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.[1] 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), form homo- or heterodimers, and translocate to the cell nucleus where they act as transcription activators. 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)[2] and through c-src non-receptor tyrosine kinase.[3][4] 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.[5]

STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins.[6] 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.[7]

STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases.[8] 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.[9]

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.[10]

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,[11] while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[12][13][14][15] It has anti-apoptotic as well as proliferative effects.[12]

STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported.[16][17][18] 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.[19]

Interactions

STAT3 has been shown to interact with:

Niclosamide seems to inhibit the STAT3 signalling pathway.[49]

References

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  2. 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.
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  5. 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.
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  7. 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.
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  27. 27.0 27.1 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.
  28. 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. PMC 84707. PMID 10490649.
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  30. 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. doi:10.1016/S0960-9822(99)00268-7. PMID 10660304.
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  45. Morris EJ, Kawamura E, Gillespie JA, Balgi A, Kannan N, Muller WJ, Roberge M, Dedhar S (May 2017). "Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1". Nature Communications. 8: 15289. doi:10.1038/ncomms15289. PMC 5424153. PMID 28474672.
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  47. 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.
  48. 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. doi:10.1073/pnas.0501643102. PMC 1149424. PMID 15919823.
  49. 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.

Further reading

  • Hoey T, Grusby MJ (1999). "STATs as mediators of cytokine-induced responses". Advances in Immunology. Advances in Immunology. 71: 145–62. doi:10.1016/S0065-2776(08)60401-0. ISBN 978-0-12-022471-5. PMID 9917912.
  • Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (February 2002). "Signaling through the JAK/STAT pathway, recent advances and future challenges". Gene. 285 (1–2): 1–24. doi:10.1016/S0378-1119(02)00398-0. PMID 12039028.
  • Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
  • Inghirami G, Chiarle R, Simmons WJ, Piva R, Schlessinger K, Levy DE (September 2005). "New and old functions of STAT3: a pivotal target for individualized treatment of cancer". Cell Cycle. 4 (9): 1131–3. doi:10.4161/cc.4.9.1985. PMID 16082218.
  • Leeman RJ, Lui VW, Grandis JR (March 2006). "STAT3 as a therapeutic target in head and neck cancer". Expert Opinion on Biological Therapy. 6 (3): 231–41. doi:10.1517/14712598.6.3.231. PMID 16503733.
  • Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, Sung B, Ichikawa H (December 2006). "Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution". Annals of the New York Academy of Sciences. 1091: 151–69. doi:10.1196/annals.1378.063. PMID 17341611.

External links