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STAT2 (Signal Transducer and Activator of Transcription 2)

Written2015-05Ming Li
Department of Immunology, Xiangya Medical College, Basic Medical College, Central South University, Changsha 410078, Hunan, P. R. China

Abstract Review on STAT2, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords STAT2; JAK/STAT pathway

(Note : for Links provided by Atlas : click)

Identity

Alias_namessignal transducer and activator of transcription 2, 113kD
signal transducer and activator of transcription 2, 113kDa
Alias_symbol (synonym)STAT113
Other alias
HGNC (Hugo) STAT2
LocusID (NCBI) 6773
Atlas_Id 42429
Location 12q13.3  [Link to chromosome band 12q13]
Location_base_pair Starts at 56341598 and ends at 56360253 bp from pter ( according to hg19-Feb_2009)  [Mapping STAT2.png]
Fusion genes
(updated 2016)
STAT2 (12q13.3) / HSPA5 (9q33.3)STAT2 (12q13.3) / STAT2 (12q13.3)VPS53 (17p13.3) / STAT2 (12q13.3)

DNA/RNA

Description 24 exons spanning 18657 bp
Transcription There are two major transcripts. In transcript variant 1, mRNA is 4576 bp. Transcript variant 2 uses an alternate in-frame splice site in exon 3; as a result, it lacks an internal 12bp insertion compared to transcript variant 1. Another spliced form is generated by reading through the intron between exons 20 and 21, which correspond to the region encoding the SH2 domain. The spliced form contains a stop codon in the SH2 domain, giving rise to a short form of STAT2 when the mRNAs are translated. The putative translated proteins lack half of the SH2 domain, the tyrosine phosphorylation site required for dimerization and DNA binding, and the C-terminal activation domain.

Protein

 
Description There are two major isoforms of STAT2. The long form is known as isoform 1 and is a 851 amino acid protein (113KDa on gels). Isoform 2 lacks an internal four amino acid segment compared to isoform 1.
The STAT2 gene product contains 6 domains: an N-terminal domain (NTD), a coiled-coil domain (CC), a DNA-binding domain (DBD), a linker domain (LD), a Src homology-2 domain (SH2), and a transactivation domain (TAD) (figure 1). NTD is required for tyrosine phosphorylation of STAT2 in response to type I IFNs, binding of STAT2 to IFN receptors and cooperative binding of STAT1:STAT2 heterodimers or ISGF3 to promoters that contain tandem GAS or ISRE, respectively. CC mediates protein interactions and is the domain IRF9 binds. DBD does not bind DNA as a part of ISGF3. DBD contains a bipartite nuclear localization signal (NLS) when ISGF3 forms. No function for LD is known. SH2 serves 2 main functions: binding to a phosphorylated IFN receptor, thereby making STAT2 available for Tyk2-mediated tyrosine phosphorylation; and binding to tyrosine phosphorylated STAT1 to form an active heterodimer. The TAD is essential for recruitment of transcription regulators. TAD also contains the nuclear export signal (NES). Nucleocytoplasmic shuttling of STAT2 is attributed to the constitutive binding of STAT2 to the NLS-containing IRF9 to transport STAT2 into the nucleus, while the STAT2 NES exports STAT2 back to the cytosol (Steen and Gamero, 2012).
Interferons (IFNs) activate the Janus kinase (JAK)/STAT pathway by binding to their corresponding receptor complex. Jak1 and TYK2 are pre-associated with type I and type III IFN receptors, and phosphorylate specific tyrosine residues within the receptor chain, which serve as docking sites for the recruitment of STATs. JAKs phosphorylate a conserved tyrosine residue situated in the C-terminal region of STAT2 (Y690) and STAT1 , thus allowing STAT1 and STAT2 to interact via reciprocal SH2-phosphotyrosyl interactions. Formation of the interferon-stimulated gene factor 3 (ISGF3) complex takes place when activated STAT1:STAT2 heterodimers are released from receptor chains to bind the DNA-binding adaptor protein, IRF9 (p48/ISGF3G). ISGF3 translocates to the nucleus and binds the DNA containing an IFN-stimulated response element (ISRE) by STAT1 and IRF9 to activate gene transcription of IFN-stimulated genes (ISGs). In addition, STAT2 can form heterodimers individually with either STAT1 or IRF9. Each of these complexes will bind IRSE or IFN-gamma activation sequences (GAS) to activate gene transcription of ISGs. Serine 287 phosphorylation can negatively regulate the biological activities of type I IFNs (Steen et al., 2013). IFNs are the only cytokines known to date that can activate STAT2.
Expression STAT2 is ubiquitously expressed in most cell types.
Localisation STAT2 predominantly resides in the cytoplasm. Nucleocytoplasmic shuttling occurs in the absence of IFN stimulation, but translocates to the nucleus upon tyrosine phosphorylation when stimulated by IFNs (Reich, 2013).
Function Transcription factor. STAT2 mediates the transcription of numerous IFN-induced genes involved in linking adaptive and innate immunity and exerting antiviral, antiproliferative, apoptotic, and antitumor effects.
Homology Shares homology with the other 6 mammalian STAT genes: STAT1, STAT3, STAT4, STAT5A, STAT5B, STAT6. Human STAT2 is relatively well conserved with macaque and chimpanzee. Human and murine STAT2 are highly homologous (76% identity over the first 712 amino acids).

Mutations

Note Two mutations in intron 4 (Hambleton,et al., 2013) as well as the intron between exon 20 and 21 were found to prevent correct splicing of STAT2 (Sugiyama et al., 1996).

Implicated in

Note
Note The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. The loss of IFN sensitivity may contribute to the development and progression of cancers. STAT2 is found to be decreased in many cancers including squamous cell carcinoma of the skin (Clifford et al., 2000; Clifford et al., 2002), fibrosarcoma (Krishnamurthy et al., 2006), astrocytomas (Ehrmann et al., 2008), melanoma (Mischiat et al., 2006), and prostate cancer (Ni et al., 2002). STAT2 has a tumor suppressor function (Clifford et al., 2002; Gamero et al., 2010; Yue et al., 2015) , though the mutations have not yet been identified in human cancer.
To evade the antiviral protective effects of IFNs, certain viruses have developed strategies to impair the IFN signaling pathway by specifically targeting STAT2. The strategies are to reduce STAT2 levels, to sequester STAT2 in the cytoplasm, or to prevent its tyrosine phosphorylation.
  

Bibliography

Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis
Clifford JL, Walch E, Yang X, Xu X, Alberts DS, Clayman GL, El-Naggar AK, Lotan R, Lippman SM
Clin Cancer Res 2002 Jul;8(7):2067-72
PMID 12114405
 
Expression of STATs and their inhibitors SOCS and PIAS in brain tumors
Ehrmann J, Strakova N, Vrzalikova K, Hezova R, Kolar Z
In vitro and in vivo study Neoplasma
PMID 18999875
 
STAT2 contributes to promotion of colorectal and skin carcinogenesis
Gamero AM, Young MR, Mentor-Marcel R, Bobe G, Scarzello AJ, Wise J, Colburn NH
Cancer Prev Res (Phila) 2010 Apr;3(4):495-504
PMID 20233899
 
STAT2 deficiency and susceptibility to viral illness in humans
Hambleton S, Goodbourn S, Young DF, Dickinson P, Mohamad SM, Valappil M, McGovern N, Cant AJ, Hackett SJ, Ghazal P, Morgan NV, Randall RE
Proc Natl Acad Sci U S A 2013 Feb 19;110(8):3053-8
PMID 23391734
 
The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways
Hernandez JM, Elahi A, Clark W, Humphries LA, Wang J, Achille A, Seto E, Shibata D
DNA Cell Biol 2015 May 19
PMID 26061044
 
Differentially regulated interferon response determines the outcome of Newcastle disease virus infection in normal and tumor cell lines
Krishnamurthy S, Takimoto T, Scroggs RA, Portner A
J Virol 2006 Jun;80(11):5145-55
PMID 16698995
 
cDNA-array profiling of melanomas and paired melanocyte cultures
Mischiati C, Natali PG, Sereni A, Sibilio L, Giorda E, Cappellacci S, Nicotra MR, Mariani G, Di Filippo F, Catricalà C, Gambari R, Grammatico P, Giacomini P
J Cell Physiol 2006 Jun;207(3):697-705
PMID 16523488
 
Selective activation of members of the signal transducers and activators of transcription family in prostate carcinoma
Ni Z, Lou W, Lee SO, Dhir R, DeMiguel F, Grandis JR, Gao AC
J Urol 2002 Apr;167(4):1859-62
PMID 11912448
 
STATs get their move on
Reich NC
JAKSTAT 2013 Oct 1;2(4):e27080
PMID 24470978
 
Identification of STAT2 serine 287 as a novel regulatory phosphorylation site in type I interferon-induced cellular responses
Steen HC, Nogusa S, Thapa RJ, Basagoudanavar SH, Gill AL, Merali S, Barrero CA, Balachandran S, Gamero AM
J Biol Chem 2013 Jan 4;288(1):747-58
PMID 23139419
 
Identification of alternative splicing form of Stat2
Sugiyama T, Nishio Y, Kishimoto T, Akira S
FEBS Lett 1996 Mar 4;381(3):191-4
PMID 8601453
 
Host STAT2/type I interferon axis controls tumor growth
Yue C, Xu J, Tan Estioko MD, Kotredes KP, Lopez-Otalora Y, Hilliard BA, Baker DP, Gallucci S, Gamero AM
Int J Cancer 2015 Jan 1;136(1):117-26
PMID 24895110
 

Citation

This paper should be referenced as such :
Li M
STAT2 (Signal Transducer and Activator of Transcription 2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/STAT2ID42429ch12q13.html


External links

Nomenclature
HGNC (Hugo)STAT2   11363
Cards
AtlasSTAT2ID42429ch12q13
Entrez_Gene (NCBI)STAT2  6773  signal transducer and activator of transcription 2
AliasesIMD44; ISGF-3; P113; STAT113
GeneCards (Weizmann)STAT2
Ensembl hg19 (Hinxton)ENSG00000170581 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000170581 [Gene_View]  chr12:56341598-56360253 [Contig_View]  STAT2 [Vega]
ICGC DataPortalENSG00000170581
TCGA cBioPortalSTAT2
AceView (NCBI)STAT2
Genatlas (Paris)STAT2
WikiGenes6773
SOURCE (Princeton)STAT2
Genetics Home Reference (NIH)STAT2
Genomic and cartography
GoldenPath hg38 (UCSC)STAT2  -     chr12:56341598-56360253 -  12q13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)STAT2  -     12q13.3   [Description]    (hg19-Feb_2009)
EnsemblSTAT2 - 12q13.3 [CytoView hg19]  STAT2 - 12q13.3 [CytoView hg38]
Mapping of homologs : NCBISTAT2 [Mapview hg19]  STAT2 [Mapview hg38]
OMIM600556   616636   
Gene and transcription
Genbank (Entrez)AK094039 AK295052 AK295114 AK296939 AK296940
RefSeq transcript (Entrez)NM_005419 NM_198332
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)STAT2
Cluster EST : UnigeneHs.530595 [ NCBI ]
CGAP (NCI)Hs.530595
Alternative Splicing GalleryENSG00000170581
Gene ExpressionSTAT2 [ NCBI-GEO ]   STAT2 [ EBI - ARRAY_EXPRESS ]   STAT2 [ SEEK ]   STAT2 [ MEM ]
Gene Expression Viewer (FireBrowse)STAT2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6773
GTEX Portal (Tissue expression)STAT2
Protein : pattern, domain, 3D structure
UniProt/SwissProtP52630   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP52630  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP52630
Splice isoforms : SwissVarP52630
PhosPhoSitePlusP52630
Domaine pattern : Prosite (Expaxy)SH2 (PS50001)   
Domains : Interpro (EBI)EF-hand-dom_pair    p53-like_TF_DNA-bd    SH2    STAT    STAT2_C    STAT_TF_alpha    STAT_TF_coiled-coil    STAT_TF_DNA-bd    STAT_TF_DNA-bd_sub    STAT_TF_prot_interaction   
Domain families : Pfam (Sanger)SH2 (PF00017)    STAT2_C (PF12188)    STAT_alpha (PF01017)    STAT_bind (PF02864)    STAT_int (PF02865)   
Domain families : Pfam (NCBI)pfam00017    pfam12188    pfam01017    pfam02864    pfam02865   
Domain families : Smart (EMBL)SH2 (SM00252)  STAT_int (SM00964)  
Conserved Domain (NCBI)STAT2
DMDM Disease mutations6773
Blocks (Seattle)STAT2
PDB (SRS)2KA4   
PDB (PDBSum)2KA4   
PDB (IMB)2KA4   
PDB (RSDB)2KA4   
Structural Biology KnowledgeBase2KA4   
SCOP (Structural Classification of Proteins)2KA4   
CATH (Classification of proteins structures)2KA4   
SuperfamilyP52630
Human Protein AtlasENSG00000170581
Peptide AtlasP52630
HPRD02778
IPIIPI00004312   IPI00219076   IPI00909389   IPI01010551   IPI00956408   IPI01025806   IPI01025689   IPI01026475   
Protein Interaction databases
DIP (DOE-UCLA)P52630
IntAct (EBI)P52630
FunCoupENSG00000170581
BioGRIDSTAT2
STRING (EMBL)STAT2
ZODIACSTAT2
Ontologies - Pathways
QuickGOP52630
Ontology : AmiGOregulation of protein phosphorylation  DNA binding  transcription factor activity, sequence-specific DNA binding  signal transducer activity  protein binding  nucleoplasm  cytosol  cytosol  plasma membrane  transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  JAK-STAT cascade  identical protein binding  defense response to virus  type I interferon signaling pathway  type I interferon signaling pathway  regulation of type I interferon-mediated signaling pathway  regulation of mitochondrial fission  
Ontology : EGO-EBIregulation of protein phosphorylation  DNA binding  transcription factor activity, sequence-specific DNA binding  signal transducer activity  protein binding  nucleoplasm  cytosol  cytosol  plasma membrane  transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  JAK-STAT cascade  identical protein binding  defense response to virus  type I interferon signaling pathway  type I interferon signaling pathway  regulation of type I interferon-mediated signaling pathway  regulation of mitochondrial fission  
Pathways : BIOCARTAIFN alpha signaling pathway [Genes]   
Pathways : KEGGChemokine signaling pathway    Osteoclast differentiation    Jak-STAT signaling pathway    Hepatitis C    Hepatitis B    Measles    Influenza A    Herpes simplex infection   
REACTOMEP52630 [protein]
REACTOME PathwaysR-HSA-912694 [pathway]   
NDEx NetworkSTAT2
Atlas of Cancer Signalling NetworkSTAT2
Wikipedia pathwaysSTAT2
Orthology - Evolution
OrthoDB6773
GeneTree (enSembl)ENSG00000170581
Phylogenetic Trees/Animal Genes : TreeFamSTAT2
HOVERGENP52630
HOGENOMP52630
Homologs : HomoloGeneSTAT2
Homology/Alignments : Family Browser (UCSC)STAT2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSTAT2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)STAT2
dbVarSTAT2
ClinVarSTAT2
1000_GenomesSTAT2 
Exome Variant ServerSTAT2
ExAC (Exome Aggregation Consortium)STAT2 (select the gene name)
Genetic variants : HAPMAP6773
Genomic Variants (DGV)STAT2 [DGVbeta]
DECIPHERSTAT2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSTAT2 
Mutations
ICGC Data PortalSTAT2 
TCGA Data PortalSTAT2 
Broad Tumor PortalSTAT2
OASIS PortalSTAT2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSTAT2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSTAT2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch STAT2
DgiDB (Drug Gene Interaction Database)STAT2
DoCM (Curated mutations)STAT2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)STAT2 (select a term)
intoGenSTAT2
NCG5 (London)STAT2
Cancer3DSTAT2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600556    616636   
Orphanet23235   
MedgenSTAT2
Genetic Testing Registry STAT2
NextProtP52630 [Medical]
TSGene6773
GENETestsSTAT2
Target ValidationSTAT2
Huge Navigator STAT2 [HugePedia]
snp3D : Map Gene to Disease6773
BioCentury BCIQSTAT2
ClinGenSTAT2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6773
Chemical/Pharm GKB GenePA36184
Clinical trialSTAT2
Miscellaneous
canSAR (ICR)STAT2 (select the gene name)
Probes
Litterature
PubMed144 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSTAT2
EVEXSTAT2
GoPubMedSTAT2
iHOPSTAT2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jun 30 11:19:08 CEST 2017

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