Affinage

STAT3

Signal transducer and activator of transcription 3 · UniProt P40763

Length
770 aa
Mass
88.1 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/10 claims corpus-supported (90%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT3 is a latent cytoplasmic transcription factor that transduces signals from cytokine and growth factor receptors to the nucleus, where it activates and represses target genes governing proliferation, apoptosis, differentiation, and migration (PMID:8272872, PMID:10458605). It is recruited to the IL-6 signal transducer gp130 together with the Jak1 kinase and undergoes tyrosine phosphorylation within this complex (PMID:8272872), and is similarly activated by growth hormone and HGF/SF through the JAK/STAT pathway, with HGF/SF producing delayed and sustained activation in contrast to the transient IL-6 response (PMID:7876144, PMID:9094433). Productive IL-6/STAT3 signaling further requires endocytic trafficking, as tyrosine-phosphorylated STAT3 associates with early endosomes and transcriptional output depends on intact clathrin/dynamin-mediated endocytosis (PMID:16407171). Nuclear residence is controlled by multiple CRM1-dependent nuclear export signals, including a post-stimulation NES and basal NES elements that export even unphosphorylated STAT3 (PMID:12588893). Beyond canonical Tyr705 phosphorylation, STAT3 activity is tuned by Ser727 phosphorylation by ZIP kinase, which enhances transcription (PMID:16219639), and by a noncanonical dual Thr714/Ser727 phosphorylation by GSK-3α/β that drives gene induction independently of Tyr705 upon EGFR/PAR-1 co-activation (PMID:24615012). As a sequence-specific factor STAT3 represses the p53 promoter to restrain apoptosis (PMID:16107692) and transcriptionally activates S1PR1 in a feed-forward loop with IL-6/JAK2 that sustains persistent activation in tumors (PMID:21102457). Its output is constrained by corepressors that physically associate with STAT3, including Tip60/HDAC7 and KAP1/TIF1β (PMID:12551922, PMID:18037959). STAT3 also acts through non-transcriptional and protein-protein routes: cytoplasmic unphosphorylated STAT3 binds stathmin to promote microtubule polymerization and cell migration (PMID:16835434), and activated STAT3 binds Smad3 to disrupt Smad3-Smad4 complex formation and antagonize TGF-β signaling (PMID:26616859). STAT3 expression itself is directly driven by the zinc-finger transcription factor ZNF341, whose loss-of-function causes an autosomal-dominant hyper-IgE syndrome-like immunodeficiency (PMID:29907690). In vivo, STAT3 is required for physiological epithelial apoptosis during mammary gland involution (PMID:10959419) and for restraining excessive type I/III interferon production during influenza A infection (PMID:37440406).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 High

    Established how STAT3 is activated, by showing it physically engages the gp130 receptor and Jak1 kinase upon IL-6-family cytokine stimulation and is tyrosine-phosphorylated in that complex.

    Evidence Reciprocal Co-IP of endogenous proteins, tyrosine phosphorylation and DNA-binding assays across cytokines/cell types

    PMID:8272872

    Open questions at the time
    • Did not resolve the phosphorylation site stoichiometry or dimer geometry
    • Did not address receptors beyond the IL-6 family
  2. 1995 Medium

    Extended the activation repertoire beyond cytokines by showing growth hormone tyrosine-phosphorylates STAT3 to enable DNA binding at SIE and APRE elements.

    Evidence Anti-STAT3 immunoprecipitation, tyrosine phosphorylation assay, gel-shift DNA binding

    PMID:7876144

    Open questions at the time
    • Did not identify the kinase coupling GH receptor to STAT3
    • Single-lab DNA-binding inference of in vivo target occupancy
  3. 1997 Medium

    Showed that signal duration is ligand-encoded, with HGF/SF producing delayed sustained STAT3 activation versus transient IL-6 activation in hepatocytes.

    Evidence Kinetic transcription factor activation assays in primary hepatocytes and HepG2 cells

    PMID:9094433

    Open questions at the time
    • Mechanism generating sustained versus transient kinetics not defined
    • Downstream target genes distinguishing the two kinetics not identified
  4. 1999 High

    Demonstrated that constitutive STAT3 activity is by itself oncogenic, establishing causality between STAT3 activation and transformation.

    Evidence SH2-domain cysteine substitution (Stat3-C), dimerization/DNA-binding/reporter assays, soft agar and nude mouse xenograft

    PMID:10458605

    Open questions at the time
    • Did not enumerate the transformation-driving target genes
    • Engineered mutant rather than naturally occurring tumor lesion
  5. 2000 High

    Defined a physiological in vivo requirement for STAT3 in tissue remodeling, showing it initiates epithelial apoptosis during mammary involution.

    Evidence Mammary-epithelium-specific lox/Cre conditional knockout, involution and apoptosis assays

    PMID:10959419

    Open questions at the time
    • Pro-apoptotic effector genes downstream of STAT3 in involution not fully resolved
    • Tissue-specific finding may not generalize
  6. 2002 High

    Placed STAT3 in developmental morphogenesis, showing maternal Wnt/beta-catenin activates Stat3 to drive gastrulation cell movements without altering fate.

    Evidence Dominant-negative Stat3, cell tracing, transplantation for cell-autonomy in zebrafish

    PMID:11879641

    Open questions at the time
    • Molecular link from Wnt/beta-catenin to Stat3 activation undefined
    • Effector genes mediating migration versus convergence not identified
  7. 2003 High

    Resolved STAT3 nucleocytoplasmic shuttling, identifying a post-stimulation NES and basal NES elements supporting phosphorylation-independent CRM1-dependent export.

    Evidence Leptomycin B treatment, NES mutagenesis, subcellular localization

    PMID:12588893

    Open questions at the time
    • Import machinery and karyopherins not mapped
    • Functional role of basal unphosphorylated nuclear STAT3 unresolved
  8. 2003 Medium

    Identified transcriptional repression of STAT3 via a corepressor, showing Tip60 binds STAT3 and recruits HDAC7 to silence STAT3 target genes.

    Evidence Endogenous Co-IP, reporter assays, siRNA/overexpression, c-myc readout

    PMID:12551922

    Open questions at the time
    • Genome-wide scope of Tip60/HDAC7 repression unknown
    • Single-lab; reciprocal validation limited
  9. 2004 Medium

    Expanded the STAT3 interactome to modulators of its activity through STRA13 binding to phosphorylated STAT3 and PIAS3 redistribution from MITF to STAT3.

    Evidence Yeast two-hybrid, GST pulldown/Co-IP with phospho-STAT3, reporter and apoptosis assays; Co-IP and gene expression in MITF-mutant cells

    PMID:15223310 PMID:15572665

    Open questions at the time
    • Physiological contexts where these interactions dominate unclear
    • Direct versus indirect effects on STAT3 targets not fully separated
  10. 2005 High

    Established STAT3 as a transcriptional repressor of p53, linking oncogenic STAT3 to apoptosis evasion.

    Evidence ChIP of in vivo binding, p53 promoter mutagenesis, STAT3 knockdown with p53/apoptosis readout

    PMID:16107692

    Open questions at the time
    • Cofactors mediating repression at the p53 promoter not identified
    • Partial abrogation by single-site mutation implies additional elements
  11. 2005 Medium

    Revealed a transcription-independent cytoplasmic function, showing unphosphorylated STAT3 binds stathmin to promote microtubule polymerization and migration.

    Evidence Co-IP/pulldown with stathmin, microtubule polymerization and migration assays

    PMID:16835434

    Open questions at the time
    • Structural basis of STAT3-stathmin binding undefined
    • In vivo relevance to metastasis not established
  12. 2005 High

    Showed that productive IL-6/STAT3 signaling requires endocytic trafficking, with phosphorylated STAT3 associating with early endosomes.

    Evidence Fractionation, EM, immunofluorescence, dominant-negative/active endocytic regulators with STAT3 reporter

    PMID:16407171

    Open questions at the time
    • Endosomal scaffold tethering STAT3 not identified
    • Whether endosomal compartment is the site of phosphorylation unresolved
  13. 2005 Medium

    Defined a nuclear serine kinase input, showing ZIP kinase specifically phosphorylates STAT3 Ser727 to enhance transcription.

    Evidence Co-IP, in vitro kinase assay with phospho-Ser727 detection, siRNA, reporter assay

    PMID:16219639

    Open questions at the time
    • Genome-wide Ser727-dependent target set not defined
    • Single-lab specificity claim among STATs
  14. 2007 Medium

    Identified a second negative regulator, KAP1/TIF1beta, that binds STAT3 and limits IL-6-driven transcription and nuclear pSer727-STAT3 accumulation.

    Evidence Yeast two-hybrid, endogenous Co-IP, siRNA, reporter and nuclear pSer727 immunostaining

    PMID:18037959

    Open questions at the time
    • Mechanism by which KAP1 controls pSer727 levels unresolved
    • Direct versus indirect repression not separated
  15. 2008 Medium

    Distinguished pathway-specific STAT3 functions, defining a JAK2/STAT2/STAT3 axis required for myogenic differentiation separate from a proliferative JAK1/STAT1/STAT3 pathway.

    Evidence siRNA and JAK2 small-molecule inhibition, differentiation assays, qPCR of MyoD/MEF2/IGF2/HGF

    PMID:18835816

    Open questions at the time
    • Direct STAT3 occupancy at the differentiation target genes not shown
    • Mechanism partitioning STAT3 between the two axes unclear
  16. 2010 High

    Uncovered a self-amplifying circuit, with STAT3 transactivating S1PR1 which in turn upregulates JAK2/IL-6 to sustain persistent STAT3 activation in cancer.

    Evidence ChIP, S1PR1 silencing in tumor and immune cells, xenograft growth/metastasis, JAK2 activity assay

    PMID:21102457

    Open questions at the time
    • Quantitative thresholds sustaining the loop not defined
    • Tissue contexts where the loop is dispensable unknown
  17. 2012 Medium

    Characterized a direct chaperone interaction, showing Hsp90beta binds STAT3 in a manner requiring an intact DNA-binding domain.

    Evidence Surface plasmon resonance of recombinant proteins, RR414/417A mutagenesis, oligonucleotide pulldown, confocal colocalization

    PMID:22271514

    Open questions at the time
    • Functional consequence of Hsp90beta binding for STAT3 stability/activity not established
    • Single-lab; in vivo relevance untested
  18. 2014 High

    Discovered a noncanonical activation mode, with GSK-3alpha/beta dually phosphorylating Thr714/Ser727 to drive gene induction independently of Tyr705 upon EGFR/PAR-1 co-activation.

    Evidence Quantitative LC-MS/MS, Thr714/Ser727 mutagenesis, GSK-3alpha/beta depletion, reporter assay, clinical tissue comparison

    PMID:24615012

    Open questions at the time
    • Target genes specifically driven by the dual phosphoform not enumerated
    • Structural effect of dual phosphorylation on STAT3 not resolved
  19. 2015 High

    Defined STAT3 antagonism of TGF-beta, showing activated STAT3 binds Smad3 and blocks Smad3-Smad4 complex formation and DNA binding.

    Evidence In vivo/in vitro Co-IP, domain mapping, Smad3-Smad4 disruption assay, STAT3 knockdown with TGF-beta phenotype readouts

    PMID:26616859

    Open questions at the time
    • Stoichiometry and structural interface of the STAT3-Smad3 complex undefined
    • Crosstalk balance in normal tissue not addressed
  20. 2018 High

    Established transcriptional control of STAT3 levels, identifying ZNF341 as a direct activator of the STAT3 promoter whose loss causes an AD-HIES-like immunodeficiency.

    Evidence Promoter binding/luciferase assays, ZNF341 mutant translocation, patient cells, STAT3 mRNA/protein quantification in consanguineous families

    PMID:29907690

    Open questions at the time
    • Other transcriptional regulators of STAT3 not mapped
    • Mechanism connecting reduced STAT3 to Th17 loss only partially defined
  21. 2022 Medium

    Linked STAT3 to epigenetic remodeling, showing a vitamin D-induced VDR-pSTAT3-TET2 complex drives DNA demethylation establishing tolerogenic dendritic cells.

    Evidence Co-IP of trimeric complex, JAK2 inhibition, DNA methylation analysis, DC tolerogenesis assay

    PMID:35045292

    Open questions at the time
    • Genome-wide demethylation sites dependent on the complex not mapped
    • Single-lab; direct ternary complex stoichiometry unconfirmed
  22. 2023 High

    Defined an antiviral restraint function, showing RIG-I/MAVS/Syk-driven STAT3 Y705 phosphorylation limits excessive type I/III interferon during influenza A infection.

    Evidence STAT3-Y705F knockin mice, IAV infection, IFN measurement, IFNAR1/IFNLR1 epistatic rescue, viral load

    PMID:37440406

    Open questions at the time
    • Direct STAT3 target genes repressing IFN not enumerated
    • Mechanism of IL-6-independent Y705 phosphorylation not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse STAT3 inputs (tyrosine versus multi-serine/threonine phosphoforms, cofactor occupancy, endosomal localization) are integrated into context-specific transcriptional and non-transcriptional outputs remains unresolved.
  • No unified model linking distinct phosphoforms to specific gene programs
  • Determinants selecting transcriptional versus cytoskeletal/mitochondrial functions undefined
  • Structural basis of corepressor versus coactivator switching unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4 GO:0060089 molecular transducer activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
DAPK3HSP90AB1IL6STJAK1KAP1PIAS3SMAD3STMN1
Complex memberships
VDR-pSTAT3-TET2 complexgp130/JAK1-STAT3 receptor complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 APRF (STAT3) associates physically with both the IL-6 signal transducer gp130 and the Jak1 protein kinase upon stimulation by IL-6-family cytokines, and undergoes tyrosine phosphorylation in this complex, establishing that Jak family kinases participate in IL-6 signaling via STAT3. Co-immunoprecipitation, tyrosine phosphorylation assays, DNA-binding assays Science High 8272872
1995 Growth hormone (GH) activates STAT3 by promoting tyrosine phosphorylation of STAT3, enabling it to bind DNA elements (SIE in c-fos promoter and APRE in alpha2-macroglobulin promoter), demonstrating GH signals through multiple STAT proteins including STAT3. Immunoprecipitation with anti-STAT3 antibodies, tyrosine phosphorylation assay, gel shift/DNA-binding assay The Journal of biological chemistry Medium 7876144
1999 Substitution of two cysteine residues within the C-terminal loop of the STAT3 SH2 domain (Stat3-C) produces a molecule that dimerizes spontaneously, binds DNA constitutively, activates transcription, and causes cellular transformation (soft agar colony formation, nude mouse tumor formation), demonstrating that constitutively active STAT3 alone is sufficient to mediate oncogenic transformation. Site-directed mutagenesis, dimerization assay, DNA-binding assay, transcriptional reporter assay, soft agar colony formation, nude mouse xenograft Cell High 10458605
1997 HGF/SF activates STAT3 in human hepatocytes and hepatoma cells (HepG2) via the JAK/STAT pathway; unlike IL-6-induced rapid and transient STAT3 activation, HGF/SF-induced STAT3 activation is delayed (5–7 h) and sustained (up to 28 h). Transcription factor activation assay, kinetic analysis in primary hepatocytes and HepG2 cells FEBS letters Medium 9094433
2002 Zebrafish Stat3 is activated on the dorsal side by the maternal Wnt/beta-catenin pathway and is required cell-autonomously for anterior migration of dorsal mesendodermal cells and non-cell-autonomously for convergence of paraxial cells during gastrulation; loss of Stat3 causes abnormal gastrulation movements without defects in early cell fate specification. Dominant-negative Stat3 expression, cell tracing, transplantation experiments, time-course analysis Developmental cell High 11879641
2003 STAT3 nuclear export is regulated by multiple nuclear export signal (NES) elements: NES Stat3(306-318) mediates post-stimulation export, while Stat3(404-414) and Stat3(524-535) regulate basal nuclear export. LMB (leptomycin B) blocks post-stimulation export and also causes nuclear accumulation of unphosphorylated Stat3 in resting cells, revealing a tyrosine phosphorylation-independent basal nuclear export pathway. Leptomycin B treatment, NES mutagenesis, subcellular fractionation/localization assays The Journal of clinical investigation High 12588893
2003 Tip60 (a histone acetyltransferase) physically associates with endogenous STAT3 and represses STAT3-driven transcription by recruiting HDAC7 through its N-terminal zinc finger region; overexpression of Tip60 abrogates IL-9-induced STAT3-dependent c-myc expression. Co-immunoprecipitation of endogenous proteins, reporter gene assay, siRNA/overexpression, endogenous target gene (c-myc) measurement The Journal of biological chemistry Medium 12551922
2004 STRA13 binds predominantly to phosphorylated (active) STAT3α and STAT3β isoforms via its HLH and C-terminal regions, activates transcription from STAT-dependent elements, and modulates STAT3-regulated pro-apoptotic Fas gene promoter activity; co-expression of STRA13 with STAT3β alleviates STRA13's pro-apoptotic effect. Yeast two-hybrid screening, GST pulldown/Co-IP with phosphorylated STAT3, reporter gene assay, apoptosis assay Journal of molecular biology Medium 15223310
2004 In mast cells and melanocytes stimulated via gp130 or c-Kit receptors, cytokine-induced phosphorylation of MITF at S409 causes dissociation of PIAS3 from MITF and its re-association with STAT3, thereby modulating STAT3-dependent gene expression; cells from MITF(di/di) mice (lacking the PIAS3-binding Zip domain of MITF) show downregulation of genes regulated by either MITF or STAT3. Co-immunoprecipitation, phosphorylation assays, mRNA expression analysis in MITF mutant cells, cell stimulation via gp130/c-Kit Molecular and cellular biology Medium 15572665
2005 Oncogenic Stat3 binds to the p53 gene promoter in vitro and in vivo (ChIP), and site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates Stat3-induced inhibition; blocking Stat3 in cancer cells upregulates p53 expression leading to p53-mediated apoptosis, placing Stat3 as a transcriptional repressor of p53. Chromatin immunoprecipitation (ChIP), promoter reporter assay with site-directed mutagenesis, Stat3 inhibition/knockdown with p53 expression and apoptosis readout Molecular and cellular biology High 16107692
2005 Cytoplasmic (non-tyrosine-phosphorylated) STAT3 mediates cell migration by associating with stathmin, potentiating microtubule polymerization; this disrupts the stathmin-microtubule interaction and promotes cell movement. Co-immunoprecipitation/pulldown of STAT3 with stathmin, microtubule polymerization assay, cell migration assay Science's STKE Medium 16835434
2005 STAT3 is constitutively associated (~5%) with the early endosome fraction; after IL-6 treatment, up to two-thirds of cytoplasmic tyrosine-phosphorylated STAT3 associates with early endosomes. STAT3 transcriptional activation is inhibited by dominant-negative dynamin K44A, epsin 2a, amphiphysin A1, and clathrin light chain, but enhanced by active dynamin MxA, demonstrating that endocytic trafficking is required for productive IL-6/STAT3 signaling. Cell fractionation, electron microscopy, immunofluorescence, detergent dissection, transient transfection with dominant-negative/active endocytic regulators and STAT3-reporter luciferase assay The Journal of biological chemistry High 16407171
2005 ZIP kinase (ZIPK) physically interacts specifically with STAT3 (but not STAT1, STAT4, STAT5a, STAT5b, or STAT6), phosphorylates STAT3 on Ser727 in the nucleus, and enhances STAT3 transcriptional activity; siRNA knockdown of ZIPK decreases LIF- and IL-6-induced STAT3-dependent transcription. Co-immunoprecipitation, in vitro kinase assay with phospho-Ser727 detection, siRNA knockdown, transcriptional reporter assay International immunology Medium 16219639
2007 KAP1/TIF1beta (a universal corepressor) physically associates with endogenous STAT3 in vivo; siRNA-mediated knockdown of KAP1 enhances IL-6-induced STAT3-dependent transcription and causes marked accumulation of Ser727-phosphorylated STAT3 in the nucleus, indicating KAP1 negatively regulates the IL-6/STAT3 signaling pathway. Yeast two-hybrid screening, Co-IP of endogenous proteins, siRNA knockdown, transcriptional reporter assay, nuclear pSer727-STAT3 immunostaining Oncogene Medium 18037959
2008 A JAK2/STAT2/STAT3 signaling axis (distinct from the JAK1/STAT1/STAT3 proliferation pathway) is required for early myogenic differentiation; inhibition by small molecule JAK2 inhibitor or siRNA against JAK2, STAT2, or STAT3 blocks myogenic differentiation. The pro-differentiation effect is partially mediated through MyoD, MEF2, IGF2, and HGF gene regulation. siRNA knockdown of JAK2/STAT2/STAT3, small molecule JAK2 inhibitor, differentiation assays, qPCR for MyoD/MEF2/IGF2/HGF The Journal of biological chemistry Medium 18835816
2010 STAT3 acts as a transcription factor for the S1PR1 gene; reciprocally, S1PR1 activates STAT3 (in part by upregulating JAK2 kinase activity) and upregulates IL-6 expression, forming a positive feedback loop that sustains persistent STAT3 activation in cancer cells. S1P-S1PR1-induced STAT3 activation is persistent, in contrast to transient IL-6-induced STAT3 activation. Chromatin immunoprecipitation, S1PR1 silencing (siRNA/shRNA) in tumor cells and immune cells, xenograft tumor growth/metastasis assay, JAK2 activity assay Nature medicine High 21102457
2012 STAT3 directly interacts with Hsp90β with high affinity (surface plasmon resonance of recombinant proteins); this interaction requires a functional DNA-binding domain (RR414/417); the interaction is not preferentially altered by a phosphomimetic mutation at tyrosine 705. Surface plasmon resonance spectroscopy with recombinant proteins, site-directed mutagenesis of STAT3 (RR414/417A), DNA-binding oligonucleotide pulldown, confocal colocalization in MCF7 cells IUBMB life Medium 22271514
2014 STAT3 is simultaneously phosphorylated at Thr714 and Ser727 by GSK-3α/β to form a noncanonical phosphoform that drives STAT3-dependent gene induction independently of Tyr705 phosphorylation in response to combined EGFR and PAR-1 activation; both residues are required and depletion of GSK-3α/β is sufficient to disrupt this signal integration. Doubly phosphorylated STAT3 (but not pTyr705-STAT3) is elevated in clear-cell renal-cell carcinoma. Quantitative LC-MS/MS mass spectrometry, site-directed mutagenesis of Thr714/Ser727, GSK-3α/β depletion (siRNA), STAT3-dependent reporter assay, clinical tissue comparison Molecular and cellular biology High 24615012
2015 Activated STAT3 directly interacts with Smad3 in vivo and in vitro; this interaction attenuates Smad3-Smad4 complex formation and suppresses Smad3 DNA-binding ability, antagonizing TGF-β signaling. The N-terminal region of the STAT3 DNA-binding domain is responsible for the STAT3-Smad3 interaction and is indispensable for STAT3-mediated TGF-β inhibition. Co-immunoprecipitation in vivo and in vitro pulldown, STAT3/Smad3 domain mapping, Smad3-Smad4 complex disruption assay, DNA-binding assay, STAT3 knockdown with TGF-β response readouts (cell cycle arrest, apoptosis, EMT) Oncogene High 26616859
2018 ZNF341, a zinc finger transcription factor, binds to and activates the STAT3 promoter; loss-of-function mutations in ZNF341 reduce STAT3 expression and result in an AD-HIES-like immunodeficiency phenotype with decreased Th17 cells, establishing ZNF341 as a direct transcriptional regulator of STAT3 expression. Promoter binding assay (ZNF341 binding to STAT3 promoter), luciferase reporter assay, nuclear translocation analysis of mutant ZNF341, patient-derived cell characterization, STAT3 mRNA/protein quantification Science immunology High 29907690
2023 IL-6-independent STAT3 Y705 phosphorylation at early stages of influenza A virus (IAV) infection is dependent on the RIG-I/MAVS/Syk signaling axis; STAT3 Y705 phosphorylation restrains IAV pathogenesis by repressing excessive production of type I and III interferons. STAT3Y705F knockin mice show impaired antiviral gene expression, severe lung injury, and poor survival; knockout of IFNAR1 or IFNLR1 in STAT3Y705F mice rescues lung injury and reduces viral load. STAT3-Y705F knockin mice, IAV infection model, IFN expression measurement, genetic epistasis (IFNAR1/IFNLR1 knockout in knockin background), viral load quantification Cell reports High 37440406
2022 VDR and phosphorylated STAT3 (phosphorylated by JAK2 specifically in response to vitamin D stimulation) interact with each other and with the DNA demethylase TET2 to form a complex that drives DNA demethylation and transcriptional activation at VDR binding sites, establishing tolerogenesis in dendritic cells; pharmacological JAK2 inhibition reverts vitamin D-induced tolerogenic properties. Co-immunoprecipitation of VDR-pSTAT3-TET2 complex, JAK2 inhibitor treatment, DNA methylation analysis, DC tolerogenesis functional assay Cell reports Medium 35045292
2000 Conditional knockout of STAT3 specifically in mammary gland epithelium (using lox/Cre system) causes decreased epithelial apoptosis and dramatic delay of mammary gland involution upon forced weaning, demonstrating that STAT3 is required for initiation of physiological apoptosis during mammary involution in vivo. Conditional gene knockout (lox/Cre), mammary gland involution assay, apoptosis quantification, STAT1/p53/p21 expression analysis Advances in experimental medicine and biology High 10959419

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Stat3 as an oncogene. Cell 2504 10458605
2020 Targeting STAT3 in Cancer Immunotherapy. Molecular cancer 872 32972405
1994 Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science (New York, N.Y.) 728 8272872
2015 The role of STAT3 in autophagy. Autophagy 445 25951043
2009 Targeting STAT3 in cancer: how successful are we? Expert opinion on investigational drugs 346 19053881
2010 STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nature medicine 342 21102457
2005 Role of Stat3 in regulating p53 expression and function. Molecular and cellular biology 332 16107692
2011 STAT3 signaling: anticancer strategies and challenges. Molecular interventions 329 21441118
2005 Targeting Stat3 in cancer therapy. Anti-cancer drugs 248 15930886
2023 Advances in the role of STAT3 in macrophage polarization. Frontiers in immunology 231 37081874
2005 Targeting STAT3 affects melanoma on multiple fronts. Cancer metastasis reviews 231 15986140
2018 Psoriasis: A STAT3-Centric View. International journal of molecular sciences 195 29316631
2015 STAT3 the oncogene - still eluding therapy? The FEBS journal 173 25825152
1995 Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. The Journal of biological chemistry 169 7876144
2020 Redox Regulation of STAT1 and STAT3 Signaling. International journal of molecular sciences 168 32987855
2020 STAT3: A key regulator in liver fibrosis. Annals of hepatology 162 32702499
2018 STAT3 and apoptosis challenges in cancer. International journal of biological macromolecules 156 29782972
2002 Stat3 Controls Cell Movements during Zebrafish Gastrulation. Developmental cell 148 11879641
2018 STAT3: a multifaceted oncoprotein. Growth factors (Chur, Switzerland) 147 29873274
2002 Stat3 activation in prostatic carcinomas. The Prostate 126 11987152
2020 STAT3 and its targeting inhibitors in osteosarcoma. Cell proliferation 121 33382511
2018 ZNF341 controls STAT3 expression and thereby immunocompetence. Science immunology 121 29907690
2008 JAK2/STAT2/STAT3 are required for myogenic differentiation. The Journal of biological chemistry 121 18835816
2016 Mitochondrial Stat3, the Need for Design Thinking. International journal of biological sciences 120 27019635
2012 STAT3 negatively regulates thyroid tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 116 22891351
2003 Regulation of Stat3 nuclear export. The Journal of clinical investigation 115 12588893
2007 Small molecule inhibitors of Stat3 signaling pathway. Current cancer drug targets 114 17305481
2011 PI3K and STAT3: a new alliance. Cancer discovery 111 22348200
2013 The role of Stat3 in glioblastoma multiforme. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 105 23688441
2014 STAT3 in Cancer-Friend or Foe? Cancers 103 24995504
2012 STAT3 signaling in pulmonary arterial hypertension. JAK-STAT 101 24058777
2022 STAT3-mediated ferroptosis is involved in ulcerative colitis. Free radical biology & medicine 99 35779691
2009 STAT3 regulation of glioblastoma pathogenesis. Current molecular medicine 99 19601808
2003 Tip60 is a co-repressor for STAT3. The Journal of biological chemistry 97 12551922
2013 STAT3 inhibitors for cancer therapy: Have all roads been explored? JAK-STAT 96 24058788
2017 Targeting STAT3 with silibinin to improve cancer therapeutics. Cancer treatment reviews 95 28686955
2007 Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis. Molecular carcinogenesis 95 17610223
2019 STAT3 and STAT5 Activation in Solid Cancers. Cancers 92 31557897
2016 Expression of STAT3 in Prostate Cancer Metastases. European urology 90 27344294
2015 STAT3 selectively interacts with Smad3 to antagonize TGF-β signalling. Oncogene 90 26616859
2006 STAT3-mediated anti-inflammatory signalling. Biochemical Society transactions 90 17073743
2021 STAT3 phosphorylation in central leptin resistance. Nutrition & metabolism 88 33849593
2019 Targeting STAT3 signaling in kidney disease. American journal of physiology. Renal physiology 87 30943069
2011 STAT3 and cardiac remodeling. Heart failure reviews 86 20407820
2000 The role of Stat3 in apoptosis and mammary gland involution. Conditional deletion of Stat3. Advances in experimental medicine and biology 86 10959419
2012 Targeting STAT3 in gastric cancer. Expert opinion on therapeutic targets 83 22834702
2020 GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway. Oncogene 76 32518375
2019 Direct Targeting Options for STAT3 and STAT5 in Cancer. Cancers 76 31817042
2015 IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene 72 25893308
2009 Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochemistry and cell biology = Biochimie et biologie cellulaire 72 19935868
2019 STAT3 Activation and Oncogenesis in Lymphoma. Cancers 70 31861597
2015 Role of STAT3 in lung cancer. JAK-STAT 69 26413424
2006 Touched and moved by STAT3. Science's STKE : signal transduction knowledge environment 69 16835434
2018 Smad3-STAT3 crosstalk in pathophysiological contexts. Acta biochimica et biophysica Sinica 68 29140406
2018 STAT3 isoforms: Alternative fates in cancer? Cytokine 68 30031681
2007 Physical and functional interactions between STAT3 and KAP1. Oncogene 65 18037959
2005 Membrane-associated STAT3 and PY-STAT3 in the cytoplasm. The Journal of biological chemistry 64 16407171
2022 STAT3-mediated osteogenesis and osteoclastogenesis in osteoporosis. Cell communication and signaling : CCS 61 35879773
2016 Mitochondrial STAT3: Powering up a potent factor. Cytokine 60 27269970
2011 The R(h)oads to Stat3: Stat3 activation by the Rho GTPases. Experimental cell research 60 21619876
2017 TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3. Molecular oncology 59 28100038
2014 STAT3 inhibitors: finding a home in lymphoma and leukemia. The oncologist 58 24705981
2016 FOXM1 and STAT3 interaction confers radioresistance in glioblastoma cells. Oncotarget 55 27764801
2004 STRA13 interacts with STAT3 and modulates transcription of STAT3-dependent targets. Journal of molecular biology 55 15223310
2004 Interplay between MITF, PIAS3, and STAT3 in mast cells and melanocytes. Molecular and cellular biology 55 15572665
2005 Physical and functional interactions between STAT3 and ZIP kinase. International immunology 54 16219639
2023 Perspective: mitochondrial STAT3 in cardioprotection. Basic research in cardiology 53 37620559
2015 Role of STAT3 pathway in genitourinary tumors. Future science OA 52 28031890
2014 Effects of JAK2-STAT3 signaling after cerebral insults. JAK-STAT 52 25105066
2020 Perspectives Regarding the Intersections between STAT3 and Oxidative Metabolism in Cancer. Cells 51 33003453
2020 STAT3 and p53: Dual Target for Cancer Therapy. Biomedicines 51 33371351
2018 STAT3 roles in viral infection: antiviral or proviral? Future virology 49 32201498
2017 EGFR-mediated apoptosis via STAT3. Experimental cell research 49 28433699
2013 The Stat3 paradox: a killer and an oncogene. Molecular and cellular endocrinology 48 23827176
2010 STAT3 in tissue fibrosis: is there a role in the lung? Pulmonary pharmacology & therapeutics 48 20951825
2022 Vitamin D receptor, STAT3, and TET2 cooperate to establish tolerogenesis. Cell reports 47 35045292
2010 PIM kinase inhibitors downregulate STAT3(Tyr705) phosphorylation. Molecular cancer therapeutics 47 20667852
2019 CPAP promotes angiogenesis and metastasis by enhancing STAT3 activity. Cell death and differentiation 46 31511651
2011 Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules. ChemMedChem 46 21618433
2023 STAT3 regulates antiviral immunity by suppressing excessive interferon signaling. Cell reports 45 37440406
2016 Understanding STAT3 signaling in cardiac ischemia. Basic research in cardiology 45 27017613
2020 STAT3 Contributes to Radioresistance in Cancer. Frontiers in oncology 44 32733808
1997 Hepatocyte growth factor/scatter factor (HGF/SF) signals via the STAT3/APRF transcription factor in human hepatoma cells and hepatocytes. FEBS letters 44 9094433
2022 KPNA2 promotes angiogenesis by regulating STAT3 phosphorylation. Journal of translational medicine 42 36578083
2020 STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy. Cancers 42 32872659
2019 Targeting STAT3 in Cancer with Nucleotide Therapeutics. Cancers 42 31671769
2022 Nintedanib induces senolytic effect via STAT3 inhibition. Cell death & disease 41 36055997
2014 Signal integration and gene induction by a functionally distinct STAT3 phosphoform. Molecular and cellular biology 39 24615012
2025 Importance of STAT3 signaling in preeclampsia (Review). International journal of molecular medicine 38 39918020
2019 STAT3beta, a distinct isoform from STAT3. The international journal of biochemistry & cell biology 38 30822557
2019 STAT3- and GSK3β-mediated Mcl-1 regulation modulates TPF resistance in oral squamous cell carcinoma. Carcinogenesis 37 30395230
2019 Global transcriptional regulation of STAT3- and MYC-mediated sepsis-induced ARDS. Therapeutic advances in respiratory disease 37 31566109
2023 FANCD2 inhibits ferroptosis by regulating the JAK2/STAT3 pathway in osteosarcoma. BMC cancer 36 36814203
2012 Stat3: linking inflammation to (gastrointestinal) tumourigenesis. Clinical and experimental pharmacology & physiology 34 22211709
2012 STAT3 genotypic variation and cellular STAT3 activation and colon leukocyte recruitment in pediatric Crohn disease. Journal of pediatric gastroenterology and nutrition 33 22197944
2012 STAT3 interacts directly with Hsp90. IUBMB life 33 22271514
2020 Silencing of p68 and STAT3 synergistically diminishes cancer progression. Life sciences 32 32142763
2024 Targeting the STAT3 pathway with STAT3 degraders. Trends in pharmacological sciences 31 39117533
2018 Stat3 activation is critical for pluripotency maintenance. Journal of cellular physiology 31 30256396
2013 JAK-STAT3 and somatic cell reprogramming. JAK-STAT 31 24470976

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