STAT3

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Signal transducer and activator of transcription 3 (acute-phase response factor)

PDB rendering based on 1bg1.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols STAT3 ; APRF; HIES
External IDs OMIM102582 MGI103038 HomoloGene7960 ChEMBL: 4026 GeneCards: STAT3 Gene
RNA expression pattern
PBB GE STAT3 208991 at tn.png
PBB GE STAT3 208992 s at tn.png
PBB GE STAT3 gnf1h01250 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6774 20848
Ensembl ENSG00000168610 ENSMUSG00000004040
UniProt P40763 P42227
RefSeq (mRNA) NM_003150 NM_011486
RefSeq (protein) NP_003141 NP_035616
Location (UCSC) Chr 17:
40.47 – 40.54 Mb
Chr 11:
100.89 – 100.94 Mb
PubMed search [1] [2]

Signal transducer and activator of transcription 3, also known as STAT3, is a transcription factor which in humans is encoded by the STAT3 gene.[1]

Function[edit]

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.

The binding of Interleukin 6—family cytokines (including IL-6, oncostatin M and leukemia inhibitory factor) to the gp130 receptor triggers STAT3 phosphorylation by JAK2. Epidermal growth factor receptor and certain other receptor tyrosine kinases, such as c-MET, phosphorylate STAT3 in response to their ligands.[2] STAT3 is also a target of the c-src non-receptor tyrosine kinase.[3] 12/15-Lipoxygenase derived reactive oxygen species (ROS), have been shown to mediate the signal transduction between the platelet-derived growth factor receptor (PDGF-R) and STAT3 activation in vascular smooth muscle cells.[4]

STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins.[5] 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.[6]

STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases.[7]

Clinical significance[edit]

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.[8]

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[9][10][11][12] It has anti-apoptotic as well as proliferative effects.[9]

Dual role in cancer[edit]

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.[13][14][15] 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.

Interactions[edit]

STAT3 has been shown to interact with:

References[edit]

  1. ^ 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. 
  2. ^ Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB and Chin YE (2004). "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Mol Cell Biol 24 (21): 9390–9400. doi:10.1128/MCB.24.21.9390-9400.2004. PMC 522220. PMID 15485908. 15485908. 
  3. ^ Silva CM (2004). "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis". Oncogene 23 (48): 8017–8023. doi:10.1038/sj.onc.1208159. PMID 15489919. 
  4. ^ Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH (October 2013). "12/15-Lipoxygenase contributes to Platelet-Derived Growth Factor- Induced Activation of Signal Transducer and Activator of Transcription 3". J. Biol. Chem. 288 (49): 35592–603. doi:10.1074/jbc.M113.489013. PMC 3853304. PMID 24165129. 
  5. ^ Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T and Akira S (1997). "Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality". PNAS 94 (8): 3801–3804. doi:10.1073/pnas.94.8.3801. PMC 20521. PMID 9108058. 
  6. ^ Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T and Yokota T (1999). "STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells". EMBO J 18 (15): 4261–4269. doi:10.1093/emboj/18.15.4261. PMC 1171502. PMID 10428964. 
  7. ^ 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". J. Biol. Chem. 282 (13): 9358–9363. doi:10.1074/jbc.C600321200. PMID 17277312. 
  8. ^ Levy DE, Loomis CA (October 2007). "STAT3 signaling and the hyper-IgE syndrome". N. Engl. J. Med. 357 (16): 1655–1658. doi:10.1056/NEJMe078197. PMID 17881746. 
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  10. ^ Alvarez JV, Greulich H, Sellers WR, Meyerson M and Frank DA (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 Res 66 (6): 3162–3168. doi:10.1158/0008-5472.CAN-05-3757. PMID 16540667. 
  11. ^ Yin W, Cheepala S, Roberts JN, Syson-Chan K, Digiovanni J and Clifford JL (2006). 15. "Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions". Mol Cancer 5 (1): 15. doi:10.1186/1476-4598-5-15. PMC 1502137. PMID 16603078. 
  12. ^ Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T and Sekine I (2006). "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer". Oncol Rep 15 (6): 1445–51. PMID 16685378. 
  13. ^ de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, Depinho RA, Bonni A (February 2008). "Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway". Genes Dev. 22 (4): 449–462. doi:10.1101/gad.1606508. PMC 2238667. PMID 18258752. 
  14. ^ Lee, Jongdae; Joanna Kim, Shee-Eun Lee, Christine Quinley, HyeRi Kim, Scott Herdman, Maripat Corr, and Eyal Raz (25 May 2012). "Signal Transducer and Activator of Transcription 3 (STAT3) Protein Suppresses Adenoma-to-carcinoma Transition in Apc min/+ 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. PMID 22496368. 
  15. ^ Musteanu, Monica; Leander Blaas, Markus Mair, Michaela Schlederer AFFILIATIONS Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria , Martin Bilban, Stefanie Tauber, Harald Esterbauer, Mathias Mueller, Emilio Casanova, Lukas Kenner, Valeria Poli, Robert Eferl (March 2010). "Stat3 Is a Negative Regulator of Intestinal Tumor Progression in ApcMin Mice". Gastroenterology 138 (3): 1003–1011. doi:10.1053/j.gastro.2009.11.049. PMID 19962983. 
  16. ^ a b Ueda T, Bruchovsky N, Sadar MD (2002). "Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways". J. Biol. Chem. 277 (9): 7076–85. doi:10.1074/jbc.M108255200. PMID 11751884. 
  17. ^ Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A (2001). "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells". Biochem. Biophys. Res. Commun. 283 (1): 179–87. doi:10.1006/bbrc.2001.4758. PMID 11322786. 
  18. ^ Collum RG, Brutsaert S, Lee G, Schindler C (2000). "A Stat3-interacting protein (StIP1) regulates cytokine signal transduction". Proc. Natl. Acad. Sci. U.S.A. 97 (18): 10120–5. doi:10.1073/pnas.170192197. PMC 27739. PMID 10954736. 
  19. ^ Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (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. PMID 10205054. 
  20. ^ a b Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE (2004). "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Mol. Cell. Biol. 24 (21): 9390–400. doi:10.1128/MCB.24.21.9390-9400.2004. PMC 522220. PMID 15485908. 
  21. ^ Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". J. Biol. Chem. 274 (24): 17209–18. doi:10.1074/jbc.274.24.17209. PMID 10358079. 
  22. ^ Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH, Kim TY, Juhnn YS, Kim SJ, Park JW, Ye SK, Chung MH (2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Exp. Mol. Med. 40 (5): 479–85. doi:10.3858/emm.2008.40.5.479. PMC 2679355. PMID 18985005. 
  23. ^ a b Spiekermann K, Biethahn S, Wilde S, Hiddemann W, Alves F (2001). "Constitutive activation of STAT transcription factors in acute myelogenous leukemia". Eur. J. Haematol. 67 (2): 63–71. PMID 11722592. 
  24. ^ Zhang X, Wrzeszczynska MH, Horvath CM, Darnell JE (1999). "Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation". Mol. Cell. Biol. 19 (10): 7138–46. PMC 84707. PMID 10490649. 
  25. ^ Sanchez-Margalet V, Martin-Romero C (2001). "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway". Cell. Immunol. 211 (1): 30–6. doi:10.1006/cimm.2001.1815. PMID 11585385. 
  26. ^ Yokogami K, Wakisaka S, Avruch J, Reeves SA (2000). "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Curr. Biol. 10 (1): 47–50. doi:10.1016/S0960-9822(99)00268-7. PMID 10660304. 
  27. ^ Kusaba H, Ghosh P, Derin R, Buchholz M, Sasaki C, Madara K, Longo DL (2005). "Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR)". J. Biol. Chem. 280 (2): 1037–43. doi:10.1074/jbc.M405204200. PMID 15522880. 
  28. ^ Kataoka Y, Matsumura I, Ezoe S, Nakata S, Takigawa E, Sato Y, Kawasaki A, Yokota T, Nakajima K, Felsani A, Kanakura Y (2003). "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". J. Biol. Chem. 278 (45): 44178–87. doi:10.1074/jbc.M304884200. PMID 12947115. 
  29. ^ Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, Poli V, Stark GR, Kalvakolanu DV (2003). "The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3". Proc. Natl. Acad. Sci. U.S.A. 100 (16): 9342–7. doi:10.1073/pnas.1633516100. PMC 170920. PMID 12867595. 
  30. ^ a b Yu Z, Zhang W, Kone BC (2002). "Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB". Biochem. J. 367 (Pt 1): 97–105. doi:10.1042/BJ20020588. PMC 1222853. PMID 12057007. 
  31. ^ Lerner L, Henriksen MA, Zhang X, Darnell JE (2003). "STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene". Genes Dev. 17 (20): 2564–77. doi:10.1101/gad.1135003. PMC 218150. PMID 14522952. 
  32. ^ Zhang Z, Jones S, Hagood JS, Fuentes NL, Fuller GM (1997). "STAT3 acts as a co-activator of glucocorticoid receptor signaling". J. Biol. Chem. 272 (49): 30607–10. doi:10.1074/jbc.272.49.30607. PMID 9388192. 
  33. ^ Giraud S, Bienvenu F, Avril S, Gascan H, Heery DM, Coqueret O (2002). "Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a". J. Biol. Chem. 277 (10): 8004–11. doi:10.1074/jbc.M111486200. PMID 11773079. 
  34. ^ Kawasaki A, Matsumura I, Kataoka Y, Takigawa E, Nakajima K, Kanakura Y (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. 
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  36. ^ Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, Park KC, Chung HK, Kim JM, Lee TH, Yu DY, Shong M (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". Mol. Endocrinol. 17 (6): 1155–66. doi:10.1210/me.2002-0401. PMID 12637586. 
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  38. ^ 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 Biol. Int. 24 (7): 467–73. doi:10.1006/cbir.2000.0525. PMID 10875894. 
  39. ^ Gunaje JJ, Bhat GJ (2001). "Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin". Biochem. Biophys. Res. Commun. 288 (1): 252–7. doi:10.1006/bbrc.2001.5759. PMID 11594781. 
  40. ^ Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, Platt A, Gilmer TM, Fu XY, Chin YE (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". J. Biol. Chem. 277 (34): 30716–23. doi:10.1074/jbc.M202823200. PMID 12070153. 
  41. ^ Cao X, Tay A, Guy GR, Tan YH (1996). "Activation and association of Stat3 with Src in v-Src-transformed cell lines". Mol. Cell. Biol. 16 (4): 1595–603. PMC 231145. PMID 8657134. 
  42. ^ Chung YH, Cho NH, Garcia MI, Lee SH, Feng P, Jung JU (2004). "Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein". J. Virol. 78 (12): 6489–97. doi:10.1128/JVI.78.12.6489-6497.2004. PMC 416526. PMID 15163742. 

Further reading[edit]

  • Hoey T, Grusby MJ (1999). "STATs as mediators of cytokine-induced responses". Adv. Immunol. Advances in Immunology 71: 145–162. doi:10.1016/S0065-2776(08)60401-0. ISBN 978-0-12-022471-5. PMID 9917912. 
  • Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (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 (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726. 
  • Inghirami G, Chiarle R, Simmons WJ et al. (2006). "New and old functions of STAT3: a pivotal target for individualized treatment of cancer". Cell Cycle 4 (9): 1131–3. PMID 16082218. 
  • Leeman RJ, Lui VW, Grandis JR (2006). "STAT3 as a therapeutic target in head and neck cancer". Expert opinion on biological therapy 6 (3): 231–241. doi:10.1517/14712598.6.3.231. PMID 16503733. 
  • Aggarwal BB, Sethi G, Ahn KS et al. (2007). "Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution". Ann. N. Y. Acad. Sci. 1091: 151–169. doi:10.1196/annals.1378.063. PMID 17341611. 

External links[edit]