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Stat3

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Stat3

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  ; APRF; HIES
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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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

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

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

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

STAT3 has been shown to interact with:

References

  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.  
  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.  
  3. ^ Silva CM (2004). "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis". Oncogene 23 (48): 8017–8023.  
  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.  
  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.  
  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.  
  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.  
  8. ^ Levy DE, Loomis CA (October 2007). "STAT3 signaling and the hyper-IgE syndrome". N. Engl. J. Med. 357 (16): 1655–1658.  
  9. ^ a b Klampfer L (2006). "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs". Curr Cancer Drug Targets 6 (2): 107–121.  
  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.  
  11. ^ Yin W, Cheepala S, Roberts JN, Syson-Chan K, Digiovanni J and Clifford JL (2006). "Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions". Mol Cancer 5 (1): 15.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  35. ^ Simon AR, Vikis HG, Stewart S, Fanburg BL, Cochran BH, Guan KL (2000). "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science 290 (5489): 144–7.  
  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.  
  37. ^ Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, Kruijer W (2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene 20 (38): 5350–8.  
  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.  
  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.  
  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.  
  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.  
  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.  

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