STAT3

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

PDB rendering based on 1bg1.
Identifiers
Symbols STAT3; APRF; FLJ20882; HIES; MGC16063
External IDs OMIM: 102582 MGI: 103038 HomoloGene: 7960 GeneCards: STAT3 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 6774 20848
Ensembl ENSG00000168610 ENSMUSG00000004040
UniProt P40763 Q8CFJ6
RefSeq (mRNA) NM_003150.3 XM_001005155
RefSeq (protein) NP_003141.2 XP_001005155
Location (UCSC) Chr 17:
40.47 – 40.54 Mb		 Chr 11:
100.75 – 100.8 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 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 interferons, epidermal growth factor, Interleukin 5, Interleukin-6, hepatocyte growth factor, leukemia inhibitory factor (LIF), bone morphogenetic protein 2 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]

STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins.[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 have been implicated in a variety of autoimmune diseases.[6]

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.[7]

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[8][9][10][11] It has anti-apoptotic as well as proliferative effects.[8]

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.[12] In this 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.

Interactions

STAT3 has been shown to interact with:


References

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  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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=522220. 
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  18. ^ 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. 24 (21): 9390–9400. doi:10.1128/MCB.24.21.9390-9400.2004. PMC 522220. PMID 15485908. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=522220. 
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  22. ^ 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. doi:10.3858/emm.2008.40.5.479. PMC 2679355. PMID 18985005. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2679355. 
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  26. ^ 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. 280 (2): 1037–1043. doi:10.1074/jbc.M405204200. PMID 15522880. 
  27. ^ 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. 278 (45): 44178–44187. doi:10.1074/jbc.M304884200. PMID 12947115. 
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  31. ^ 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 101 (9): 3668–3673. doi:10.1182/blood-2002-08-2474. PMID 12506013. 
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  39. ^ 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. 277 (34): 30716–30723. doi:10.1074/jbc.M202823200. PMID 12070153. 
  40. ^ 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. 78 (12): 6489–6497. doi:10.1128/JVI.78.12.6489-6497.2004. PMC 416526. PMID 15163742. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=416526. 

Further reading

  • 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 9780120224715. 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

Ligand
Cytokine receptor
Janus kinase
JAK1 · JAK2 · JAK3 · TYK2
Adaptor proteins
STAT1 · STAT2 · STAT3 · STAT4 · STAT5 · STAT6
PIAS1 · PIAS2 · PIAS3 · PIAS4
1, 2, 3, 4, 5, 6, 7
IRF1 · IRF2 · IRF3 · IRF4 · IRF5 · IRF6 · IRF7 · IRF8
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)