ID STAT4_MOUSE Reviewed; 749 AA.
AC P42228;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 27-MAR-2024, entry version 181.
DE RecName: Full=Signal transducer and activator of transcription 4;
GN Name=Stat4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Thymus;
RX PubMed=7545930; DOI=10.1073/pnas.91.11.4806;
RA Zhong Z., Wen Z., Darnell J.E. Jr.;
RT "Stat3 and Stat4: members of the family of signal transducers and
RT activators of transcription.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:4806-4810(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ; TISSUE=Testis;
RX PubMed=8007943; DOI=10.1128/mcb.14.7.4342-4349.1994;
RA Yamamoto K., Quelle F.W., Thierfelder W.E., Kreider B.L., Gilbert D.J.,
RA Jenkins N.A., Copeland N.G., Silvennoinen O., Ihle J.N.;
RT "Stat4, a novel gamma interferon activation site-binding protein expressed
RT in early myeloid differentiation.";
RL Mol. Cell. Biol. 14:4342-4349(1994).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=8700209; DOI=10.1038/382174a0;
RA Kaplan M.H., Sun Y.L., Hoey T., Grusby M.J.;
RT "Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-
RT deficient mice.";
RL Nature 382:174-177(1996).
RN [4]
RP FUNCTION, AND INTERACTION WITH JUN.
RX PubMed=14734615; DOI=10.1093/intimm/dxh034;
RA Park W.R., Nakahira M., Sugimoto N., Bian Y., Yashiro-Ohtani Y., Zhou X.Y.,
RA Yang Y.F., Hamaoka T., Fujiwara H.;
RT "A mechanism underlying STAT4-mediated up-regulation of IFN-gamma induction
RT inTCR-triggered T cells.";
RL Int. Immunol. 16:295-302(2004).
RN [5]
RP INTERACTION WITH ARL2BP.
RX PubMed=18234692; DOI=10.1093/intimm/dxm154;
RA Muromoto R., Sekine Y., Imoto S., Ikeda O., Okayama T., Sato N.,
RA Matsuda T.;
RT "BART is essential for nuclear retention of STAT3.";
RL Int. Immunol. 20:395-403(2008).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=34138758; DOI=10.1172/jci.insight.141326;
RA Mehrpouya-Bahrami P., Moriarty A.K., De Melo P., Keeter W.C.,
RA Alakhras N.S., Nelson A.S., Hoover M., Barrios M.S., Nadler J.L.,
RA Serezani C.H., Kaplan M.H., Galkina E.V.;
RT "STAT4 is expressed in neutrophils and promotes antimicrobial immunity.";
RL JCI Insight 6:0-0(2021).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 1-123.
RX PubMed=9461439; DOI=10.1126/science.279.5353.1048;
RA Vinkemeier U., Moarefi I., Darnell J.E. Jr., Kuriyan J.;
RT "Structure of the amino-terminal protein interaction domain of STAT-4.";
RL Science 279:1048-1052(1998).
CC -!- FUNCTION: Transcriptional regulator mainly expressed in hematopoietic
CC cells that plays a critical role in cellular growth, differentiation
CC and immune response. Plays a key role in the differentiation of T-
CC helper 1 cells and the production of interferon-gamma (PubMed:8700209).
CC Participates also in multiple neutrophil functions including chemotaxis
CC and production of the neutrophil extracellular traps (PubMed:34138758).
CC After IL12 binding to its receptor IL12RB2, STAT4 interacts with the
CC intracellular domain of IL12RB2 and becomes tyrosine phosphorylated.
CC Phosphorylated STAT4 then homodimerizes and migrates to the nucleus
CC where it can recognize STAT target sequences present in IL12 responsive
CC genes. Although IL12 appears to be the predominant activating signal,
CC STAT4 can also be phosphorylated and activated in response to IFN-gamma
CC stimulation via JAK1 and TYK2 and in response to different interleukins
CC including IL23, IL2 and IL35 (By similarity). Transcription activation
CC of IFN-gamma gene is mediated by interaction with JUN that forms a
CC complex that efficiently interacts with the AP-1-related sequence of
CC the IFN-gamma promoter (PubMed:14734615). In response to IFN-alpha/beta
CC signaling, acts as a transcriptional repressor and suppresses IL5 and
CC IL13 mRNA expression during response to T-cell receptor (TCR)
CC activation (By similarity). {ECO:0000250|UniProtKB:Q14765,
CC ECO:0000269|PubMed:14734615, ECO:0000269|PubMed:34138758,
CC ECO:0000269|PubMed:8700209}.
CC -!- SUBUNIT: Forms a homodimer or a heterodimer with a related family
CC member (By similarity). Interacts with ARL2BP. Interacts with STAT1 (By
CC similarity). Interacts with JUN; this complex efficiently interacts
CC with the AP-1-related sequence of the IFN-gamma promoter
CC (PubMed:14734615). {ECO:0000250|UniProtKB:Q14765,
CC ECO:0000269|PubMed:14734615, ECO:0000269|PubMed:18234692}.
CC -!- INTERACTION:
CC P42228; P42225: Stat1; NbExp=2; IntAct=EBI-6253572, EBI-647118;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus
CC {ECO:0000250|UniProtKB:Q14765}. Note=Translocated into the nucleus in
CC response to phosphorylation. {ECO:0000250|UniProtKB:Q14765}.
CC -!- TISSUE SPECIFICITY: Expression is restricted to testis, thymus, and
CC spleen. {ECO:0000269|PubMed:7545930}.
CC -!- PTM: Acetylation at Lys-668 is required for JAK2-mediated
CC phosphorylation and activation of STAT4.
CC {ECO:0000250|UniProtKB:Q14765}.
CC -!- PTM: Tyrosine phosphorylated upon IL12 and IFN-alpha activation, but
CC not by IFN-gamma in T-lymphocytes and NK cells. Serine phosphorylation
CC is required for maximal transcriptional activity but not for DNA
CC binding. Phosphorylation by MAP2K6 at Ser-722 is required for full
CC transcriptional activity induced by IL12. However this serine
CC phosphorylation is not required for cell proliferation although
CC critical for IFN-gamma production. {ECO:0000250|UniProtKB:Q14765}.
CC -!- DISRUPTION PHENOTYPE: STAT4-deficient mice are grossly
CC indistinguishable from wild-type mice. However, the development of T-
CC helper 1 cells in response to either IL12 or Listeria monocytogenes is
CC strongly impaired (PubMed:8700209). In addition, mice are acutely
CC sensitive to methicillin-resistant Staphylococcus aureus (MRSA)
CC infection (PubMed:34138758). {ECO:0000269|PubMed:34138758,
CC ECO:0000269|PubMed:8700209}.
CC -!- SIMILARITY: Belongs to the transcription factor STAT family.
CC {ECO:0000305}.
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DR EMBL; U06923; AAA19453.1; -; mRNA.
DR EMBL; U09351; AAA19692.1; -; mRNA.
DR PIR; A56047; A56047.
DR RefSeq; NP_001295195.1; NM_001308266.1.
DR RefSeq; NP_035617.1; NM_011487.5.
DR PDB; 1BGF; X-ray; 1.45 A; A=2-123.
DR PDBsum; 1BGF; -.
DR AlphaFoldDB; P42228; -.
DR BMRB; P42228; -.
DR SMR; P42228; -.
DR BioGRID; 203524; 1.
DR DIP; DIP-1170N; -.
DR IntAct; P42228; 2.
DR STRING; 10090.ENSMUSP00000027277; -.
DR iPTMnet; P42228; -.
DR PhosphoSitePlus; P42228; -.
DR SwissPalm; P42228; -.
DR EPD; P42228; -.
DR MaxQB; P42228; -.
DR PaxDb; 10090-ENSMUSP00000027277; -.
DR ProteomicsDB; 257369; -.
DR DNASU; 20849; -.
DR GeneID; 20849; -.
DR KEGG; mmu:20849; -.
DR AGR; MGI:103062; -.
DR CTD; 6775; -.
DR MGI; MGI:103062; Stat4.
DR eggNOG; KOG3667; Eukaryota.
DR InParanoid; P42228; -.
DR OrthoDB; 7823at2759; -.
DR PhylomeDB; P42228; -.
DR Reactome; R-MMU-8854691; Interleukin-20 family signaling.
DR Reactome; R-MMU-8984722; Interleukin-35 Signalling.
DR Reactome; R-MMU-9020591; Interleukin-12 signaling.
DR Reactome; R-MMU-9020933; Interleukin-23 signaling.
DR Reactome; R-MMU-9020958; Interleukin-21 signaling.
DR BioGRID-ORCS; 20849; 3 hits in 82 CRISPR screens.
DR ChiTaRS; Stat4; mouse.
DR EvolutionaryTrace; P42228; -.
DR PRO; PR:P42228; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; P42228; Protein.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IMP:NTNU_SB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR GO; GO:0071310; P:cellular response to organic substance; IDA:MGI.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:MGI.
DR GO; GO:0006952; P:defense response; IBA:GO_Central.
DR GO; GO:0061484; P:hematopoietic stem cell homeostasis; IMP:MGI.
DR GO; GO:0035722; P:interleukin-12-mediated signaling pathway; ISO:MGI.
DR GO; GO:0070661; P:leukocyte proliferation; IDA:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IGI:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
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 GO; GO:0045063; P:T-helper 1 cell differentiation; ISO:MGI.
DR CDD; cd10375; SH2_STAT4; 1.
DR CDD; cd16854; STAT4_CCD; 1.
DR CDD; cd16848; STAT4_DBD; 1.
DR Gene3D; 1.10.238.10; EF-hand; 1.
DR Gene3D; 3.30.505.10; SH2 domain; 1.
DR Gene3D; 1.20.1050.20; STAT transcription factor, all-alpha domain; 1.
DR Gene3D; 2.60.40.630; STAT transcription factor, DNA-binding domain; 1.
DR Gene3D; 1.10.532.10; STAT transcription factor, N-terminal domain; 1.
DR IDEAL; IID50278; -.
DR InterPro; IPR008967; p53-like_TF_DNA-bd_sf.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR001217; STAT.
DR InterPro; IPR046991; STAT4_CCD.
DR InterPro; IPR029839; STAT4_DBD.
DR InterPro; IPR035856; STAT4_SH2.
DR InterPro; IPR048988; STAT_linker.
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; SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION; 1.
DR PANTHER; PTHR11801:SF19; SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4; 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 Pfam; PF21354; STAT_linker; 1.
DR SMART; SM00964; STAT_int; 1.
DR SUPFAM; SSF49417; p53-like transcription factors; 1.
DR SUPFAM; SSF55550; SH2 domain; 1.
DR SUPFAM; SSF47655; STAT; 1.
DR SUPFAM; SSF48092; Transcription factor STAT-4 N-domain; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Cytoplasm; DNA-binding; Nucleus;
KW Phosphoprotein; Reference proteome; SH2 domain; Transcription;
KW Transcription regulation.
FT CHAIN 1..749
FT /note="Signal transducer and activator of transcription 4"
FT /id="PRO_0000182421"
FT DOMAIN 570..665
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT MOD_RES 668
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q14765"
FT MOD_RES 694
FT /note="Phosphotyrosine; by JAK"
FT /evidence="ECO:0000250|UniProtKB:Q14765"
FT MOD_RES 722
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14765"
FT CONFLICT 199
FT /note="Missing (in Ref. 2; AAA19692)"
FT /evidence="ECO:0000305"
FT CONFLICT 638
FT /note="A -> P (in Ref. 2; AAA19692)"
FT /evidence="ECO:0000305"
FT HELIX 3..9
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 12..14
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 15..18
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 19..21
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 28..33
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 35..40
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 43..46
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 50..74
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 77..95
FT /evidence="ECO:0007829|PDB:1BGF"
FT HELIX 98..118
FT /evidence="ECO:0007829|PDB:1BGF"
SQ SEQUENCE 749 AA; 85941 MW; A88B837E49FCFEBC CRC64;
MSQWNQVQQL EIKFLEQVDQ FYDDNFPMEI RHLLAQWIET QDWEVASNNE TMATILLQNL
LIQLDEQLGR VSKEKNLLLI HNLKRIRKVL QGKFHGNPMH VAVVISNCLR EERRILAAAN
MPIQGPLEKS LQSSSVSERQ RNVEHKVSAI KNSVQMTEQD TKYLEDLQDE FDYRYKTIQT
MDQGDKNSIL VNQEVLTLLQ EMLNSLDFKR KEALSKMTQI VNETDLLMNS MLLEELQDWK
KRQQIACIGG PLHNGLDQLQ NCFTLLAESL FQLRQQLEKL QEQSTKMTYE GDPIPAQRAH
LLERATFLIY NLFKNSFVVE RQPCMPTHPQ RPMVLKTLIQ FTVKLRLLIK LPELNYQVKV
KASIDKNVST LSNRRFVLCG THVKAMSSEE SSNGSLSVEF RHLQPKEMKC STGSKGNEGC
HMVTEELHSI TFETQICLYG LTINLETSSL PVVMISNVSQ LPNAWASIIW YNVSTNDSQN
LVFFNNPPSV TLGQLLEVMS WQFSSYVGRG LNSEQLNMLA EKLTVQSNYN DGHLTWAKFC
KEHLPGKTFT FWTWLEAILD LIKKHILPLW IDGYIMGFVS KEKERLLLKD KMPGTFLLRF
SESHLGGITF TWVDQSENGE VRFHSVEPYN KGRLSALAFA DILRDYKVIM AENIPENPLK
YLYPDIPKDK AFGKHYSSQP CEVSRPTERG DKGYVPSVFI PISTIRSDST EPQSPSDLLP
MSPSAYAVLR ENLSPTTIET AMNSPYSAE
//
