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

PDB rendering based on 1bg1.
Available structures
1bg1
Identifiers
Symbols STAT3; APRF; FLJ20882; MGC16063
External IDs OMIM102582 MGI103038 HomoloGene7960 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 Q8CFJ6
RefSeq (mRNA) NM_003150 XM_001005155
RefSeq (protein) NP_003141 XP_001005155
Location (UCSC) Chr 17:
37.72 - 37.79 Mb
Chr 11:
100.7 - 100.76 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]

Contents

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 the 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 two residues, tyrosine 705 and serine 727, in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. 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 IL-6 family cytokines (including IL-6, oncostatin M and leukemia inhibitory factor) to the gp130 receptor triggers STAT3 phosphorylation by JAK2. EGF-R 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]

STAT3-deficient mouse embryos can not develop beyond embryonic day 7 (E7.0), when gastrulation initiates.[4] 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.[5]

STAT3 is essential for the differentiation of the TH17 helper T cells which has been implicated in a variety of autoimmune diseases.[6]

Clinical significance

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[7][8][9][10] It has anti-apoptotic as well as proliferative effects.[7]

Dual role in cancer

Although no natural mutation in Stat3 has been reported so far, 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.[11] In this report on human glioblastoma tumor, or brain cancer, Stat3 was shown to have a 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.

Interactions

STAT3 has been shown to interact with RET proto-oncogene,[12][13][14] KHDRBS1,[15] RPA2,[16] NDUFA13,[17] Janus kinase 1,[18][19] Glucocorticoid receptor,[20][21] RELA,[22] NFKB1,[22] STAT1,[19][23][24] Src,[25] ELP2,[26] Androgen receptor,[18][27] TRIP10,[28] HIF1A,[29] Epidermal growth factor receptor,[12][30] Mammalian target of rapamycin,[31][32] Nuclear receptor coactivator 1,[33] RAC1,[34] MyoD,[35] EP300,[36] C-jun[37] and Promyelocytic leukemia protein.[38]

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. 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. 15485908.  
  3. ^ Silva CM (2004). "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis". Oncogene 23 (48): 8017–8023. PMID 15489919.  
  4. ^ 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): 3801–3084. PMID 9108058.  
  5. ^ 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. PMID 10428964.  
  6. ^ 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): 9358–63. doi:10.1074/jbc.C600321200. PMID 17277312.  
  7. ^ 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. PMID 16529541.  
  8. ^ 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. PMID 16540667.  
  9. ^ 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). PMID 16603078.  
  10. ^ 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): 1445–1451. PMID 16685378.  
  11. ^ 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): 449–62. doi:10.1101/gad.1606508. PMID 18258752.  
  12. ^ a b Yuan, Zheng-Long; Guan Ying-Jie, Wang Lijuan, Wei Wenyi, Kane Agnes B, Chin Y Eugene (Nov. 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. (United States) 24 (21): 9390–400. doi:10.1128/MCB.24.21.9390-9400.2004. PMID 15485908.  
  13. ^ Hwang, Jung Hwan; Kim Dong Wook, Suh Jae Mi, Kim Ho, Song Jung Hun, Hwang Eun Suk, Park Ki Cheol, Chung Hyo Kyun, Kim Jin Man, Lee Tae-Hoon, Yu Dae-Yeul, Shong Minho (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". Mol. Endocrinol. (United States) 17 (6): 1155–66. doi:10.1210/me.2002-0401. PMID 12637586.  
  14. ^ Schuringa, J J; Wojtachnio K, Hagens W, Vellenga E, Buys C H, Hofstra R, Kruijer W (Aug. 2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene (England) 20 (38): 5350–8. doi:10.1038/sj.onc.1204715. PMID 11536047.  
  15. ^ Sanchez-Margalet, V; Martin-Romero C (Jul. 2001). "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway". Cell. Immunol. (United States) 211 (1): 30–6. doi:10.1006/cimm.2001.1815. PMID 11585385.  
  16. ^ 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. (ENGLAND) 24 (7): 467–73. doi:10.1006/cbir.2000.0525. PMID 10875894.  
  17. ^ Zhang, Jun; Yang Jinbo, Roy Sanjit K, Tininini Silvia, Hu Jiadi, Bromberg Jacqueline F, Poli Valeria, Stark George R, Kalvakolanu Dhananjaya V (Aug. 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. (United States) 100 (16): 9342–7. doi:10.1073/pnas.1633516100. PMID 12867595.  
  18. ^ a b Ueda, Takeshi; Bruchovsky Nicholas, Sadar Marianne D (Mar. 2002). "Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways". J. Biol. Chem. (United States) 277 (9): 7076–85. doi:10.1074/jbc.M108255200. PMID 11751884.  
  19. ^ a b Spiekermann, K; Biethahn S, Wilde S, Hiddemann W, Alves F (Aug. 2001). "Constitutive activation of STAT transcription factors in acute myelogenous leukemia". Eur. J. Haematol. (Denmark) 67 (2): 63–71. PMID 11722592.  
  20. ^ Lerner, Lorena; Henriksen Melissa A, Zhang Xiaokui, Darnell James E (Oct. 2003). "STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene". Genes Dev. (United States) 17 (20): 2564–77. doi:10.1101/gad.1135003. PMID 14522952.  
  21. ^ Zhang, Z; Jones S, Hagood J S, Fuentes N L, Fuller G M (Dec. 1997). "STAT3 acts as a co-activator of glucocorticoid receptor signaling". J. Biol. Chem. (UNITED STATES) 272 (49): 30607–10. PMID 9388192.  
  22. ^ a b Yu, Zhiyuan; Zhang Wenzheng, Kone Bruce C (Oct. 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. (England) 367 (Pt 1): 97–105. doi:10.1042/BJ20020588. PMID 12057007.  
  23. ^ Gunaje, J J; Bhat G J (Oct. 2001). "Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin". Biochem. Biophys. Res. Commun. (United States) 288 (1): 252–7. doi:10.1006/bbrc.2001.5759. PMID 11594781.  
  24. ^ Xia, Ling; Wang Lijuan, Chung Alicia S, Ivanov Stanimir S, Ling Mike Y, Dragoi Ana M, Platt Adam, Gilmer Tona M, Fu Xin-Yuan, Chin Y Eugene (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". J. Biol. Chem. (United States) 277 (34): 30716–23. doi:10.1074/jbc.M202823200. PMID 12070153.  
  25. ^ Cao, X; Tay A, Guy G R, Tan Y H (Apr. 1996). "Activation and association of Stat3 with Src in v-Src-transformed cell lines". Mol. Cell. Biol. (UNITED STATES) 16 (4): 1595–603. PMID 8657134.  
  26. ^ Collum, R G; Brutsaert S, Lee G, Schindler C (Aug. 2000). "A Stat3-interacting protein (StIP1) regulates cytokine signal transduction". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (18): 10120–5. doi:10.1073/pnas.170192197. PMID 10954736.  
  27. ^ 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". Biochem. Biophys. Res. Commun. (United States) 283 (1): 179–87. doi:10.1006/bbrc.2001.4758. PMID 11322786.  
  28. ^ Chung, Young-Hwa; Cho Nam-hyuk, Garcia Maria Ines, Lee Sun-Hwa, Feng Pinghui, Jung Jae U (Jun. 2004). "Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein". J. Virol. (United States) 78 (12): 6489–97. doi:10.1128/JVI.78.12.6489-6497.2004. PMID 15163742.  
  29. ^ Jung, Joo Eun; Kim Hong Sook, Lee Chang Seok, Shin Yong Jae, Kim Yong Nyun, Kang Gyeong Hoon, Kim Tae You, Juhnn Yong Sung, Kim Sung Joon, Park Jong Wan, Ye Sang Kyu, Chung Myung Hee (Oct. 2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Exp. Mol. Med. (Korea (South)) 40 (5): 479–85. PMID 18985005.  
  30. ^ Olayioye, M A; Beuvink I, Horsch K, Daly J M, Hynes N E (Jun. 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". J. Biol. Chem. (UNITED STATES) 274 (24): 17209–18. PMID 10358079.  
  31. ^ Yokogami, K; Wakisaka S, Avruch J, Reeves S A (Jan. 2000). "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Curr. Biol. (ENGLAND) 10 (1): 47–50. PMID 10660304.  
  32. ^ Kusaba, Hitoshi; Ghosh Paritosh, Derin Rachel, Buchholz Meredith, Sasaki Carl, Madara Karen, Longo Dan L (Jan. 2005). "Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR)". J. Biol. Chem. (United States) 280 (2): 1037–43. doi:10.1074/jbc.M405204200. PMID 15522880.  
  33. ^ Giraud, Sandrine; Bienvenu Frédéric, Avril Sylvie, Gascan Hugues, Heery David M, Coqueret Olivier (Mar. 2002). "Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a". J. Biol. Chem. (United States) 277 (10): 8004–11. doi:10.1074/jbc.M111486200. PMID 11773079.  
  34. ^ Simon, A R; Vikis H G, Stewart S, Fanburg B L, Cochran B H, Guan K L (Oct. 2000). "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science (UNITED STATES) 290 (5489): 144–7. PMID 11021801.  
  35. ^ Kataoka, Yoshihisa; Matsumura Itaru, Ezoe Sachiko, Nakata Soichi, Takigawa Eri, Sato Yusuke, Kawasaki Akira, Yokota Takashi, Nakajima Koichi, Felsani Armando, Kanakura Yuzuru (Nov. 2003). "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". J. Biol. Chem. (United States) 278 (45): 44178–87. doi:10.1074/jbc.M304884200. PMID 12947115.  
  36. ^ 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". Science (UNITED STATES) 284 (5413): 479–82. PMID 10232991.  
  37. ^ Zhang, X; Wrzeszczynska M H, Horvath C M, Darnell J E (Oct. 1999). "Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation". Mol. Cell. Biol. (UNITED STATES) 19 (10): 7138–46. PMID 10490649.  
  38. ^ Kawasaki, Akira; Matsumura Itaru, Kataoka Yoshihisa, Takigawa Eri, Nakajima Koichi, Kanakura Yuzuru (May. 2003). "Opposing effects of PML and PML/RAR alpha on STAT3 activity". Blood (United States) 101 (9): 3668–73. doi:10.1182/blood-2002-08-2474. PMID 12506013.  

Further reading

  • Hoey T, Grusby MJ (1999). "STATs as mediators of cytokine-induced responses.". Adv. Immunol. 71: 145–62. doi:10.1016/S0065-2776(08)60401-0. 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): 231–41. 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: 151–69. doi:10.1196/annals.1378.063. PMID 17341611.  
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