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Protein

Signal transducer and activator of transcription 1

Gene

Stat1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.4 Publications

GO - Molecular functioni

  1. double-stranded DNA binding Source: MGI
  2. enzyme binding Source: MGI
  3. identical protein binding Source: MGI
  4. protein homodimerization activity Source: MGI
  5. RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: MGI
  6. RNA polymerase II core promoter sequence-specific DNA binding Source: MGI
  7. RNA polymerase II core promoter sequence-specific DNA binding transcription factor activity Source: MGI
  8. sequence-specific DNA binding transcription factor activity Source: MGI
  9. signal transducer activity Source: InterPro
  10. tumor necrosis factor receptor binding Source: MGI

GO - Biological processi

  1. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  2. apoptotic process Source: UniProtKB
  3. blood circulation Source: UniProtKB
  4. cellular response to interferon-beta Source: MGI
  5. cellular response to lipopolysaccharide Source: MGI
  6. cytokine-mediated signaling pathway Source: MGI
  7. interferon-gamma-mediated signaling pathway Source: UniProtKB
  8. JAK-STAT cascade Source: MGI
  9. lipopolysaccharide-mediated signaling pathway Source: MGI
  10. metanephric mesenchymal cell differentiation Source: UniProtKB
  11. metanephric mesenchymal cell proliferation involved in metanephros development Source: UniProtKB
  12. negative regulation by virus of viral protein levels in host cell Source: MGI
  13. negative regulation of angiogenesis Source: MGI
  14. negative regulation of endothelial cell proliferation Source: MGI
  15. negative regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  16. negative regulation of macrophage fusion Source: MGI
  17. negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis Source: UniProtKB
  18. negative regulation of metanephric nephron tubule epithelial cell differentiation Source: UniProtKB
  19. negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  20. positive regulation of mesenchymal cell proliferation Source: UniProtKB
  21. positive regulation of smooth muscle cell proliferation Source: UniProtKB
  22. positive regulation of transcription, DNA-templated Source: MGI
  23. positive regulation of transcription from RNA polymerase II promoter Source: MGI
  24. renal tubule development Source: UniProtKB
  25. response to bacterium Source: MGI
  26. response to cAMP Source: UniProtKB
  27. response to cytokine Source: UniProtKB
  28. response to exogenous dsRNA Source: MGI
  29. response to lipopolysaccharide Source: MGI
  30. response to peptide hormone Source: UniProtKB
  31. transcription, DNA-templated Source: MGI
  32. transcription from RNA polymerase II promoter Source: MGI
  33. tumor necrosis factor-mediated signaling pathway Source: MGI
  34. type I interferon signaling pathway Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiREACT_317434. Growth hormone receptor signaling.
SABIO-RKP42225.

Names & Taxonomyi

Protein namesi
Recommended name:
Signal transducer and activator of transcription 1
Gene namesi
Name:Stat1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:103063. Stat1.

Subcellular locationi

  1. Cytoplasm 1 Publication
  2. Nucleus 1 Publication

  3. Note: Translocated into the nucleus upon tyrosine phosphorylation and dimerization, in response to IFN-gamma and signaling by activated FGFR1; FGFR2; FGFR3 or FGFR4.By similarity

GO - Cellular componenti

  1. axon Source: UniProtKB
  2. cytoplasm Source: MGI
  3. cytosol Source: Reactome
  4. dendrite Source: UniProtKB
  5. nuclear chromatin Source: MGI
  6. nucleolus Source: MGI
  7. nucleoplasm Source: MGI
  8. nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi708 – 7081Missing : Strongly decreases ISGF3 binding to the ISRE of IKBKE-dependent genes but noo effect on ISGF3 binding to the ISRE of IKBKE-independent genes. 1 Publication
Mutagenesisi744 – 7474SMMS → MM: No effect on ISGF3 binding to ISREs. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 749748Signal transducer and activator of transcription 1PRO_0000182411Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity
Modified residuei701 – 7011Phosphotyrosine; by JAK1, JAK2 or TYK22 Publications
Cross-linki703 – 703Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity
Modified residuei708 – 7081Phosphoserine; by IKKE2 Publications
Modified residuei727 – 7271Phosphoserine; by MAPK14By similarity
Modified residuei744 – 7441Phosphoserine; by IKKE1 Publication

Post-translational modificationi

Phosphorylated on tyrosine and serine residues in response to a variety of cytokines/growth hormones including IFN-alpha, IFN-gamma, PDGF and EGF. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus. Growth hormone (GH) activates STAT1 signaling only via JAK2. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2 and CAMKII on IFN-gamma stimulation, regulates STAT1 transcriptional activity. Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS. Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents. Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling. Upon viral infection or IFN induction, phosphorylation on Ser-708 occurs much later than phosphorylation on Tyr-701 and is required for the binding of ISGF3 on the ISREs of a subset of IFN-stimulated genes IKBKE-dependent. Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701.7 Publications
Sumoylated with SUMO1, SUMO2 and SUMO3. Sumoylation is enhanced by IFN-gamma-induced phosphorylation on Ser-727, and by interaction with PIAS proteins. Enhances the transactivation activity (By similarity).By similarity
ISGylated.1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP42225.
PaxDbiP42225.
PRIDEiP42225.

PTM databases

PhosphoSiteiP42225.

Expressioni

Inductioni

By IFN and EGF.

Gene expression databases

GenevestigatoriP42225.

Interactioni

Subunit structurei

Homodimerizes upon IFN-gamma induced phosphorylation. Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation. The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9. Interacts (phosphorylated at Ser-727) with PIAS1 (dimethylated on arginine); the interaction results in release of STAT1 from its target gene. Interacts with IFNAR1, IFNAR2, NMI, PTK2/FAK1 and SRC. Interacts with ERBB4 (phosphorylated).2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Ptpn6P293512EBI-647118,EBI-2620699
Stat4P422282EBI-647118,EBI-6253572
Usf1Q610692EBI-647118,EBI-2325635
Usf2Q647053EBI-647118,EBI-647583

Protein-protein interaction databases

DIPiDIP-38739N.
IntActiP42225. 14 interactions.

Structurei

3D structure databases

ProteinModelPortaliP42225.
SMRiP42225. Positions 2-749.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini573 – 67098SH2PROSITE-ProRule annotationAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili136 – 317182By similarityAdd
BLAST

Sequence similaritiesi

Belongs to the transcription factor STAT family.Curated
Contains 1 SH2 domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil, SH2 domain

Phylogenomic databases

eggNOGiNOG310130.
HOVERGENiHBG055669.
InParanoidiP42225.
PhylomeDBiP42225.

Family and domain databases

Gene3Di1.10.238.10. 1 hit.
1.10.532.10. 1 hit.
1.20.1050.20. 1 hit.
2.60.40.630. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR011992. EF-hand-dom_pair.
IPR008967. p53-like_TF_DNA-bd.
IPR000980. SH2.
IPR001217. STAT.
IPR022752. STAT1_TAZ2-bd_C.
IPR013800. STAT_TF_alpha.
IPR015988. STAT_TF_coiled-coil.
IPR013801. STAT_TF_DNA-bd.
IPR012345. STAT_TF_DNA-bd_sub.
IPR013799. STAT_TF_prot_interaction.
[Graphical view]
PANTHERiPTHR11801. PTHR11801. 1 hit.
PfamiPF00017. SH2. 1 hit.
PF12162. STAT1_TAZ2bind. 1 hit.
PF01017. STAT_alpha. 1 hit.
PF02864. STAT_bind. 1 hit.
PF02865. STAT_int. 1 hit.
[Graphical view]
SMARTiSM00252. SH2. 1 hit.
SM00964. STAT_int. 1 hit.
[Graphical view]
SUPFAMiSSF47655. SSF47655. 1 hit.
SSF48092. SSF48092. 1 hit.
SSF49417. SSF49417. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS50001. SH2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P42225-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSQWFELQQL DSKFLEQVHQ LYDDSFPMEI RQYLAQWLEK QDWEHAAYDV
60 70 80 90 100
SFATIRFHDL LSQLDDQYSR FSLENNFLLQ HNIRKSKRNL QDNFQEDPVQ
110 120 130 140 150
MSMIIYNCLK EERKILENAQ RFNQAQEGNI QNTVMLDKQK ELDSKVRNVK
160 170 180 190 200
DQVMCIEQEI KTLEELQDEY DFKCKTSQNR EGEANGVAKS DQKQEQLLLH
210 220 230 240 250
KMFLMLDNKR KEIIHKIREL LNSIELTQNT LINDELVEWK RRQQSACIGG
260 270 280 290 300
PPNACLDQLQ TWFTIVAETL QQIRQQLKKL EELEQKFTYE PDPITKNKQV
310 320 330 340 350
LSDRTFLLFQ QLIQSSFVVE RQPCMPTHPQ RPLVLKTGVQ FTVKSRLLVK
360 370 380 390 400
LQESNLLTKV KCHFDKDVNE KNTVKGFRKF NILGTHTKVM NMEESTNGSL
410 420 430 440 450
AAELRHLQLK EQKNAGNRTN EGPLIVTEEL HSLSFETQLC QPGLVIDLET
460 470 480 490 500
TSLPVVVISN VSQLPSGWAS ILWYNMLVTE PRNLSFFLNP PCAWWSQLSE
510 520 530 540 550
VLSWQFSSVT KRGLNADQLS MLGEKLLGPN AGPDGLIPWT RFCKENINDK
560 570 580 590 600
NFSFWPWIDT ILELIKNDLL CLWNDGCIMG FISKERERAL LKDQQPGTFL
610 620 630 640 650
LRFSESSREG AITFTWVERS QNGGEPDFHA VEPYTKKELS AVTFPDIIRN
660 670 680 690 700
YKVMAAENIP ENPLKYLYPN IDKDHAFGKY YSRPKEAPEP MELDDPKRTG
710 720 730 740
YIKTELISVS EVHPSRLQTT DNLLPMSPEE FDEMSRIVGP EFDSMMSTV
Length:749
Mass (Da):87,197
Last modified:November 1, 1995 - v1
Checksum:i249D919952BE65F1
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U06924 mRNA. Translation: AAA19454.1.
CCDSiCCDS56628.1.
UniGeneiMm.277406.
Mm.487336.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U06924 mRNA. Translation: AAA19454.1.
CCDSiCCDS56628.1.
UniGeneiMm.277406.
Mm.487336.

3D structure databases

ProteinModelPortaliP42225.
SMRiP42225. Positions 2-749.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-38739N.
IntActiP42225. 14 interactions.

Chemistry

BindingDBiP42225.
ChEMBLiCHEMBL1667670.

PTM databases

PhosphoSiteiP42225.

Proteomic databases

MaxQBiP42225.
PaxDbiP42225.
PRIDEiP42225.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Organism-specific databases

MGIiMGI:103063. Stat1.

Phylogenomic databases

eggNOGiNOG310130.
HOVERGENiHBG055669.
InParanoidiP42225.
PhylomeDBiP42225.

Enzyme and pathway databases

ReactomeiREACT_317434. Growth hormone receptor signaling.
SABIO-RKP42225.

Miscellaneous databases

ChiTaRSiStat1. mouse.
PROiP42225.
SOURCEiSearch...

Gene expression databases

GenevestigatoriP42225.

Family and domain databases

Gene3Di1.10.238.10. 1 hit.
1.10.532.10. 1 hit.
1.20.1050.20. 1 hit.
2.60.40.630. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR011992. EF-hand-dom_pair.
IPR008967. p53-like_TF_DNA-bd.
IPR000980. SH2.
IPR001217. STAT.
IPR022752. STAT1_TAZ2-bd_C.
IPR013800. STAT_TF_alpha.
IPR015988. STAT_TF_coiled-coil.
IPR013801. STAT_TF_DNA-bd.
IPR012345. STAT_TF_DNA-bd_sub.
IPR013799. STAT_TF_prot_interaction.
[Graphical view]
PANTHERiPTHR11801. PTHR11801. 1 hit.
PfamiPF00017. SH2. 1 hit.
PF12162. STAT1_TAZ2bind. 1 hit.
PF01017. STAT_alpha. 1 hit.
PF02864. STAT_bind. 1 hit.
PF02865. STAT_int. 1 hit.
[Graphical view]
SMARTiSM00252. SH2. 1 hit.
SM00964. STAT_int. 1 hit.
[Graphical view]
SUPFAMiSSF47655. SSF47655. 1 hit.
SSF48092. SSF48092. 1 hit.
SSF49417. SSF49417. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS50001. SH2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Stat3 and Stat4: members of the family of signal transducers and activators of transcription."
    Zhong Z., Wen Z., Darnell J.E. Jr.
    Proc. Natl. Acad. Sci. U.S.A. 91:4806-4810(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Thymus.
  2. "c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells."
    Cirri P., Chiarugi P., Marra F., Raugei G., Camici G., Manao G., Ramponi G.
    Biochem. Biophys. Res. Commun. 239:493-497(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION, FUNCTION, INTERACTION WITH SRC.
  3. "Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation."
    Hart K.C., Robertson S.C., Donoghue D.J.
    Mol. Biol. Cell 12:931-942(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION.
  4. Cited for: PHOSPHORYLATION, DEPHOSPHORYLATION BY PTPN2.
  5. Cited for: ISGYLATION.
  6. "Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity."
    Tenoever B.R., Ng S.L., Chua M.A., McWhirter S.M., Garcia-Sastre A., Maniatis T.
    Science 315:1274-1278(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION IN THE ISGF3 COMPLEX, PHOSPHORYLATION AT SER-708 AND SER-744, MUTAGENESIS OF SER-708 AND 744-SER--SER-747.
  7. "Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage."
    Krejci P., Salazar L., Kashiwada T.A., Chlebova K., Salasova A., Thompson L.M., Bryja V., Kozubik A., Wilcox W.R.
    PLoS ONE 3:E3961-E3961(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PHOSPHORYLATION AT TYR-701 IN RESPONSE TO CONSTITUTIVELY ACTIVATED FGFR3.
  8. "Mechanisms of STAT protein activation by oncogenic KIT mutants in neoplastic mast cells."
    Chaix A., Lopez S., Voisset E., Gros L., Dubreuil P., De Sepulveda P.
    J. Biol. Chem. 286:5956-5966(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION IN RESPONSE TO KIT SIGNALING.
  9. "Inhibitor of kappaB kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection."
    Perwitasari O., Cho H., Diamond M.S., Gale M. Jr.
    J. Biol. Chem. 286:44412-44423(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PHOSPHORYLATION AT TYR-701; SER-708 AND SER-727.

Entry informationi

Entry nameiSTAT1_MOUSE
AccessioniPrimary (citable) accession number: P42225
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: April 1, 2015
This is version 133 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.