Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3gene.[1] It is a member of the STAT protein family.
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]
Niclosamide seems to inhibit the STAT3 signalling pathway.[49]
References
↑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. PMID7512451.
↑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. PMID23329648.
↑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. PMID15489919.
↑Lim CP, Cao X (November 2006). "Structure, function, and regulation of STAT proteins". Molecular bioSystems. 2 (11): 536–50. doi:10.1039/B606246F. PMID17216035..
↑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. PMID17881746.
↑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. PMC4304103. PMID25359994.
↑ 12.012.1Klampfer 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. PMID16529541.
↑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. PMID16540667.
↑Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T, Sekine I (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. PMID16685378.
↑Musteanu M, Blaas L, Mair M, Schlederer M, Bilban M, Tauber S, Esterbauer H, Mueller M, Casanova E, Kenner L, Poli V, Eferl R (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. PMID19962983.
↑ 20.020.1Ueda 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. PMID11751884.
↑Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A (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. PMID11322786.
↑Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (April 1999). "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science. 284 (5413): 479–82. doi:10.1126/science.284.5413.479. PMID10205054.
↑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. PMID10358079.
↑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. PMID11585385.
↑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. PMID10660304.
↑Kusaba H, Ghosh P, Derin R, Buchholz M, Sasaki C, Madara K, Longo DL (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. PMID15522880.
↑Kataoka Y, Matsumura I, Ezoe S, Nakata S, Takigawa E, Sato Y, Kawasaki A, Yokota T, Nakajima K, Felsani A, Kanakura Y (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. PMID12947115.
↑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. PMID9388192.
↑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. PMID11773079.
↑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. PMID12506013.
↑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. doi:10.1126/science.290.5489.144. PMID11021801.
↑Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, Park KC, Chung HK, Kim JM, Lee TH, Yu DY, Shong M (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. PMID12637586.
↑Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, Kruijer W (August 2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene. 20 (38): 5350–8. doi:10.1038/sj.onc.1204715. PMID11536047.
↑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. PMID10875894.
↑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. PMID11594781.
↑Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, Platt A, Gilmer TM, Fu XY, Chin YE (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. PMID12070153.
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. PMID12039028.
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. PMID15638726.
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. PMID16082218.
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. PMID16503733.
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. PMID17341611.