The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by receptor-associated kinases and then form homo- or heterodimers that translocate to the cell nucleus, where they act as transcription activators. This protein is activated through phosphorylation of tyrosine 705, in response to various cytokines and growth factors including interferons, epidermal growth factor (EGF), Interleukin (IL-)5, IL-6, hepatocyte growth factor (HGF), leukemia inhibitory factor (LIF), bone morphogenetic protein 2 (BMP-2), IL-10, and also the hormone leptin. 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. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. Three alternatively spliced transcript variants encoding distinct isoforms have been described.
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.
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.
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. Very recently 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. In addition, two recent studies performed in APC mutant mice showed that STAT3 has an inhibiting role in colon carcinogenesis depending on tumor stage.
^Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (Apr 1994). "Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway". Cell77 (1): 63–71. doi:10.1016/0092-8674(94)90235-6. PMID7512451.
^ abKlampfer L (Mar 2006). "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs". Current Cancer Drug Targets6 (2): 107–121. doi:10.2174/156800906776056491. PMID16529541.
^Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA (Mar 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 Research66 (6): 3162–3168. 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 (Jun 2006). "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer". Oncology Reports15 (6): 1445–51. doi:10.3892/or.15.6.1445. PMID16685378.
^Lee J, Kim JC, Lee SE, Quinley C, Kim H, Herdman S, Corr M, Raz E (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): 18182–18189. doi:10.1074/jbc.M111.328831. PMID22496368.
^Musteanu M, Blaas L, Mair M, Schlederer M, Bilban M, Tauber S, Esterbauer H, Mueller M, Casanova E, Kenner L, Poli V, Eferl R (Mar 2010). "Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice". Gastroenterology138 (3): 1003–1011. doi:10.1053/j.gastro.2009.11.049. PMID19962983.
^ abUeda T, Bruchovsky N, Sadar MD (Mar 2002). "Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways". The Journal of Biological Chemistry277 (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 (Apr 2001). "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells". Biochemical and Biophysical Research Communications283 (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 (Apr 1999). "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science284 (5413): 479–82. doi:10.1126/science.284.5413.479. PMID10205054.
^Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (Jun 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry274 (24): 17209–18. doi:10.1074/jbc.274.24.17209. PMID10358079.
^Sanchez-Margalet V, Martin-Romero C (Jul 2001). "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway". Cellular Immunology211 (1): 30–6. doi:10.1006/cimm.2001.1815. PMID11585385.
^Yokogami K, Wakisaka S, Avruch J, Reeves SA (Jan 2000). "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Current Biology10 (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 (Jan 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 Chemistry280 (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 (Nov 2003). "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". The Journal of Biological Chemistry278 (45): 44178–87. doi:10.1074/jbc.M304884200. PMID12947115.
^Zhang Z, Jones S, Hagood JS, Fuentes NL, Fuller GM (Dec 1997). "STAT3 acts as a co-activator of glucocorticoid receptor signaling". The Journal of Biological Chemistry272 (49): 30607–10. doi:10.1074/jbc.272.49.30607. PMID9388192.
^Giraud S, Bienvenu F, Avril S, Gascan H, Heery DM, Coqueret O (Mar 2002). "Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a". The Journal of Biological Chemistry277 (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". Blood101 (9): 3668–73. doi:10.1182/blood-2002-08-2474. PMID12506013.
^Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, Park KC, Chung HK, Kim JM, Lee TH, Yu DY, Shong M (Jun 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 Endocrinology17 (6): 1155–66. doi:10.1210/me.2002-0401. PMID12637586.
^Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, Kruijer W (Aug 2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene20 (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 International24 (7): 467–73. doi:10.1006/cbir.2000.0525. PMID10875894.
^Gunaje JJ, Bhat GJ (Oct 2001). "Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin". Biochemical and Biophysical Research Communications288 (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 (Aug 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 Chemistry277 (34): 30716–23. doi:10.1074/jbc.M202823200. PMID12070153.
Inghirami G, Chiarle R, Simmons WJ, Piva R, Schlessinger K, Levy DE (Sep 2005). "New and old functions of STAT3: a pivotal target for individualized treatment of cancer". Cell Cycle4 (9): 1131–3. doi:10.4161/cc.4.9.1985. PMID16082218.
Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, Sung B, Ichikawa H (Dec 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 Sciences1091: 151–169. doi:10.1196/annals.1378.063. PMID17341611.