STAT3

信号转导及转录激活蛋白3（英語：Signal transducer and activator of transcription 3，STAT3）是一种由人类基因STAT3 编码的转录因子^[1]。

Signal transducer and activator of transcription 3 (acute-phase response factor) 信号转导及转录激活蛋白3（急性期反应因子）
PDB rendering based on 1bg1.
有效结构 PDB 直系同源检索：PDBe, RCSB PDB查询代码列表 1bg1
标识
代号	STAT3; APRF; HIES
扩展标识	遗传学：102582 鼠基因：103038 同源基因：7960 ChEMBL: 4026 GeneCards: STAT3 Gene
基因本体论描述 分子功能 · RNA polymerase II repressing transcription factor binding · DNA binding · sequence-specific DNA binding transcription factor activity · signal transducer activity · ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity · calcium ion binding · protein binding · transcription factor binding · protein kinase binding · CCR5 chemokine receptor binding · glucocorticoid receptor binding · sequence-specific DNA binding · transcription regulatory region DNA binding · protein dimerization activity 细胞成分 · nucleus · nucleoplasm · nucleolus · cytoplasm · cytosol · plasma membrane 生物过程 · negative regulation of transcription from RNA polymerase II promoter · temperature homeostasis · eye photoreceptor cell differentiation · regulation of transcription, DNA-dependent · regulation of transcription from RNA polymerase II promoter · protein import into nucleus · cellular component movement · acute-phase response · signal transduction · JAK-STAT cascade · nervous system development · cell proliferation · virus-host interaction · cytokine-mediated signaling pathway · stem cell maintenance · sexual reproduction · intracellular receptor signaling pathway · response to estradiol stimulus · cellular response to hormone stimulus · regulation of multicellular organism growth · response to drug · glucose homeostasis · eating behavior · response to ethanol · positive regulation of Notch signaling pathway · positive regulation of transcription, DNA-dependent · positive regulation of transcription from RNA polymerase II promoter · neurotrophin TRK receptor signaling pathway · astrocyte differentiation · radial glial cell differentiation · growth hormone receptor signaling pathway · JAK-STAT cascade involved in growth hormone signaling pathway · interleukin-6-mediated signaling pathway Sources: Amigo / QuickGO
RNA表达模式
更多表达数据
直系同源体
物种	人类	小鼠
Entrez	6774	20848
Ensembl	ENSG00000168610	ENSMUSG00000004040
UniProt	P40763	P42227
mRNA序列	NM_003150	NM_011486
蛋白序列	NP_003141	NP_035616
基因位置	Chr 17: 40.47 – 40.54 Mb	Chr 11: 100.89 – 100.94 Mb
PubMed查询	[1]	[2]
查 论 编

功能

STAT3是STAT蛋白家族的成员。受到细胞因子和生长因子的调节，STAT3被受体相关的Janus激酶（JAK）磷酸化，形成同源或异源二聚体，并转移到细胞核，在那里它们起转录激活剂的作用。具体而言，干扰素，表皮生长因子（EGF），白细胞介素（IL-5和IL-6）等配体作用于受体，导致酪氨酸705磷酸化后，STAT3被激活。此外，STAT3可能通过丝裂原活化蛋白激酶（MAPK）^[2]和c-src非受体酪氨酸激酶磷酸化丝氨酸727而激活。^[3][4]STAT3介导响应细胞刺激的各种基因的表达，因此在许多细胞过程如细胞生长和细胞凋亡中起关键作用。^[5]

当原肠胚形成开始时，STAT3缺陷的小鼠胚胎不能在胚胎发育第7天以后发育。^[6]看来在这些发育的早期阶段，STAT3激活是胚胎干细胞（ESC）自我更新所必需的。事实上，如果STAT3通过其他方式被激活，LIF可以被省略，该LIF被提供给小鼠ESC培养物以保持其未分化状态。^[7]

STAT3对于TH17辅助性T细胞的分化至关重要，TH17辅助性T细胞已涉及多种自體免疫性疾病。^[8]在病毒感染期间，缺乏T细胞中STAT3的小鼠显示产生T-滤泡辅助（Tfh）细胞的能力受损，并且不能维持基于抗体的免疫性。^[9]

临床意义

在癌症中的双重作用

相互作用

STAT3能与下列蛋白質发生交互作用：

• AR^[10][11]
• ELP2^[12]
• EP300^[13]
• EGFR^[14][15]
• HIF1A^[16]
• JAK1^[10][17]
• JUN^[18]
• KHDRBS1^[19]
• MTOR^[20][21]
• MYOD1^[22]
• NDUFA13^[23]
• NFKB1^[24]
• NR3C1^[25][26]
• NCOA1^[27]
• PML^[28]
• RAC1^[29]
• RELA^[24]
• RET^[14][30][31]
• RPA2^[32]
• STAT1^[17][33][34]
• Src^[35]
• TRIP10^[36]

参考文献

1. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. April 1994, 77 (1): 63–71. PMID 7512451. doi:10.1016/0092-8674(94)90235-6.
2. Tkach, Mercedes; Rosemblit, Cinthia; Rivas, Martín A.; Proietti, Cecilia J.; Díaz Flaqué, María Celeste; Mercogliano, María Florencia; Beguelin, Wendy; Maronna, Esteban; Guzmán, Pablo. p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth. Endocrine-Related Cancer. April 2013, 20 (2): 197–212 [2018-02-11]. ISSN 1479-6821. PMID 23329648. doi:10.1530/ERC-12-0194. （原始内容存档于2018-02-18）.
3. Silva, Corinne M. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene. 2004-10-18, 23 (48): 8017–8023 [2018-02-11]. ISSN 0950-9232. PMID 15489919. doi:10.1038/sj.onc.1208159. （原始内容存档于2018-02-18）.
4. Lim, Cheh Peng; Cao, Xinmin. Structure, function, and regulation of STAT proteins. Molecular bioSystems. November 2006, 2 (11): 536–550 [2018-02-11]. ISSN 1742-206X. PMID 17216035. doi:10.1039/b606246f. （原始内容存档于2018-02-18）.
5. Yuan, Zheng-Long; Guan, Ying-Jie; Wang, Lijuan; Wei, Wenyi; Kane, Agnes B.; Chin, Y. Eugene. Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. Molecular and Cellular Biology. November 2004, 24 (21): 9390–9400 [2018-02-11]. ISSN 0270-7306. PMID 15485908. doi:10.1128/MCB.24.21.9390-9400.2004. （原始内容存档于2018-02-18）.
6. Takeda, K.; Noguchi, K.; Shi, W.; Tanaka, T.; Matsumoto, M.; Yoshida, N.; Kishimoto, T.; Akira, S. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proceedings of the National Academy of Sciences of the United States of America. 1997-04-15, 94 (8): 3801–3804 [2018-02-11]. ISSN 0027-8424. PMID 9108058. （原始内容存档于2018-07-24）.
7. Matsuda, T; Nakamura, T; Nakao, K; Arai, T; Katsuki, M; Heike, T; Yokota, T. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells.. The EMBO Journal. 1999-08-02, 18 (15): 4261–4269. ISSN 0261-4189. PMC 1171502 . PMID 10428964. doi:10.1093/emboj/18.15.4261.
8. Yang, Xuexian O.; Panopoulos, Athanasia D.; Nurieva, Roza; Chang, Seon Hee; Wang, Demin; Watowich, Stephanie S.; Dong, Chen. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. The Journal of Biological Chemistry. 2007-03-30, 282 (13): 9358–9363 [2018-02-11]. ISSN 0021-9258. PMID 17277312. doi:10.1074/jbc.C600321200. （原始内容存档于2018-07-23）.
9. McIlwain, David R.; Grusdat, Melanie; Pozdeev, Vitaly I.; Xu, Haifeng C.; Shinde, Prashant; Reardon, Colin; Hao, Zhenyue; Beyer, Marc; Bergthaler, Andreas. T-cell STAT3 is required for the maintenance of humoral immunity to LCMV. European Journal of Immunology. February 2015, 45 (2): 418–427 [2018-02-11]. ISSN 1521-4141. PMC 4383653 . PMID 25393615. doi:10.1002/eji.201445060. （原始内容存档于2018-07-23）.
10. Ueda T, Bruchovsky N, Sadar MD. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J. Biol. Chem. 2002, 277 (9): 7076–85. PMID 11751884. doi:10.1074/jbc.M108255200.
11. Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A. Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells. Biochem. Biophys. Res. Commun. 2001, 283 (1): 179–87. PMID 11322786. doi:10.1006/bbrc.2001.4758.
12. Collum RG, Brutsaert S, Lee G, Schindler C. A Stat3-interacting protein (StIP1) regulates cytokine signal transduction. Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (18): 10120–5. PMC 27739 . PMID 10954736. doi:10.1073/pnas.170192197.
13. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science. 1999, 284 (5413): 479–82. PMID 10205054. doi:10.1126/science.284.5413.479.
14. Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE. 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. 2004, 24 (21): 9390–400. PMC 522220 . PMID 15485908. doi:10.1128/MCB.24.21.9390-9400.2004.
15. Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE. ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J. Biol. Chem. 1999, 274 (24): 17209–18. PMID 10358079. doi:10.1074/jbc.274.24.17209.
16. Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH, Kim TY, Juhnn YS, Kim SJ, Park JW, Ye SK, Chung MH. STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination. Exp. Mol. Med. 2008, 40 (5): 479–85. PMC 2679355 . PMID 18985005. doi:10.3858/emm.2008.40.5.479.
17. Spiekermann K, Biethahn S, Wilde S, Hiddemann W, Alves F. Constitutive activation of STAT transcription factors in acute myelogenous leukemia. Eur. J. Haematol. 2001, 67 (2): 63–71. PMID 11722592.
18. Zhang X, Wrzeszczynska MH, Horvath CM, Darnell JE. Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation. Mol. Cell. Biol. 1999, 19 (10): 7138–46. PMC 84707 . PMID 10490649.
19. Sanchez-Margalet V, Martin-Romero C. Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. Cell. Immunol. 2001, 211 (1): 30–6. PMID 11585385. doi:10.1006/cimm.2001.1815.
20. Yokogami K, Wakisaka S, Avruch J, Reeves SA. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr. Biol. 2000, 10 (1): 47–50. PMID 10660304. doi:10.1016/S0960-9822(99)00268-7.
21. Kusaba H, Ghosh P, Derin R, Buchholz M, Sasaki C, Madara K, Longo DL. Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR). J. Biol. Chem. 2005, 280 (2): 1037–43. PMID 15522880. doi:10.1074/jbc.M405204200.
22. Kataoka Y, Matsumura I, Ezoe S, Nakata S, Takigawa E, Sato Y, Kawasaki A, Yokota T, Nakajima K, Felsani A, Kanakura Y. Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts. J. Biol. Chem. 2003, 278 (45): 44178–87. PMID 12947115. doi:10.1074/jbc.M304884200.
23. Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, Poli V, Stark GR, Kalvakolanu DV. The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proc. Natl. Acad. Sci. U.S.A. 2003, 100 (16): 9342–7. PMC 170920 . PMID 12867595. doi:10.1073/pnas.1633516100.
24. Yu Z, Zhang W, Kone BC. 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. 2002, 367 (Pt 1): 97–105. PMC 1222853 . PMID 12057007. doi:10.1042/BJ20020588.
25. Lerner L, Henriksen MA, Zhang X, Darnell JE. STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene. Genes Dev. 2003, 17 (20): 2564–77. PMC 218150 . PMID 14522952. doi:10.1101/gad.1135003.
26. Zhang Z, Jones S, Hagood JS, Fuentes NL, Fuller GM. STAT3 acts as a co-activator of glucocorticoid receptor signaling. J. Biol. Chem. 1997, 272 (49): 30607–10. PMID 9388192. doi:10.1074/jbc.272.49.30607.
27. Giraud S, Bienvenu F, Avril S, Gascan H, Heery DM, Coqueret O. Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a. J. Biol. Chem. 2002, 277 (10): 8004–11. PMID 11773079. doi:10.1074/jbc.M111486200.
28. Kawasaki A, Matsumura I, Kataoka Y, Takigawa E, Nakajima K, Kanakura Y. Opposing effects of PML and PML/RAR alpha on STAT3 activity. Blood. 2003, 101 (9): 3668–73. PMID 12506013. doi:10.1182/blood-2002-08-2474.
29. Simon AR, Vikis HG, Stewart S, Fanburg BL, Cochran BH, Guan KL. Regulation of STAT3 by direct binding to the Rac1 GTPase. Science. 2000, 290 (5489): 144–7. PMID 11021801. doi:10.1126/science.290.5489.144.
30. Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, Park KC, Chung HK, Kim JM, Lee TH, Yu DY, Shong M. 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. 2003, 17 (6): 1155–66. PMID 12637586. doi:10.1210/me.2002-0401.
31. Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, Kruijer W. MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene. 2001, 20 (38): 5350–8. PMID 11536047. doi:10.1038/sj.onc.1204715.
32. Kim J, Kim D, Chung J. Replication protein a 32 kDa subunit (RPA p32) binds the SH2 domain of STAT3 and regulates its transcriptional activity. Cell Biol. Int. 2000, 24 (7): 467–73. PMID 10875894. doi:10.1006/cbir.2000.0525.
33. Gunaje JJ, Bhat GJ. Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin. Biochem. Biophys. Res. Commun. 2001, 288 (1): 252–7. PMID 11594781. doi:10.1006/bbrc.2001.5759.
34. Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, Platt A, Gilmer TM, Fu XY, Chin YE. 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. 2002, 277 (34): 30716–23. PMID 12070153. doi:10.1074/jbc.M202823200.
35. Cao X, Tay A, Guy GR, Tan YH. Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol. Cell. Biol. 1996, 16 (4): 1595–603. PMC 231145 . PMID 8657134.
36. Chung YH, Cho NH, Garcia MI, Lee SH, Feng P, Jung JU. Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein. J. Virol. 2004, 78 (12): 6489–97. PMC 416526 . PMID 15163742. doi:10.1128/JVI.78.12.6489-6497.2004.

延伸阅读

• Hoey T, Grusby MJ. STATs as mediators of cytokine-induced responses. Adv. Immunol. Advances in Immunology. 1999, 71: 145–162. ISBN 978-0-12-022471-5. PMID 9917912. doi:10.1016/S0065-2776(08)60401-0.
• Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002, 285 (1–2): 1–24. PMID 12039028. doi:10.1016/S0378-1119(02)00398-0.
• Joseph AM, Kumar M, Mitra D. Nef: "necessary and enforcing factor" in HIV infection. Curr. HIV Res. 2005, 3 (1): 87–94. PMID 15638726. doi:10.2174/1570162052773013.
• Inghirami G; Chiarle R; Simmons WJ; et al. New and old functions of STAT3: a pivotal target for individualized treatment of cancer. Cell Cycle. 2006, 4 (9): 1131–3. PMID 16082218.
• Leeman RJ, Lui VW, Grandis JR. STAT3 as a therapeutic target in head and neck cancer. Expert opinion on biological therapy. 2006, 6 (3): 231–241. PMID 16503733. doi:10.1517/14712598.6.3.231.
• Aggarwal BB; Sethi G; Ahn KS; et al. Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann. N. Y. Acad. Sci. 2007, 1091: 151–169. PMID 17341611. doi:10.1196/annals.1378.063.

外部链接

• FactorBook STAT3