STAT3

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene.[5] It is a member of the STAT protein family.

STAT3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSTAT3, ADMIO, APRF, HIES, signal transducer and activator of transcription 3, ADMIO1
External IDsOMIM: 102582 MGI: 103038 HomoloGene: 7960 GeneCards: STAT3
Orthologs
SpeciesHumanMouse
Entrez

6774

20848

Ensembl

ENSG00000168610

ENSMUSG00000004040

UniProt

P40763

P42227

RefSeq (mRNA)

NM_011486
NM_213659
NM_213660

RefSeq (protein)

NP_035616
NP_998824
NP_998825

Location (UCSC)Chr 17: 42.31 – 42.39 MbChr 11: 100.78 – 100.83 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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)[6] and through c-src non-receptor tyrosine kinase.[7][8] 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.[9]

STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins.[10] 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.[11]

STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases.[12] 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.[13]

STAT3 caused upregulation in E-selectin, a factor in metastasis of cancers. [14]

Hyperactivation of STAT3 occurs in COVID-19 infection and other viral infections.[15][16]

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.[17]

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,[18] while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[19][20][21][22] It has anti-apoptotic as well as proliferative effects.[19]

STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported.[23][24][25] 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.

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.[26]

Interactions

STAT3 has been shown to interact with:

Niclosamide seems to inhibit the STAT3 signalling pathway.[56]

Nicotinamide (a type of Vitamin B3) naturally inhibits STAT3. [57] However NAC (Acetylcysteine) inhibits STAT3 inhibitors.[58]

References
  1. GRCh38: Ensembl release 89: ENSG00000168610 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000004040 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (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. 77 (1): 63–71. doi:10.1016/0092-8674(94)90235-6. PMID 7512451. S2CID 42211976.
  6. Tkach M, Rosemblit C, Rivas MA, Proietti CJ, Díaz Flaqué MC, Mercogliano MF, Beguelin W, Maronna E, Guzmán P, Gercovich FG, Deza EG, Elizalde PV, Schillaci R (April 2013). "p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth". Endocrine-Related Cancer. 20 (2): 197–212. doi:10.1530/ERC-12-0194. PMID 23329648.
  7. Silva CM (October 2004). "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis". Oncogene. 23 (48): 8017–23. doi:10.1038/sj.onc.1208159. PMID 15489919.
  8. Lim CP, Cao X (November 2006). "Structure, function, and regulation of STAT proteins". Molecular BioSystems. 2 (11): 536–50. doi:10.1039/B606246F. PMID 17216035..
  9. Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE (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. 24 (21): 9390–400. doi:10.1128/MCB.24.21.9390-9400.2004. PMC 522220. PMID 15485908. 15485908.
  10. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S (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. 94 (8): 3801–4. Bibcode:1997PNAS...94.3801T. doi:10.1073/pnas.94.8.3801. PMC 20521. PMID 9108058.
  11. Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, Yokota T (August 1999). "STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells". The EMBO Journal. 18 (15): 4261–9. doi:10.1093/emboj/18.15.4261. PMC 1171502. PMID 10428964.
  12. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (March 2007). "STAT3 regulates cytokine-mediated generation of inflammatory helper T cells". The Journal of Biological Chemistry. 282 (13): 9358–63. doi:10.1074/jbc.C600321200. PMID 17277312.
  13. McIlwain DR, Grusdat M, Pozdeev VI, Xu HC, Shinde P, Reardon C, Hao Z, Beyer M, Bergthaler A, Häussinger D, Nolan GP, Lang KS, Lang PA (February 2015). "T-cell STAT3 is required for the maintenance of humoral immunity to LCMV". European Journal of Immunology. 45 (2): 418–27. doi:10.1002/eji.201445060. PMC 4383653. PMID 25393615.
  14. Coppo, R.; Orso, F.; Virga, F.; Dalmasso, A.; Baruffaldi, D.; Nie, L.; Clapero, F.; Dettori, D.; Quirico, L.; Grassi, E.; Defilippi, P.; Provero, P.; Valdembri, D.; Serini, G.; Sadeghi, M. M.; Mazzone, M.; Taverna, D. (2021). "ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3". Cancer Letters. 510: 13–23. doi:10.1016/j.canlet.2021.04.005. hdl:2318/1791282. ISSN 0304-3835. PMC 8581997. PMID 33862151.
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  18. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson ED, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, Perminow G, Rao VK, O'Connell MP, Price S, Su HC, Butrick M, McElwee J, Hughes JD, Willet J, Swan D, Xu Y, Santibanez-Koref M, Slowik V, Dinwiddie DL, Ciaccio CE, Saunders CJ, Septer S, Kingsmore SF, White AJ, Cant AJ, Hambleton S, Cooper MA (January 2015). "Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations". Blood. 125 (4): 591–9. doi:10.1182/blood-2014-09-602763. PMC 4304103. PMID 25359994.
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  45. Kawasaki A, Matsumura I, Kataoka Y, Takigawa E, Nakajima K, Kanakura Y (May 2003). "Opposing effects of PML and PML/RAR alpha on STAT3 activity". Blood. 101 (9): 3668–73. doi:10.1182/blood-2002-08-2474. PMID 12506013.
  46. Simon AR, Vikis HG, Stewart S, Fanburg BL, Cochran BH, Guan KL (October 2000). "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science. 290 (5489): 144–7. Bibcode:2000Sci...290..144S. doi:10.1126/science.290.5489.144. PMID 11021801.
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  50. Gunaje JJ, Bhat GJ (October 2001). "Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin". Biochemical and Biophysical Research Communications. 288 (1): 252–7. doi:10.1006/bbrc.2001.5759. PMID 11594781.
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  55. Liu L, McBride KM, Reich NC (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. 102 (23): 8150–5. Bibcode:2005PNAS..102.8150L. doi:10.1073/pnas.0501643102. PMC 1149424. PMID 15919823.
  56. Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, Pan J, Pei D, Ding K (2010). "Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway". ACS Medicinal Chemistry Letters. 1 (9): 454–9. doi:10.1021/ml100146z. PMC 4007964. PMID 24900231.
  57. Wang W, Hu Y, Yang C, Zhu S, Wang X, Zhang Z; et al. (2018). "Decreased NAD Activates STAT3 and Integrin Pathways to Drive Epithelial-Mesenchymal Transition". Mol Cell Proteomics. 17 (10): 2005–2017. doi:10.1074/mcp.RA118.000882. PMC 6166677. PMID 29980616.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  58. Uchihara Y, Ohe T, Mashino T, Kidokoro T, Tago K, Tamura H; et al. (2019). "N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties". Pharmacol Rep. 71 (6): 1067–1078. doi:10.1016/j.pharep.2019.05.021. PMID 31627175.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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