STAT2 (Signal Transducer and Activator of Transcription 2)

2015-05-01   Ming Li 

Department of Immunology, Xiangya Medical College, Basic Medical College, Central South University, Changsha 410078, Hunan, P. R. China

Identity

HGNC
LOCATION
12q13.3
LOCUSID
ALIAS
IMD44,ISGF-3,P113,PTORCH3,STAT113
FUSION GENES

Abstract

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

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.

Proteins

Atlas Image

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

Bibliography

Pubmed IDLast YearTitleAuthors
121144052002Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis.Clifford JL et al
189998752008Expression of STATs and their inhibitors SOCS and PIAS in brain tumors. In vitro and in vivo study.Ehrmann J et al
202338992010STAT2 contributes to promotion of colorectal and skin carcinogenesis.Gamero AM et al
233917342013STAT2 deficiency and susceptibility to viral illness in humans.Hambleton S et al
260610442015The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways.Hernandez JM et al
166989952006Differentially regulated interferon response determines the outcome of Newcastle disease virus infection in normal and tumor cell lines.Krishnamurthy S et al
165234882006cDNA-array profiling of melanomas and paired melanocyte cultures.Mischiati C et al
119124482002Selective activation of members of the signal transducers and activators of transcription family in prostate carcinoma.Ni Z et al
244709782013STATs get their move on.Reich NC et al
231394192013Identification of STAT2 serine 287 as a novel regulatory phosphorylation site in type I interferon-induced cellular responses.Steen HC et al
86014531996Identification of alternative splicing form of Stat2.Sugiyama T et al
248951102015Host STAT2/type I interferon axis controls tumor growth.Yue C et al

Other Information

Locus ID:

NCBI: 6773
MIM: 600556
HGNC: 11363
Ensembl: ENSG00000170581

Variants:

dbSNP: 6773
ClinVar: 6773
TCGA: ENSG00000170581
COSMIC: STAT2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000170581ENST00000314128P52630
ENSG00000170581ENST00000314128R9QE65
ENSG00000170581ENST00000418572B4DLC8
ENSG00000170581ENST00000555646G3V319
ENSG00000170581ENST00000557235P52630
ENSG00000170581ENST00000650805B4DHE0
ENSG00000170581ENST00000651301A0A494C0B5
ENSG00000170581ENST00000651915A0A494C164
ENSG00000170581ENST00000652398B4DHE0
ENSG00000170581ENST00000652624A0A494C1L3
ENSG00000170581ENST00000652741B4DHE0

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Jak-STAT signaling pathwayKEGGko04630
Jak-STAT signaling pathwayKEGGhsa04630
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Hepatitis BKEGGhsa05161
JAK-STAT signalingKEGGhsa_M00684
JAK-STAT signalingKEGGM00684
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Interferon alpha/beta signalingREACTOMER-HSA-909733
Regulation of IFNA signalingREACTOMER-HSA-912694

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134885765SOCS3GenePathwayassociated26111151
PA134992438CAMK1DGenePathwayassociated
PA24684AKT1GenePathwayassociated
PA24685AKT2GenePathwayassociated
PA24686AKT3GenePathwayassociated
PA248NFKB1GenePathwayassociated
PA26048CAMK1GenePathwayassociated
PA26049CAMK1GGenePathwayassociated
PA27749ELK1GenePathwayassociated
PA28212FOSGenePathwayassociated
PA283MAPK8GenePathwayassociated
PA296RELAGenePathwayassociated
PA29988JAK1GenePathwayassociated
PA30006JUNGenePathwayassociated
PA30616MAPK1GenePathwayassociated
PA30622MAPK3GenePathwayassociated
PA31353MYCGenePathwayassociated
PA31600NFKB2GenePathwayassociated
PA337STAT3GenePathwayassociated
PA33759PRKCAGenePathwayassociated
PA33761PRKCBGenePathwayassociated
PA33766PRKCGGenePathwayassociated
PA338STAT5AGenePathwayassociated
PA36042SP1GenePathwayassociated
PA36183STAT1GenePathwayassociated
PA36185STAT4GenePathwayassociated
PA36186STAT5BGenePathwayassociated
PA37242USP18GenePathwayassociated26111151
PA90CAMK2AGenePathwayassociated
PA91CAMK2BGenePathwayassociated
PA92CAMK2DGenePathwayassociated
PA93CAMK2GGenePathwayassociated

References

Pubmed IDYearTitleCitations
192791062009NS5 of dengue virus mediates STAT2 binding and degradation.186
156502192005Inhibition of interferon signaling by the New York 99 strain and Kunjin subtype of West Nile virus involves blockage of STAT1 and STAT2 activation by nonstructural proteins.134
123887092002Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation.123
197543072009Dengue virus NS5 inhibits interferon-alpha signaling by blocking signal transducer and activator of transcription 2 phosphorylation.104
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
210753522010Mouse STAT2 restricts early dengue virus replication.85
235552652013Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.82
165010772006Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2.80
128047712003Measles virus V protein blocks interferon (IFN)-alpha/beta but not IFN-gamma signaling by inhibiting STAT1 and STAT2 phosphorylation.76
119323842002Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction.70

Citation

Ming Li

STAT2 (Signal Transducer and Activator of Transcription 2)

Atlas Genet Cytogenet Oncol Haematol. 2015-05-01

Online version: http://atlasgeneticsoncology.org/gene/42429/stat2-(signal-transducer-and-activator-of-transcription-2)