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
//