form a complex with methylcytosine dioxygenase TET2 specifically upon vitamin D stimulation; pharmacological inhibition of JAK2 reverts vitamin D-induced tolerogenic properties of dendritic cells, establishing a VDR/pSTAT3/TET2 complex as a driver of epigenetic remodeling during DC tolerogenesis. Co-immunoprecipitation, JAK2 inhibitor treatment, DC differentiation assays, gene expression analysis Cell reports Medium 35045292
2023 STAT3 Y705 phosphorylation is activated early during viral infection via the RIG-I/MAVS/Syk axis (independent of IL-6); knockin STAT3Y705F mice show impaired antiviral gene expression, severe lung injury, and poor survival; mechanistically, STAT3 Y705 phosphorylation restrains excessive type I and III IFN production, and IFNAR1/IFNLR1 knockout reverses the phenotype of STAT3Y705F mice. STAT3Y705F knockin mice, viral infection models, gene expression analysis, genetic epistasis (IFNAR1/IFNLR1 knockout), signaling pathway inhibition Cell reports High 37440406
2007 STAT3 mutations in the SH2 and DNA-binding domains underlie sporadic and dominant forms of hyper-IgE syndrome (Job's syndrome); functional characterization shows defective IL-6 signaling through STAT3 in patient cells, with 18 discrete mutations at hot spots, establishing loss-of-function STAT3 mutations as the molecular cause of this primary immunodeficiency. Patient mutation sequencing, cytokine stimulation assays, gene expression profiling in patient cells The New England journal of medicine High 17881745
2019 CPAP (centrosomal P4.1-associated protein) directly binds STAT3 and acts as a transcriptional coactivator, enhancing IL-6-mediated STAT3 activation and upregulating STAT3 target genes (IL-8, CD44); interrupting CPAP-STAT3 interaction attenuates STAT3-mediated tumor growth and angiogenesis. Co-immunoprecipitation (direct binding), reporter assays, siRNA knockdown, in vivo tumor models Cell death and differentiation Medium 31511651
2020 STAT3 inhibition induces mitochondrial translocation of STAT3 (mitoSTAT3) via GRIM-19; mitoSTAT3 associates with mitochondrial transcription factor A (TFAM) and binds mitochondrial DNA (mtDNA), negatively regulating mitochondrial-encoded genes and disrupting oxidative phosphorylation complex activity, leading to apoptosis in TMZ-resistant glioblastoma cells. GRIM-19 knockout, LC-MS/MS subcellular drug localization, co-immunoprecipitation (mitoSTAT3/TFAM), mitochondrial respiratory assays, xenograft models Cellular signalling Medium 32165236
2006 Daxx (a type I IFN-induced protein) physically interacts with STAT3 and co-localizes with it in the nucleus; Daxx overexpression inhibits IL-6/STAT3-mediated transcriptional activation, while siRNA-mediated Daxx knockdown enhances IL-6/LIF-induced STAT3 transcription, identifying Daxx as a negative regulator of STAT3 activity mediating IFN-induced suppression of IL-6/STAT3 signaling. Co-immunoprecipitation, nuclear co-localization (immunofluorescence), siRNA knockdown, reporter gene assays Oncogene Medium 16331268

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2009 STATs in cancer inflammation and immunity: a leading role for STAT3. Nature reviews. Cancer 3543 19851315
2005 Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2780 15864272
1999 Stat3 as an oncogene. Cell 2503 10458605
2018 Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nature reviews. Clinical oncology 2427 29405201
2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature genetics 2108 18587394
2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2101 21833088
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
1994 Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science (New York, N.Y.) 1856 8140422
1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1854 8608603
2014 Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature reviews. Cancer 1769 25342631
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