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STAT3 (Signal Transducer and Activator of Transcription 3)

Identity

Other namesAcute Phase Response Factor, APRF
HGNC (Hugo) STAT3
LocusID (NCBI) 6774
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
Cards
AtlasSTAT3ID444
Entrez_Gene (NCBI)STAT3  6774  signal transducer and activator of transcription 3 (acute-phase response factor)
GeneCards (Weizmann)STAT3
Ensembl (Hinxton)ENSG00000168610 [Gene_View]  chr17:40465343-40540513 [Contig_View]  STAT3 [Vega]
AceView (NCBI)STAT3
Genatlas (Paris)STAT3
WikiGenes6774
SOURCE (Princeton)NM_003150 NM_139276 NM_213662
Genomic and cartography
GoldenPath (UCSC)STAT3  -  17q21.2   chr17:40465343-40540513 -  17q21   [Description]    (hg19-Feb_2009)
EnsemblSTAT3 - 17q21 [CytoView]
Mapping of homologs : NCBISTAT3 [Mapview]
OMIM102582   147060   
Gene and transcription
Genbank (Entrez)AB451232 AF029311 AI631896 AJ012463 AK024535
RefSeq transcript (Entrez)NM_003150 NM_139276 NM_213662
RefSeq genomic (Entrez)AC_000149 NC_000017 NC_018928 NG_007370 NT_010783 NW_001838436 NW_004929407
Consensus coding sequences : CCDS (NCBI)STAT3
Cluster EST : UnigeneHs.463059 [ NCBI ]
CGAP (NCI)Hs.463059
Alternative Splicing : Fast-db (Paris)GSHG0013420
Alternative Splicing GalleryENSG00000168610
Gene ExpressionSTAT3 [ NCBI-GEO ]     STAT3 [ SEEK ]   STAT3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP40763 (Uniprot)
NextProtP40763  [Medical]
With graphics : InterProP40763
Splice isoforms : SwissVarP40763 (Swissvar)
Domaine pattern : Prosite (Expaxy)SH2 (PS50001)   
Domains : Interpro (EBI)EF-hand-dom_pair    p53-like_TF_DNA-bd    SH2    STAT    STAT_TF_alpha    STAT_TF_coiled-coil    STAT_TF_DNA-bd    STAT_TF_DNA-bd_sub    STAT_TF_prot_interaction   
Related proteins : CluSTrP40763
Domain families : Pfam (Sanger)SH2 (PF00017)    STAT_alpha (PF01017)    STAT_bind (PF02864)    STAT_int (PF02865)   
Domain families : Pfam (NCBI)pfam00017    pfam01017    pfam02864    pfam02865   
Domain families : Smart (EMBL)SH2 (SM00252)  STAT_int (SM00964)  
DMDM Disease mutations6774
Blocks (Seattle)P40763
Human Protein AtlasENSG00000168610
Peptide AtlasP40763
HPRD00026
IPIIPI00784414   IPI00306436   IPI01013059   IPI00412752   
Protein Interaction databases
DIP (DOE-UCLA)P40763
IntAct (EBI)P40763
FunCoupENSG00000168610
BioGRIDSTAT3
InParanoidP40763
Interologous Interaction database P40763
IntegromeDBSTAT3
STRING (EMBL)STAT3
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II repressing transcription factor binding  temperature homeostasis  eye photoreceptor cell differentiation  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  nucleus  nucleus  nucleoplasm  nucleolus  cytoplasm  cytoplasm  cytosol  plasma membrane  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  transcription factor binding  cell proliferation  phosphorylation  modulation by virus of host morphology or physiology  cytokine-mediated signaling pathway  stem cell maintenance  protein kinase binding  protein phosphatase binding  sexual reproduction  intracellular receptor signaling pathway  CCR5 chemokine receptor binding  response to estradiol  cellular response to hormone stimulus  glucocorticoid receptor binding  regulation of multicellular organism growth  response to drug  glucose homeostasis  eating behavior  sequence-specific DNA binding  transcription regulatory region DNA binding  response to ethanol  positive regulation of Notch signaling pathway  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  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  JAK-STAT cascade involved in growth hormone signaling pathway  JAK-STAT cascade involved in growth hormone signaling pathway  interleukin-6-mediated signaling pathway  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II repressing transcription factor binding  temperature homeostasis  eye photoreceptor cell differentiation  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  nucleus  nucleus  nucleoplasm  nucleolus  cytoplasm  cytoplasm  cytosol  plasma membrane  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  transcription factor binding  cell proliferation  phosphorylation  modulation by virus of host morphology or physiology  cytokine-mediated signaling pathway  stem cell maintenance  protein kinase binding  protein phosphatase binding  sexual reproduction  intracellular receptor signaling pathway  CCR5 chemokine receptor binding  response to estradiol  cellular response to hormone stimulus  glucocorticoid receptor binding  regulation of multicellular organism growth  response to drug  glucose homeostasis  eating behavior  sequence-specific DNA binding  transcription regulatory region DNA binding  response to ethanol  positive regulation of Notch signaling pathway  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  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  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 : KEGGChemokine signaling pathway    HIF-1 signaling pathway    FoxO signaling pathway    Jak-STAT signaling pathway    Prolactin signaling pathway    Adipocytokine signaling pathway    Toxoplasmosis    Hepatitis C    Hepatitis B    Measles    Epstein-Barr virus infection    Pathways in cancer    Viral carcinogenesis    Proteoglycans in cancer    MicroRNAs in cancer    Pancreatic cancer    Acute myeloid leukemia    Inflammatory bowel disease (IBD)   
REACTOMESTAT3
Protein Interaction DatabaseSTAT3
Wikipedia pathwaysSTAT3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)STAT3
SNP (GeneSNP Utah)STAT3
SNP : HGBaseSTAT3
Genetic variants : HAPMAPSTAT3
1000_GenomesSTAT3 
ICGC programENSG00000168610 
Cancer Gene: CensusSTAT3 
Somatic Mutations in Cancer : COSMICSTAT3 
CONAN: Copy Number AnalysisSTAT3 
Mutations and Diseases : HGMDSTAT3
OMIM102582    147060   
GENETestsSTAT3
Disease Genetic AssociationSTAT3
Huge Navigator STAT3 [HugePedia]  STAT3 [HugeCancerGEM]
Genomic VariantsSTAT3  STAT3 [DGVbeta]
Exome VariantSTAT3
dbVarSTAT3
ClinVarSTAT3
snp3D : Map Gene to Disease6774
General knowledge
Homologs : HomoloGeneSTAT3
Homology/Alignments : Family Browser (UCSC)STAT3
Phylogenetic Trees/Animal Genes : TreeFamSTAT3
Chemical/Protein Interactions : CTD6774
Chemical/Pharm GKB GenePA337
Clinical trialSTAT3
Cancer Resource (Charite)ENSG00000168610
Other databases
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineSTAT3
iHOPSTAT3

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

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38096/1/05-2004-STAT3ID444.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:28:37 CEST 2014

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