STAT4_HUMAN
ID STAT4_HUMAN Reviewed; 748 AA.
AC Q14765; Q96NZ6;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Signal transducer and activator of transcription 4;
GN Name=STAT4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Xu X., Sun Y.L., Hoey T.;
RT "The STAT amino-terminal domain mediates cooperative DNA binding and
RT confers selective sequence recognition.";
RL Submitted (AUG-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 91-748.
RG SeattleSNPs variation discovery resource;
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP INTERACTION WITH IL12RB2.
RX PubMed=10415122; DOI=10.1006/abbi.1999.1302;
RA Yao B.B., Niu P., Surowy C.S., Faltynek C.R.;
RT "Direct interaction of STAT4 with the IL-12 receptor.";
RL Arch. Biochem. Biophys. 368:147-155(1999).
RN [5]
RP INTERACTION WITH IL12RB2.
RX PubMed=9890938; DOI=10.1074/jbc.274.4.1875;
RA Naeger L.K., McKinney J., Salvekar A., Hoey T.;
RT "Identification of a STAT4 binding site in the interleukin-12 receptor
RT required for signaling.";
RL J. Biol. Chem. 274:1875-1878(1999).
RN [6]
RP INVOLVEMENT IN SLEB11.
RX PubMed=19109131; DOI=10.4049/jimmunol.182.1.34;
RA Kariuki S.N., Kirou K.A., MacDermott E.J., Barillas-Arias L., Crow M.K.,
RA Niewold T.B.;
RT "Cutting edge: autoimmune disease risk variant of STAT4 confers increased
RT sensitivity to IFN-alpha in lupus patients in vivo.";
RL J. Immunol. 182:34-38(2009).
RN [7]
RP VARIANT [LARGE SCALE ANALYSIS] GLN-112.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [8]
RP INVOLVEMENT IN SLEB11 AND RA.
RX PubMed=17804842; DOI=10.1056/nejmoa073003;
RA Remmers E.F., Plenge R.M., Lee A.T., Graham R.R., Hom G., Behrens T.W.,
RA de Bakker P.I.W., Le J.M., Lee H.-S., Batliwalla F., Li W., Masters S.L.,
RA Booty M.G., Carulli J.P., Padyukov L., Alfredsson L., Klareskog L.,
RA Chen W.V., Amos C.I., Criswell L.A., Seldin M.F., Kastner D.L.,
RA Gregersen P.K.;
RT "STAT4 and the risk of rheumatoid arthritis and systemic lupus
RT erythematosus.";
RL N. Engl. J. Med. 357:977-986(2007).
CC -!- FUNCTION: Carries out a dual function: signal transduction and
CC activation of transcription. Involved in IL12 signaling.
CC -!- SUBUNIT: Forms a homodimer or a heterodimer with a related family
CC member. Interacts with ARL2BP (By similarity). The SH2 domain
CC interacts, in vitro, with IL12RB2 via a short cytoplasmic domain.
CC {ECO:0000250, ECO:0000269|PubMed:10415122, ECO:0000269|PubMed:9890938}.
CC -!- INTERACTION:
CC Q14765; O14901: KLF11; NbExp=3; IntAct=EBI-1186538, EBI-948266;
CC Q14765; O43504: LAMTOR5; NbExp=2; IntAct=EBI-1186538, EBI-713382;
CC Q14765; Q9BVL2: NUP58; NbExp=3; IntAct=EBI-1186538, EBI-2811583;
CC Q14765; Q14765: STAT4; NbExp=2; IntAct=EBI-1186538, EBI-1186538;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocated into the
CC nucleus in response to phosphorylation.
CC -!- PTM: Tyrosine phosphorylated. Serine phosphorylation is also required
CC for maximal transcriptional activity (By similarity). {ECO:0000250}.
CC -!- DISEASE: Systemic lupus erythematosus 11 (SLEB11) [MIM:612253]: A
CC chronic, relapsing, inflammatory, and often febrile multisystemic
CC disorder of connective tissue, characterized principally by involvement
CC of the skin, joints, kidneys and serosal membranes. It is of unknown
CC etiology, but is thought to represent a failure of the regulatory
CC mechanisms of the autoimmune system. The disease is marked by a wide
CC range of system dysfunctions, an elevated erythrocyte sedimentation
CC rate, and the formation of LE cells in the blood or bone marrow.
CC {ECO:0000269|PubMed:17804842, ECO:0000269|PubMed:19109131}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory
CC disease with autoimmune features and a complex genetic component. It
CC primarily affects the joints and is characterized by inflammatory
CC changes in the synovial membranes and articular structures, widespread
CC fibrinoid degeneration of the collagen fibers in mesenchymal tissues,
CC and by atrophy and rarefaction of bony structures.
CC {ECO:0000269|PubMed:17804842}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the transcription factor STAT family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/stat4/";
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DR EMBL; L78440; AAB05605.1; -; mRNA.
DR EMBL; BC031212; AAH31212.1; -; mRNA.
DR EMBL; AF423072; AAL12164.1; -; Genomic_DNA.
DR CCDS; CCDS2310.1; -.
DR RefSeq; NP_001230764.1; NM_001243835.1.
DR RefSeq; NP_003142.1; NM_003151.3.
DR RefSeq; XP_006712782.1; XM_006712719.3.
DR RefSeq; XP_011510007.1; XM_011511705.2.
DR AlphaFoldDB; Q14765; -.
DR BMRB; Q14765; -.
DR SMR; Q14765; -.
DR BioGRID; 112652; 30.
DR ComplexPortal; CPX-6042; STAT1/STAT4 complex.
DR ComplexPortal; CPX-6046; STAT3/STAT4 complex.
DR ComplexPortal; CPX-6050; STAT4 homodimer.
DR DIP; DIP-39854N; -.
DR IntAct; Q14765; 41.
DR MINT; Q14765; -.
DR STRING; 9606.ENSP00000376134; -.
DR BindingDB; Q14765; -.
DR ChEMBL; CHEMBL4523296; -.
DR GlyGen; Q14765; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; Q14765; -.
DR PhosphoSitePlus; Q14765; -.
DR BioMuta; STAT4; -.
DR DMDM; 6226158; -.
DR CPTAC; CPTAC-1277; -.
DR EPD; Q14765; -.
DR jPOST; Q14765; -.
DR MassIVE; Q14765; -.
DR PaxDb; Q14765; -.
DR PeptideAtlas; Q14765; -.
DR PRIDE; Q14765; -.
DR ProteomicsDB; 60158; -.
DR Antibodypedia; 661; 1184 antibodies from 47 providers.
DR DNASU; 6775; -.
DR Ensembl; ENST00000358470.8; ENSP00000351255.4; ENSG00000138378.19.
DR Ensembl; ENST00000392320.7; ENSP00000376134.2; ENSG00000138378.19.
DR GeneID; 6775; -.
DR KEGG; hsa:6775; -.
DR MANE-Select; ENST00000392320.7; ENSP00000376134.2; NM_003151.4; NP_003142.1.
DR UCSC; uc002usm.3; human.
DR CTD; 6775; -.
DR DisGeNET; 6775; -.
DR GeneCards; STAT4; -.
DR HGNC; HGNC:11365; STAT4.
DR HPA; ENSG00000138378; Tissue enhanced (testis).
DR MalaCards; STAT4; -.
DR MIM; 180300; phenotype.
DR MIM; 600558; gene.
DR MIM; 612253; phenotype.
DR neXtProt; NX_Q14765; -.
DR OpenTargets; ENSG00000138378; -.
DR Orphanet; 117; Behcet disease.
DR Orphanet; 85410; Oligoarticular juvenile idiopathic arthritis.
DR Orphanet; 93552; Pediatric systemic lupus erythematosus.
DR Orphanet; 85408; Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis.
DR Orphanet; 536; Systemic lupus erythematosus.
DR PharmGKB; PA36185; -.
DR VEuPathDB; HostDB:ENSG00000138378; -.
DR eggNOG; KOG3667; Eukaryota.
DR GeneTree; ENSGT01050000244905; -.
DR HOGENOM; CLU_014189_3_0_1; -.
DR InParanoid; Q14765; -.
DR OMA; YKVIMSE; -.
DR OrthoDB; 327469at2759; -.
DR PhylomeDB; Q14765; -.
DR TreeFam; TF318648; -.
DR PathwayCommons; Q14765; -.
DR Reactome; R-HSA-8854691; Interleukin-20 family signaling.
DR Reactome; R-HSA-8950505; Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation.
DR Reactome; R-HSA-8984722; Interleukin-35 Signalling.
DR Reactome; R-HSA-9020591; Interleukin-12 signaling.
DR Reactome; R-HSA-9020933; Interleukin-23 signaling.
DR Reactome; R-HSA-9020958; Interleukin-21 signaling.
DR SignaLink; Q14765; -.
DR SIGNOR; Q14765; -.
DR BioGRID-ORCS; 6775; 7 hits in 1093 CRISPR screens.
DR ChiTaRS; STAT4; human.
DR GeneWiki; STAT4; -.
DR GenomeRNAi; 6775; -.
DR Pharos; Q14765; Tchem.
DR PRO; PR:Q14765; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q14765; protein.
DR Bgee; ENSG00000138378; Expressed in granulocyte and 121 other tissues.
DR ExpressionAtlas; Q14765; baseline and differential.
DR Genevisible; Q14765; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IPI:ComplexPortal.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0006952; P:defense response; IBA:GO_Central.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IC:ComplexPortal.
DR GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; IBA:GO_Central.
DR GO; GO:0042127; P:regulation of cell population proliferation; IBA:GO_Central.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0043434; P:response to peptide hormone; IBA:GO_Central.
DR CDD; cd10375; SH2_STAT4; 1.
DR Gene3D; 1.10.532.10; -; 1.
DR Gene3D; 2.60.40.630; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR001217; STAT.
DR InterPro; IPR029839; STAT4.
DR InterPro; IPR035856; STAT4_SH2.
DR InterPro; IPR036535; STAT_N_sf.
DR InterPro; IPR013800; STAT_TF_alpha.
DR InterPro; IPR015988; STAT_TF_coiled-coil.
DR InterPro; IPR013801; STAT_TF_DNA-bd.
DR InterPro; IPR012345; STAT_TF_DNA-bd_N.
DR InterPro; IPR013799; STAT_TF_prot_interaction.
DR PANTHER; PTHR11801; PTHR11801; 1.
DR PANTHER; PTHR11801:SF19; PTHR11801:SF19; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF01017; STAT_alpha; 1.
DR Pfam; PF02864; STAT_bind; 1.
DR Pfam; PF02865; STAT_int; 1.
DR SMART; SM00964; STAT_int; 1.
DR SUPFAM; SSF47655; SSF47655; 1.
DR SUPFAM; SSF48092; SSF48092; 1.
DR SUPFAM; SSF49417; SSF49417; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW Activator; Cytoplasm; DNA-binding; Nucleus; Phosphoprotein;
KW Reference proteome; SH2 domain; Systemic lupus erythematosus;
KW Transcription; Transcription regulation.
FT CHAIN 1..748
FT /note="Signal transducer and activator of transcription 4"
FT /id="PRO_0000182420"
FT DOMAIN 569..664
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT MOD_RES 693
FT /note="Phosphotyrosine; by JAK"
FT /evidence="ECO:0000250"
FT VARIANT 112
FT /note="E -> Q (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036002"
FT VARIANT 115
FT /note="I -> V (in dbSNP:rs3024839)"
FT /id="VAR_020190"
FT VARIANT 584
FT /note="R -> W (in dbSNP:rs3024933)"
FT /id="VAR_047939"
FT CONFLICT 365..371
FT /note="KNVSTLS -> N (in Ref. 3; AAL12164)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 748 AA; 85941 MW; 11E43803A9AF4FFA CRC64;
MSQWNQVQQL EIKFLEQVDQ FYDDNFPMEI RHLLAQWIEN QDWEAASNNE TMATILLQNL
LIQLDEQLGR VSKEKNLLLI HNLKRIRKVL QGKFHGNPMH VAVVISNCLR EERRILAAAN
MPVQGPLEKS LQSSSVSERQ RNVEHKVAAI KNSVQMTEQD TKYLEDLQDE FDYRYKTIQT
MDQSDKNSAM VNQEVLTLQE MLNSLDFKRK EALSKMTQII HETDLLMNTM LIEELQDWKR
RQQIACIGGP LHNGLDQLQN CFTLLAESLF QLRRQLEKLE EQSTKMTYEG DPIPMQRTHM
LERVTFLIYN LFKNSFVVER QPCMPTHPQR PLVLKTLIQF TVKLRLLIKL PELNYQVKVK
ASIDKNVSTL SNRRFVLCGT NVKAMSIEES SNGSLSVEFR HLQPKEMKSS AGGKGNEGCH
MVTEELHSIT FETQICLYGL TIDLETSSLP VVMISNVSQL PNAWASIIWY NVSTNDSQNL
VFFNNPPPAT LSQLLEVMSW QFSSYVGRGL NSDQLHMLAE KLTVQSSYSD GHLTWAKFCK
EHLPGKSFTF WTWLEAILDL IKKHILPLWI DGYVMGFVSK EKERLLLKDK MPGTFLLRFS
ESHLGGITFT WVDHSESGEV RFHSVEPYNK GRLSALPFAD ILRDYKVIMA ENIPENPLKY
LYPDIPKDKA FGKHYSSQPC EVSRPTERGD KGYVPSVFIP ISTIRSDSTE PHSPSDLLPM
SPSVYAVLRE NLSPTTIETA MKSPYSAE
