STAT3

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Signal transducer and activator of transcription 3 (acute-phase response factor)
PDB rendering based on 1bg1.
Available structures: 1bg1
Identifiers
Symbol(s) STAT3; APRF; FLJ20882; MGC16063
External IDs OMIM: 102582 MGI: 103038 HomoloGene: 7960
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 6774 20848
Ensembl ENSG00000168610 ENSMUSG00000004040
Uniprot P40763 Q8CFJ6
Refseq NM_003150 (mRNA)
NP_003141 (protein)		 XM_001005155 (mRNA)
XP_001005155 (protein)
Location Chr 17: 37.72 - 37.79 Mb Chr 11: 100.7 - 100.76 Mb
Pubmed search [1] [2]

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 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.[1] STAT3 is also a target of the c-src non-receptor tyrosine kinase.[2]

STAT3-deficient mouse embryos can not develop beyond embryonic day 7 (E7.0), when gastrulation initiates.[3] 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 ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.[4]

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[5][6][7][8] It has anti-apoptotic as well as proliferative effects.[5]

[edit] References

  1. ^ 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" in Mol Cell Biol Volume 24 (21), pages 9390-9400. Entrez PubMed 15485908
  2. ^ Silva CM (2004) "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis" in Oncogene Volume 23 (48), pages 8017-8023. Entrez PubMed 15489919
  3. ^ 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" in PNAS Volume 94 (8), pages 3801-3084. Entrez PubMed 9108058
  4. ^ 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" in EMBO J Volume 18 (15), pages 4261-4269. Entrez PubMed 10428964
  5. ^ a b Klampfer L (2006) "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs" in Curr Cancer Drug Targets Volume 6 (2), pages 107-121. Entrez PubMed 16529541
  6. ^ 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" in Cancer Res Volume 66 (6), pages 3162-3168. Entrez PubMed 16540667
  7. ^ 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" in Mol Cancer Volume 5 (1), article number 15. Entrez PubMed 16603078
  8. ^ 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" in Oncol Rep Volume 15 (6), pages 1445-1451. Entrez PubMed 16685378

[edit] Further reading

  • Hoey T, Grusby MJ (1999). "STATs as mediators of cytokine-induced responses.". Adv. Immunol. 71: 145–62. 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. PMID 12039028. 
  • Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection.". Curr. HIV Res. 3 (1): 87–94. 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. 
v • d • e
Transcription factors and intracellular receptors
(1) Basic domains
(1.1) Basic leucine zipper (bZIP)
Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • BATF • BLZF1 • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3, L1) • CREM • DBP • DDIT3 • GABPA • HLF • MAF (B, F, G, K) • NFE (2, L1, L2) • NRL • NRF1 • XBP1
(1.2) Basic helix-loop-helix (bHLH)
ATOH1 • AhR • AHRR • ARNT • ASCL1 • BHLHB2 • BMAL (ARNTL, ARNTL2) • CLOCK • EPAS1 • HAND (1, 2) • HES (5, 6) • HEY (1, 2, L) • HES1 • HIF (1A, 3A) • ID (1, 2, 3, 4) • LYL1 • MXD4 • MYCL1 • MYCN • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • Neurogenins • NeuroD (1, 2) • NPAS (1, 2, 3) • OLIG (1, 2) • Scleraxis • TAL1 • Twist • USF1
(1.3) bHLH-ZIP
MAX • MITF • MNT • MLX • MXI1 • Myc • SREBP (1, 2)
(1.6) Basic helix-span-helix (bHSH)
(2) Zinc finger
DNA-binding domains
(2.1) Nuclear receptor (Cys4)
subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP)
(2.2) Other Cys4
GATA (1, 2, 3, 4, 5, 6) • MTA (1, 2, 3)
(2.3) Cys2His2
ATBF1 • BCL(6, 11A, 11B) • CTCF • E4F1 • EGR (2, 3) • ERV3 • General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF: 1, 2, TFIIH: 1, 2, 4, 2I, 3A, 3C1, 3C2) • GFI1 • GLI-Krüppel family (1, 2, 3, YY1) • HIC (1, 2) • HIVEP (1, 2, 3) • IKZF (1, 2, 3) • ILF (2, 3) • KLF (2, 4, 5, 6, 9, 10, 11, 12, 13) • MTF1 • MYT1 • OSR1 • Sp1 • zinc finger ((3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 318, 330, 346, 350, 365, 366, 384, 451, 452, 471, 593, 638, 649, 655) • Zbtb7 (7A) • ZBT (16, 17, 33)
(2.4) Cys6
(2.5) Alternating composition
AIRE • DIDO1 • GRLF1 • ING (1, 2, 4) • JARID (1A, 1B, 1C, 1D, 2) • JMJD1B
(3) Helix-turn-helix
domains
ARX • CDX (1, 2) • CRX • CUTL1 • DLX (3, 4, 5) • EMX2 • EN (1, 2) • FHL (1, 2, 3) • HESX1 • HHEX • HLX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) • HOPX • MEIS (1, 2) • MEOX2 • MNX1 • MSX (1, 2) • NANOG • NKX (2-1, 2-5, 3-1) • PHF (3, 6, 10, 17) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7) • OTX (1, 2) • PDX1
(3.2) Paired box
PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, K2, L2, M1, N3, O1A, , O3A, O4, P1, P2, P3)
HSF (1, 2, 4)
(3.5) Tryptophan clusters
ELF (4, 5) • EGF • ELK (1, 3, 4) • ERF • ERG • ETS (1, 2) • ETV (1, 4, 5, 6) • FLI1 • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB • MYBL2
(3.6) TEA domain
transcriptional enhancer factor 1, 2
(4) β-Scaffold factors with
minor groove contacts
(4.1) Rel homology region
NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (C1, C2, C3, C4, 5)
(4.2) STAT
STAT (1, 2, 3, 4, 5, 6)
(4.3) p53
(4.4) MADS box
Mef2 (A, B, C, D) • SRF
HNF (1A, 1B) • LEF1 • SOX (2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 15, 18) • SRY • SSRP1
(4.10) Cold-shock domain
(4.11) Runt
(0) Other
transcription factors
(0.2) HMGI(Y)
HMGA (1, 2) • HBP1
Rb • RBL1 • RBL2
(0.5) AP-2/EREBP-related factors
Apetala 2 • EREBP • B3
(0.6) Miscellaneous
ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • IFI (16, 35) • MLL (2, 3, T1) • MNDA • NFI (A, B, C, X) • NFY (A, B, C) • Rho/Sigma • R-SMAD
v • d • e
Cell signaling: carrier proteins: adaptor proteins
STAT
STAT1 - STAT2 - STAT3 - STAT4 - STAT5 - STAT6
Interferon regulatory factors
Growth factor receptor-bound protein
other