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STAT3 (Signal Transducer and Activator of Transcription 3)

Identity

Other namesAcute Phase Response Factor, APRF
HGNC (Hugo) STAT3
Location 17q21.2
Location_base_pair Starts at 40465343 and ends at 40540513 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order STAT3 is flanked by STAT5a and PTRF

DNA/RNA

Note 24 exons spanning 74444 bp.
Transcription There are two major transcripts, STAT3a and STAT3b. STAT3a mRNA is 4973 bp. The STAT3b arises due to an alternate splice acceptor site in exon 23 which gives rise to a protein that is essentially truncated after amino acid 715. Another variant differs by 1 amino acid.

Protein

 
Description There are two major isoforms of STAT3. The long form is known as STAT3 (or STAT3a) and is a 770 amino acid protein (93 kDa on gels). Notable features are STAT family DNA binding domain, an SH2 domain, a major tyrosine phosphorylation site at Y705 and a major serine phosphorylation site at S727. Phosphorylation leads to dimerization of STAT3 via intermolecular pTyr-SH2 interactions. STAT3 can also heterodimerize with STAT1. (Recent data suggests that STAT3 can possibly form a dimmer without tyrosine phosphorylation and that phosphorylation leads to changes dimmer conformation). Tyrosine of the protein activates its high affinity DNA binding activity (TTCNNNGAA) and can stimulate nuclear translocation of the protein. Stimulation of STAT3 tyrosine phosphorylation occurs in response to a variety of cytokines and growth factors including LIF, OSM, IL-6, leptin, EGF, PDGF, and HGF. The C terminal domain is a transcriptional activation domain whose activity is enhanced by phosphorylation of serine 727. The STAT3 beta isoform (84 kDa) is missing this domain (1-715 + 7 unique amino acids resulting from frameshift) and is sometimes used as a dominant negative though there is also evidence that it regulates distinct genes as well.
Expression near ubiquitous
Localisation Cytoplasmic, but translocates to the nucleus upon tyrosine phosphorylation.
Function Transcription regulation.
Homology Shares homology with the other 6 mammalian STAT genes: STAT1, STAT2, STAT4, STAT5A, STAT5B, STAT6.

Implicated in

Disease Upregulated in many cancers including glioblastoma, head and neck cancer, prostate cancer, and breast cancer. A constitutively active form of STAT3 is oncogenic, though these mutations have not been identified in human cancer as yet. STAT 3 activation is associated with Crohn's disease, and other inflammatory diseases such as pulmonary fibrosis and acute lung injury. STAT3 is critical for leptin signaling and its mutation leads to obesity in mice.
  

External links

Nomenclature
HGNC (Hugo)STAT3   11364
Entrez_Gene (NCBI)STAT3  6774  signal transducer and activator of transcription 3 (acute-phase response factor)
Cards
AtlasSTAT3ID444
GeneCards (Weizmann)STAT3
Ensembl (Hinxton)ENSG00000168610 [Gene_View]  STAT3 [Vega]
AceView (NCBI)STAT3
Genatlas (Paris)STAT3
euGene (Indiana)6774
SOURCE (Stanford)NM_003150 NM_139276 NM_213662
Gene Expression (Array Express) ENSG00000168610
Genomic and cartography
GoldenPath (UCSC)STAT3  -  17q21.2   chr17:40465343-40540513 -  17q21.31   [Description]    (hg19-Feb_2009)
EnsemblSTAT3 - 17q21.31 [CytoView]
Mapping of homologs : NCBISTAT3 [Mapview]
OMIM102582   147060   
Gene and transcription
Gene : Genbank (Entrez)AB451232 AF029311 AI631896 AJ012463 AK024535
Reference sequence (RefSeq transcript) :SRSNM_003150 NM_139276 NM_213662
Reference transcript : EntrezNM_003150 NM_139276 NM_213662
RefSeq genomic : SRSAC_000060 AC_000149 NC_000017 NG_007370 NT_010783 NW_001838436 NW_926828
RefSeq genomic : EntrezAC_000060 AC_000149 NC_000017 NG_007370 NT_010783 NW_001838436 NW_926828
Consensus coding sequences : CCDS NCBISTAT3
Cluster EST : UnigeneHs.463059 [ SRS ] Hs.463059 [ NCBI ]
Alternative Splicing : Fast-db (Paris)10536
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtP40763 (SRS) P40763 (Expasy) P40763 (Uniprot)
With graphics : InterProP40763
Splice isoforms : VarSplice FASTAP40763(VarSplice FASTA)
Domaine pattern : Prosite (SRS)SH2 (PS50001)   
Domain pattern : Prosite (Expaxy)SH2 (PS50001)   
Domains : Interpro (SRS)EF-hand-like_dom    p53-like_TF_DNA-bd    SH2    STAT_TF_alpha    STAT_TF_coiled-coil    STAT_TF_core    STAT_TF_DNA-bd    STAT_TF_DNA-bd_sub    STAT_TF_prot_interaction   
Domains : Interpro (EBI)EF-hand-like_dom    p53-like_TF_DNA-bd    SH2    STAT_TF_alpha    STAT_TF_coiled-coil    STAT_TF_core    STAT_TF_DNA-bd    STAT_TF_DNA-bd_sub    STAT_TF_prot_interaction   
Related proteins : CluSTrP40763
Domain families : Pfam SRSSH2 (PF00017)    STAT_alpha (PF01017)    STAT_bind (PF02864)    STAT_int (PF02865)   
Domain families : Pfam SangerSH2 (PF00017)    STAT_alpha (PF01017)    STAT_bind (PF02864)    STAT_int (PF02865)   
Domain families : Pfam NCBIpfam00017    pfam01017    pfam02864    pfam02865   
Domain families : Smart EMBLSH2 (SM00252)  
Blocks (Seattle)P40763
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
Human Protein AtlasENSG00000168610
HPRD00026
Protein Interaction databases
DIP (DOE-UCLA)P40763
IntAct (EBI)P40763
FunCoupENSG00000168610
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBISTAT3
SNP : GeneSNP UtahSTAT3
SNP : HGBaseSTAT3
Genetic variants : HAPMAPSTAT3
Somatic Mutations in Cancer : COSMICSTAT3 
Mutations and Diseases : HGMDSTAT3
Hereditary diseases : OMIM102582    147060   
Hereditary diseases : GENETests102582    147060   
Diseases : Genetic AssociationSTAT3
General knowledge
Homologs : HomoloGeneSTAT3
Homology/Alignments : Family Browser UCSCSTAT3
Phylogenetic Trees/Animal Genes : TreeFamSTAT3
Chemical/Protein Interactions : CTD6774
Keywords Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  temperature homeostasis  eye photoreceptor cell differentiation  DNA binding  transcription factor activity  signal transducer activity  hematopoietin/interferon-class (D200-domain) cytokine receptor signal transducer activity  calcium ion binding  protein binding  nucleus  nucleus  nucleolus  cytoplasm  cytoplasm  plasma membrane  regulation of transcription from RNA polymerase II promoter  cellular component movement  acute-phase response  signal transduction  JAK-STAT cascade  nervous system development  transcription factor binding  response to organic cyclic substance  transcription activator activity  cytokine-mediated signaling pathway  protein kinase binding  sexual reproduction  response to estradiol stimulus  cellular response to hormone stimulus  response to cytokine stimulus  regulation of multicellular organism growth  response to drug  glucose homeostasis  eating behavior  response to peptide hormone stimulus  sequence-specific DNA binding  interspecies interaction between organisms  regulation of transcription  response to ethanol  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  JAK-STAT cascade involved in growth hormone signaling pathway  JAK-STAT cascade involved in growth hormone signaling pathway  interleukin-6-mediated signaling pathway  
Keywords Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  temperature homeostasis  eye photoreceptor cell differentiation  DNA binding  transcription factor activity  signal transducer activity  hematopoietin/interferon-class (D200-domain) cytokine receptor signal transducer activity  calcium ion binding  protein binding  nucleus  nucleus  nucleolus  cytoplasm  cytoplasm  plasma membrane  regulation of transcription from RNA polymerase II promoter  cellular component movement  acute-phase response  signal transduction  JAK-STAT cascade  nervous system development  transcription factor binding  response to organic cyclic substance  transcription activator activity  cytokine-mediated signaling pathway  protein kinase binding  sexual reproduction  response to estradiol stimulus  cellular response to hormone stimulus  response to cytokine stimulus  regulation of multicellular organism growth  response to drug  glucose homeostasis  eating behavior  response to peptide hormone stimulus  sequence-specific DNA binding  interspecies interaction between organisms  regulation of transcription  response to ethanol  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  JAK-STAT cascade involved in growth hormone signaling pathway  JAK-STAT cascade involved in growth hormone signaling pathway  interleukin-6-mediated signaling pathway  
Pathways : BIOCARTAIL 6 signaling pathway [Genes]    PDGF Signaling Pathway [Genes]    Erk1/Erk2 Mapk Signaling pathway [Genes]    Role of ERBB2 in Signal Transduction and Oncology [Genes]    EGF Signaling Pathway [Genes]    IL-10 Anti-inflammatory Signaling Pathway [Genes]    TPO Signaling Pathway [Genes]    Signaling of Hepatocyte Growth Factor Receptor [Genes]    Stat3 Signaling Pathway [Genes]    Bioactive Peptide Induced Signaling Pathway [Genes]    IL22 Soluble Receptor Signaling [Genes]   
Pathways : KEGGAdipocytokine signaling pathwayJak-STAT signaling pathway
Other databases
Probes
Probes : ImagenesSTAT3 Related clones (RZPD - Berlin)
Literature
PubMed499 Pubmed reference(s) in Entrez
PubGeneSTAT3

Bibliography

Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.
Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T
Cell. 1994 ; 77 (1) : 63-71.
PMID 7512451
 
Stat3 and Stat4: members of the family of signal transducers and activators of transcription.
Zhong Z, Wen Z, Darnell JE Jr
Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (11) : 4806-4810.
PMID 7545930
 
Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.
Zhong Z, Wen Z, Darnell JE Jr
Science (New York, N.Y.). 1994 ; 264 (5155) : 95-98.
PMID 8140422
 
A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain.
Horvath CM, Wen Z, Darnell JE Jr
Genes & development. 1995 ; 9 (8) : 984-994.
PMID 7774815
 
Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation.
Wen Z, Zhong Z, Darnell JE Jr
Cell. 1995 ; 82 (2) : 241-250.
PMID 7543024
 
STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription.
Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP
The Journal of biological chemistry. 1996 ; 271 (22) : 13221-13227.
PMID 8675499
 
Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells.
Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 1997 ; 8 (12) : 1267-1276.
PMID 9419415
 
Three-dimensional structure of the Stat3beta homodimer bound to DNA.
Becker S, Groner B, Mˆºller CW
Nature. 1998 ; 394 (6689) : 145-151.
PMID 9671298
 
Stat3 activation is required for cellular transformation by v-src.
Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr
Molecular and cellular biology. 1998 ; 18 (5) : 2553-2558.
PMID 9566875
 
Stat3 as an oncogene.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr
Cell. 1999 ; 98 (3) : 295-303.
PMID 10458605
 
Roles of STAT3 defined by tissue-specific gene targeting.
Akira S
Oncogene. 2000 ; 19 (21) : 2607-2611.
PMID 10851059
 
Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock.
Yoo JY, Huso DL, Nathans D, Desiderio S
Cell. 2002 ; 108 (3) : 331-344.
PMID 11853668
 
STAT3 signalling is required for leptin regulation of energy balance but not reproduction.
Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr
Nature. 2003 ; 421 (6925) : 856-859.
PMID 12594516
 
STATs dimerize in the absence of phosphorylation.
Braunstein J, Brutsaert S, Olson R, Schindler C
The Journal of biological chemistry. 2003 ; 278 (36) : 34133-34140.
PMID 12832402
 
Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells.
Konnikova L, Kotecki M, Kruger MM, Cochran BH
BMC cancer. 2003 ; 3 : page 23.
PMID 13678425
 
Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease.
Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, Eriksen KW, Woetmann A, ˆ̣dum N
The Journal of biological chemistry. 2003 ; 278 (19) : 16777-16781.
PMID 12615922
 
A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation.
Ma J, Zhang T, Novotny-Diermayr V, Tan AL, Cao X
The Journal of biological chemistry. 2003 ; 278 (31) : 29252-29260.
PMID 12746441
 
The STAT3 isoforms alpha and beta have unique and specific functions.
Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, Murray-Tait V, Chiarle R, Poli V
Nature immunology. 2004 ; 5 (4) : 401-409.
PMID 15021879
 
Activation of the STAT pathway in acute lung injury.
Severgnini M, Takahashi S, Rozo LM, Homer RJ, Kuhn C, Jhung JW, Perides G, Steer M, Hassoun PM, Fanburg BL, Cochran BH, Simon AR
American journal of physiology. Lung cellular and molecular physiology. 2004 ; 286 (6) : L1282-L1292.
PMID 14729509
 
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Contributor(s)

Written05-2004Brent H Cochran
Dept. of Physiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA

Citation

This paper should be referenced as such :
Cochran BH . STAT3 (Signal Transducer and Activator of Transcription 3). Atlas Genet Cytogenet Oncol Haematol. May 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/STAT3ID444.html

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indexed on : Thu Jul 15 14:46:24 CEST 2010
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