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STAT3

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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; OMA:STAT3 - orthologs
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

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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

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000168610 – Ensembl, May 2017
  2. ^ a b c 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, et al. (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, et al. (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. hdl:11336/5548. 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. S2CID 9420068.
  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, et al. (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, et al. (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, et al. (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, et al. (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, et al. (July 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. PMC 8581997. PMID 33862151.
  15. ^ Matsuyama T, Kubli SP, Yoshinaga SK, Pfeffer K, Mak TW (December 2020). "An aberrant STAT pathway is central to COVID-19". Cell Death and Differentiation. 27 (12): 3209–3225. doi:10.1038/s41418-020-00633-7. PMC 7545020. PMID 33037393.
  16. ^ Chang Z, Wang Y, Zhou X, Long JE (August 2018). "STAT3 roles in viral infection: antiviral or proviral?". Future Virology. 13 (8): 557–574. doi:10.2217/fvl-2018-0033. PMC 7079998. PMID 32201498.
  17. ^ Levy DE, Loomis CA (October 2007). "STAT3 signaling and the hyper-IgE syndrome". The New England Journal of Medicine. 357 (16): 1655–8. doi:10.1056/NEJMe078197. PMID 17881746.
  18. ^ Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. (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.
  19. ^ a b Klampfer L (March 2006). "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs". Current Cancer Drug Targets. 6 (2): 107–21. doi:10.2174/156800906776056491. PMID 16529541.
  20. ^ Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA (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. 66 (6): 3162–8. doi:10.1158/0008-5472.CAN-05-3757. PMID 16540667.
  21. ^ Yin W, Cheepala S, Roberts JN, Syson-Chan K, DiGiovanni J, Clifford JL (April 2006). "Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions". Molecular Cancer. 5 (1): 15. doi:10.1186/1476-4598-5-15. PMC 1502137. PMID 16603078.
  22. ^ Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, et al. (June 2006). "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer". Oncology Reports. 15 (6): 1445–51. doi:10.3892/or.15.6.1445. PMID 16685378.
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  24. ^ Lee J, Kim JC, Lee SE, Quinley C, Kim H, Herdman S, et al. (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. 22. 287 (22): 18182–9. doi:10.1074/jbc.M111.328831. PMC 3365759. PMID 22496368.
  25. ^ Musteanu M, Blaas L, Mair M, Schlederer M, Bilban M, Tauber S, et al. (March 2010). "Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice". Gastroenterology. 138 (3): 1003–11.e1–5. doi:10.1053/j.gastro.2009.11.049. PMID 19962983.
  26. ^ Vlahopoulos SA (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. 14 (3): 254–270. doi:10.20892/j.issn.2095-3941.2017.0029. PMC 5570602. PMID 28884042.
  27. ^ a b Ueda T, Bruchovsky N, Sadar MD (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. 277 (9): 7076–85. doi:10.1074/jbc.M108255200. PMID 11751884.
  28. ^ Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, et al. (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. 283 (1): 179–87. doi:10.1006/bbrc.2001.4758. PMID 11322786.
  29. ^ Collum RG, Brutsaert S, Lee G, Schindler C (August 2000). "A Stat3-interacting protein (StIP1) regulates cytokine signal transduction". Proceedings of the National Academy of Sciences of the United States of America. 97 (18): 10120–5. Bibcode:2000PNAS...9710120C. doi:10.1073/pnas.170192197. PMC 27739. PMID 10954736.
  30. ^ Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, et al. (April 1999). "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science. 284 (5413): 479–82. Bibcode:1999Sci...284..479N. doi:10.1126/science.284.5413.479. PMID 10205054.
  31. ^ a b 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.
  32. ^ Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (June 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry. 274 (24): 17209–18. doi:10.1074/jbc.274.24.17209. PMID 10358079.
  33. ^ Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH, et al. (October 2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Experimental & Molecular Medicine. 40 (5): 479–85. doi:10.3858/emm.2008.40.5.479. PMC 2679355. PMID 18985005.
  34. ^ a b Spiekermann K, Biethahn S, Wilde S, Hiddemann W, Alves F (August 2001). "Constitutive activation of STAT transcription factors in acute myelogenous leukemia". European Journal of Haematology. 67 (2): 63–71. doi:10.1034/j.1600-0609.2001.t01-1-00385.x. PMID 11722592. S2CID 38074766.
  35. ^ Zhang X, Wrzeszczynska MH, Horvath CM, Darnell JE (October 1999). "Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation". Molecular and Cellular Biology. 19 (10): 7138–46. doi:10.1128/MCB.19.10.7138. PMC 84707. PMID 10490649.
  36. ^ Sanchez-Margalet V, Martin-Romero C (July 2001). "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway". Cellular Immunology. 211 (1): 30–6. doi:10.1006/cimm.2001.1815. PMID 11585385.
  37. ^ Yokogami K, Wakisaka S, Avruch J, Reeves SA (January 2000). "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Current Biology. 10 (1): 47–50. Bibcode:2000CBio...10...47Y. doi:10.1016/S0960-9822(99)00268-7. PMID 10660304. S2CID 14181036.
  38. ^ Kusaba H, Ghosh P, Derin R, Buchholz M, Sasaki C, Madara K, et al. (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. 280 (2): 1037–43. doi:10.1074/jbc.M405204200. PMID 15522880.
  39. ^ Kataoka Y, Matsumura I, Ezoe S, Nakata S, Takigawa E, Sato Y, et al. (November 2003). "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". The Journal of Biological Chemistry. 278 (45): 44178–87. doi:10.1074/jbc.M304884200. PMID 12947115.
  40. ^ Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, et al. (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. 100 (16): 9342–7. Bibcode:2003PNAS..100.9342Z. doi:10.1073/pnas.1633516100. PMC 170920. PMID 12867595.
  41. ^ a b Yu Z, Zhang W, Kone BC (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. 367 (Pt 1): 97–105. doi:10.1042/BJ20020588. PMC 1222853. PMID 12057007.
  42. ^ Lerner L, Henriksen MA, Zhang X, Darnell JE (October 2003). "STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene". Genes & Development. 17 (20): 2564–77. doi:10.1101/gad.1135003. PMC 218150. PMID 14522952.
  43. ^ Zhang Z, Jones S, Hagood JS, Fuentes NL, Fuller GM (December 1997). "STAT3 acts as a co-activator of glucocorticoid receptor signaling". The Journal of Biological Chemistry. 272 (49): 30607–10. doi:10.1074/jbc.272.49.30607. PMID 9388192.
  44. ^ Giraud S, Bienvenu F, Avril S, Gascan H, Heery DM, Coqueret O (March 2002). "Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a". The Journal of Biological Chemistry. 277 (10): 8004–11. doi:10.1074/jbc.M111486200. PMID 11773079.
  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.
  47. ^ Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, et al. (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. 17 (6): 1155–66. doi:10.1210/me.2002-0401. PMID 12637586.
  48. ^ Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, et al. (August 2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene. 20 (38): 5350–8. doi:10.1038/sj.onc.1204715. PMID 11536047.
  49. ^ Kim J, Kim D, Chung J (2000). "Replication protein a 32 kDa subunit (RPA p32) binds the SH2 domain of STAT3 and regulates its transcriptional activity". Cell Biology International. 24 (7): 467–73. doi:10.1006/cbir.2000.0525. PMID 10875894. S2CID 23783745.
  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.
  51. ^ Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, et al. (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. 277 (34): 30716–23. doi:10.1074/jbc.M202823200. PMID 12070153.
  52. ^ Morris EJ, Kawamura E, Gillespie JA, Balgi A, Kannan N, Muller WJ, et al. (May 2017). "Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1". Nature Communications. 8: 15289. Bibcode:2017NatCo...815289M. doi:10.1038/ncomms15289. PMC 5424153. PMID 28474672.
  53. ^ Cao X, Tay A, Guy GR, Tan YH (April 1996). "Activation and association of Stat3 with Src in v-Src-transformed cell lines". Molecular and Cellular Biology. 16 (4): 1595–603. doi:10.1128/MCB.16.4.1595. PMC 231145. PMID 8657134.
  54. ^ Chung YH, Cho NH, Garcia MI, Lee SH, Feng P, Jung JU (June 2004). "Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein". Journal of Virology. 78 (12): 6489–97. doi:10.1128/JVI.78.12.6489-6497.2004. PMC 416526. PMID 15163742.
  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, et al. (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. (October 2018). "Decreased NAD Activates STAT3 and Integrin Pathways to Drive Epithelial-Mesenchymal Transition". Molecular & Cellular Proteomics. 17 (10): 2005–2017. doi:10.1074/mcp.RA118.000882. PMC 6166677. PMID 29980616.
  58. ^ Uchihara Y, Ohe T, Mashino T, Kidokoro T, Tago K, Tamura H, et al. (December 2019). "N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties". Pharmacological Reports. 71 (6): 1067–1078. doi:10.1016/j.pharep.2019.05.021. PMID 31627175. S2CID 210983316.

Further reading

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