STAT3

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Protein-coding gene in humans

title: "STAT3" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["gene-expression", "immune-system", "proteins", "transcription-factors", "signal-transduction", "moonlighting-proteins"] description: "Protein-coding gene in humans" topic_path: "arts/film" source: "https://en.wikipedia.org/wiki/STAT3" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in humans ::

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene. It is a member of the STAT protein family.

Function

STAT3 is a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated Janus kinases (JAK), forms homo- or heterodimers, and translocates to the cell nucleus where it acts as a transcription activator. Specifically, STAT3 becomes activated after phosphorylation of tyrosine 705 in response to such ligands as interferons, epidermal growth factor (EGF), interleukin (IL-)5 and IL-6. Additionally, activation of STAT3 may occur via phosphorylation of serine 727 by mitogen-activated protein kinases (MAPK) and through c-src non-receptor tyrosine kinase. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis.

STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins. It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to murine ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.

STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases. During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody based immunity.

STAT3 caused upregulation in E-selectin, a factor in metastasis of cancers.

Hyperactivation of STAT3 occurs in COVID-19 infection and other viral infections.

Clinical significance

Loss-of-function mutations in the STAT3 gene result in hyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development.

Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto-immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts, while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects.

STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported. In the report on human glioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown. Overactivation of STAT3 promotes tumor survival and reduces sensitivity to temozolomide (TMZ), the standard chemotherapy for this cancer. Systemic inhibition of STAT3, however, risks immune dysregulation, complicating its therapeutic targeting. Recent studies highlight a non-coding RNA transcribed from a STAT3 enhancer region, termed TMZR1-eRNA, which regulates STAT3 expression. Silencing TMZR1-eRNA reduces STAT3 mRNA and protein levels, sensitizing glioblastoma cells to TMZ-induced cell death. Mechanistically, TMZR1-eRNA enhances STAT3 promoter activity, creating a feedback loop that sustains STAT3 expression. Importantly, TMZR1-eRNA expression is minimal in healthy brain tissue and peripheral blood cells, suggesting its suppression could offer a tumor-specific strategy to overcome chemoresistance with reduced off-target effects compared to direct STAT3 inhibitors

Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.

Interactions

STAT3 has been shown to interact with:

Ligands

;Inhibitors

Napabucasin
Niclosamide seems to inhibit the STAT3 signalling pathway.
Nicotinamide (a type of vitamin B3) naturally inhibits STAT3. However NAC (Acetylcysteine) inhibits STAT3 inhibitors.
Stattic

;PROTACs

SD36

References

(April 1994). "Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway". Cell.
(April 2013). "p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth". Endocrine-Related Cancer.
(October 2004). "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis". Oncogene.
(November 2006). "Structure, function, and regulation of STAT proteins". Molecular BioSystems.
(November 2004). "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Molecular and Cellular Biology.
(April 1997). "Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality". Proceedings of the National Academy of Sciences of the United States of America.
(August 1999). "STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells". The EMBO Journal.
(March 2007). "STAT3 regulates cytokine-mediated generation of inflammatory helper T cells". The Journal of Biological Chemistry.
(February 2015). "T-cell STAT3 is required for the maintenance of humoral immunity to LCMV". European Journal of Immunology.
(July 2021). "ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3". Cancer Letters.
(December 2020). "An aberrant STAT pathway is central to COVID-19". Cell Death and Differentiation.
(August 2018). "STAT3 roles in viral infection: antiviral or proviral?". Future Virology.
(October 2007). "STAT3 signaling and the hyper-IgE syndrome". The New England Journal of Medicine.
(January 2015). "Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations". Blood.
(March 2006). "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs". [[Current Cancer Drug Targets]].
(March 2006). "Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor". Cancer Research.
(April 2006). "Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions". Molecular Cancer.
(June 2006). "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer". Oncology Reports.
(February 2008). "Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway". Genes & Development.
(May 2012). "Signal transducer and activator of transcription 3 (STAT3) protein suppresses adenoma-to-carcinoma transition in Apcmin/+ mice via regulation of Snail-1 (SNAI) protein stability". The Journal of Biological Chemistry.
(March 2010). "Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice". Gastroenterology.
(April 2025). "Enhancer RNA from STAT3 locus affects temozolomide chemoresistance of glioblastoma cells". Gene.
(August 2017). "Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode". Cancer Biology & Medicine.
(April 2001). "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells". Biochemical and Biophysical Research Communications.
(August 2000). "A Stat3-interacting protein (StIP1) regulates cytokine signal transduction". Proceedings of the National Academy of Sciences of the United States of America.
(April 1999). "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science.
(June 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry.
(October 2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Experimental & Molecular Medicine.
(March 2002). "Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways". The Journal of Biological Chemistry.
(August 2001). "Constitutive activation of STAT transcription factors in acute myelogenous leukemia". European Journal of Haematology.
(October 1999). "Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation". Molecular and Cellular Biology.
(July 2001). "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway". Cellular Immunology.
(January 2000). "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Current Biology.
(January 2005). "Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR)". The Journal of Biological Chemistry.
(November 2003). "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". The Journal of Biological Chemistry.
(August 2003). "The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3". Proceedings of the National Academy of Sciences of the United States of America.
(October 2003). "STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene". Genes & Development.
(December 1997). "STAT3 acts as a co-activator of glucocorticoid receptor signaling". The Journal of Biological Chemistry.
(March 2002). "Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a". The Journal of Biological Chemistry.
(May 2003). "Opposing effects of PML and PML/RAR alpha on STAT3 activity". Blood.
(October 2000). "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science.
(October 2002). "Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB". The Biochemical Journal.
(November 2004). "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Molecular and Cellular Biology.
(June 2003). "Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation". Molecular Endocrinology.
(August 2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene.
(2000). "Replication protein a 32 kDa subunit (RPA p32) binds the SH2 domain of STAT3 and regulates its transcriptional activity". Cell Biology International.
(October 2001). "Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin". Biochemical and Biophysical Research Communications.
(August 2002). "Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation". The Journal of Biological Chemistry.
(May 2017). "Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1". Nature Communications.
(April 1996). "Activation and association of Stat3 with Src in v-Src-transformed cell lines". Molecular and Cellular Biology.
(June 2004). "Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein". Journal of Virology.
(June 2005). "STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3". Proceedings of the National Academy of Sciences of the United States of America.
Thuya WL, Cao Y, Ho PC, Wong AL, Wang L, Zhou J, Nicot C, Goh BC. Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy. ''Cytokine Growth Factor Rev''. 2025 Oct;85:26-42. {{doi. 10.1016/j.cytogfr.2025.01.003 {{pmid. 39893129
(2010). "Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway". ACS Medicinal Chemistry Letters.
(October 2018). "Decreased NAD Activates STAT3 and Integrin Pathways to Drive Epithelial-Mesenchymal Transition". Molecular & Cellular Proteomics.
(December 2019). "N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties". Pharmacological Reports.
Samad MA, Ahmad I, Hasan A, Alhashmi MH, Ayub A, Al-Abbasi FA, Kumer A, Tabrez S. STAT3 Signaling Pathway in Health and Disease. ''MedComm'' (2020). 2025 Mar 30;6(4):e70152. {{doi. 10.1002/mco2.70152 {{pmid. 40166646
Zhou H, Bai L, Xu R, Zhao Y, Chen J, McEachern D, Chinnaswamy K, Wen B, Dai L, Kumar P, Yang CY, Liu Z, Wang M, Liu L, Meagher JL, Yi H, Sun D, Stuckey JA, Wang S. Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. ''J Med Chem''. 2019 Dec 26;62(24):11280-11300. {{doi. 10.1021/acs.jmedchem.9b01530 {{pmid. 31747516

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