ID   FOXO4_MOUSE             Reviewed;         505 AA.
AC   Q9WVH3;
DT   11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1999, sequence version 1.
DT   27-MAR-2024, entry version 181.
DE   RecName: Full=Forkhead box protein O4;
DE   AltName: Full=Afxh;
DE   AltName: Full=Fork head domain transcription factor AFX1;
GN   Name=Foxo4; Synonyms=Afx, Afx1, Fkhr3, Mllt7;
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=Embryo;
RX   PubMed=11353388; DOI=10.1007/s003350020002;
RA   Biggs W.H. III, Cavenee W.K., Arden K.C.;
RT   "Identification and characterization of members of the FKHR (FOX O)
RT   subclass of winged-helix transcription factors in the mouse.";
RL   Mamm. Genome 12:416-425(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Furuyama T., Nakazawa T., Mori N.;
RT   "Mouse AFX, a forkhead type transcription factor.";
RL   Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   FUNCTION, AND INDUCTION.
RX   PubMed=16054032; DOI=10.1016/j.devcel.2005.05.017;
RA   Liu Z.-P., Wang Z., Yanagisawa H., Olson E.N.;
RT   "Phenotypic modulation of smooth muscle cells through interaction of Foxo4
RT   and myocardin.";
RL   Dev. Cell 9:261-270(2005).
RN   [4]
RP   TISSUE SPECIFICITY.
RX   PubMed=22510882; DOI=10.1038/emboj.2012.97;
RA   Nakae J., Cao Y., Hakuno F., Takemori H., Kawano Y., Sekioka R., Abe T.,
RA   Kiyonari H., Tanaka T., Sakai J., Takahashi S., Itoh H.;
RT   "Novel repressor regulates insulin sensitivity through interaction with
RT   Foxo1.";
RL   EMBO J. 31:2275-2295(2012).
RN   [5]
RP   INTERACTION WITH FOXK1.
RX   PubMed=22956541; DOI=10.1242/jcs.105239;
RA   Shi X., Wallis A.M., Gerard R.D., Voelker K.A., Grange R.W., DePinho R.A.,
RA   Garry M.G., Garry D.J.;
RT   "Foxk1 promotes cell proliferation and represses myogenic differentiation
RT   by regulating Foxo4 and Mef2.";
RL   J. Cell Sci. 125:5329-5337(2012).
CC   -!- FUNCTION: Transcription factor involved in the regulation of the
CC       insulin signaling pathway. Binds to insulin-response elements (IREs)
CC       and can activate transcription of IGFBP1. Down-regulates expression of
CC       HIF1A and suppresses hypoxia-induced transcriptional activation of
CC       HIF1A-modulated genes. Also involved in negative regulation of the cell
CC       cycle. Involved in increased proteasome activity in embryonic stem
CC       cells (ESCs) by activating expression of PSMD11 in ESCs, leading to
CC       enhanced assembly of the 26S proteasome, followed by higher proteasome
CC       activity (By similarity). Represses smooth muscle cell differentiation
CC       by inhibiting the transcriptional coactivator activity of myocardin.
CC       {ECO:0000250|UniProtKB:P98177, ECO:0000269|PubMed:16054032}.
CC   -!- SUBUNIT: Interacts with CREBBP/CBP, MYOCD, SIRT1, SRF and YWHAZ.
CC       Acetylated by CREBBP/CBP and deacetylated by SIRT1. Binding of YWHAZ
CC       inhibits DNA-binding. Interacts with USP7; the interaction is enhanced
CC       in presence of hydrogen peroxide and occurs independently of TP53.
CC       Interacts with NLK, and this inhibits monoubiquitination and
CC       transcriptional activity (By similarity). Interacts with FOXK1; the
CC       interaction inhibits MEF2C transactivation activity (PubMed:22956541).
CC       {ECO:0000250|UniProtKB:P98177, ECO:0000269|PubMed:22956541}.
CC   -!- INTERACTION:
CC       Q9WVH3; P56558: Ogt; Xeno; NbExp=2; IntAct=EBI-4567305, EBI-7614183;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=When phosphorylated,
CC       translocated from nucleus to cytoplasm. Dephosphorylation triggers
CC       nuclear translocation. Monoubiquitination increases nuclear
CC       localization. When deubiquitinated, translocated from nucleus to
CC       cytoplasm (By similarity). {ECO:0000250|UniProtKB:P98177}.
CC   -!- TISSUE SPECIFICITY: Strongly expressed in brown adipose tissue and
CC       weakly in white adipose tissue (at protein level). Expressed in
CC       skeletal muscle. {ECO:0000269|PubMed:11353388,
CC       ECO:0000269|PubMed:22510882}.
CC   -!- INDUCTION: By artery ligation in proliferating neointimal smooth muscle
CC       cells. {ECO:0000269|PubMed:16054032}.
CC   -!- PTM: Acetylation by CREBBP/CBP is induced by oxidative stress and
CC       inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-
CC       dependent and stimulates transcriptional activity (By similarity).
CC       {ECO:0000250|UniProtKB:P98177}.
CC   -!- PTM: Phosphorylation by PKB/AKT1 inhibits transcriptional activity and
CC       is responsible for cytoplasmic localization. May be phosphorylated at
CC       multiple sites by NLK (By similarity). {ECO:0000250|UniProtKB:P98177}.
CC   -!- PTM: Monoubiquitinated; monoubiquitination is induced by oxidative
CC       stress and reduced by deacetylase inhibitors; results in its
CC       relocalization to the nucleus and its increased transcriptional
CC       activity. Deubiquitinated by USP7; deubiquitination is induced by
CC       oxidative stress; enhances its interaction with USP7 and consequently,
CC       deubiquitination; increases its translocation to the cytoplasm and
CC       inhibits its transcriptional activity. Hydrogene-peroxide-induced
CC       ubiquitination and USP7-mediated deubiquitination have no major effect
CC       on its protein stability (By similarity).
CC       {ECO:0000250|UniProtKB:P98177}.
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DR   EMBL; AF114260; AAD42108.1; -; mRNA.
DR   EMBL; AB032770; BAA86199.1; -; mRNA.
DR   CCDS; CCDS41077.1; -.
DR   RefSeq; NP_061259.1; NM_018789.2.
DR   AlphaFoldDB; Q9WVH3; -.
DR   BMRB; Q9WVH3; -.
DR   SMR; Q9WVH3; -.
DR   BioGRID; 207680; 1.
DR   CORUM; Q9WVH3; -.
DR   IntAct; Q9WVH3; 2.
DR   MINT; Q9WVH3; -.
DR   STRING; 10090.ENSMUSP00000059420; -.
DR   iPTMnet; Q9WVH3; -.
DR   PhosphoSitePlus; Q9WVH3; -.
DR   MaxQB; Q9WVH3; -.
DR   PaxDb; 10090-ENSMUSP00000059420; -.
DR   ProteomicsDB; 271715; -.
DR   Antibodypedia; 6096; 1224 antibodies from 46 providers.
DR   DNASU; 54601; -.
DR   Ensembl; ENSMUST00000062000.6; ENSMUSP00000059420.5; ENSMUSG00000042903.9.
DR   GeneID; 54601; -.
DR   KEGG; mmu:54601; -.
DR   UCSC; uc009twz.2; mouse.
DR   AGR; MGI:1891915; -.
DR   CTD; 4303; -.
DR   MGI; MGI:1891915; Foxo4.
DR   VEuPathDB; HostDB:ENSMUSG00000042903; -.
DR   eggNOG; KOG2294; Eukaryota.
DR   GeneTree; ENSGT00940000159334; -.
DR   InParanoid; Q9WVH3; -.
DR   OMA; VHTEGHS; -.
DR   OrthoDB; 5385885at2759; -.
DR   PhylomeDB; Q9WVH3; -.
DR   TreeFam; TF315583; -.
DR   Reactome; R-MMU-198693; AKT phosphorylates targets in the nucleus.
DR   Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR   Reactome; R-MMU-9614399; Regulation of localization of FOXO transcription factors.
DR   Reactome; R-MMU-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR   Reactome; R-MMU-9617828; FOXO-mediated transcription of cell cycle genes.
DR   BioGRID-ORCS; 54601; 2 hits in 82 CRISPR screens.
DR   ChiTaRS; Foxo4; mouse.
DR   PRO; PR:Q9WVH3; -.
DR   Proteomes; UP000000589; Chromosome X.
DR   RNAct; Q9WVH3; Protein.
DR   Bgee; ENSMUSG00000042903; Expressed in placenta labyrinth and 198 other cell types or tissues.
DR   ExpressionAtlas; Q9WVH3; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR   GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR   GO; GO:0016607; C:nuclear speck; ISO:MGI.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0008013; F:beta-catenin binding; ISO:MGI.
DR   GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR   GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:MGI.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR   GO; GO:0140297; F:DNA-binding transcription factor binding; ISS:UniProtKB.
DR   GO; GO:0019899; F:enzyme binding; ISS:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0003676; F:nucleic acid binding; ISO:MGI.
DR   GO; GO:1990841; F:promoter-specific chromatin binding; ISO:MGI.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR   GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; IDA:MGI.
DR   GO; GO:0007517; P:muscle organ development; IEA:UniProtKB-KW.
DR   GO; GO:0016525; P:negative regulation of angiogenesis; ISS:UniProtKB.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:MGI.
DR   GO; GO:0070317; P:negative regulation of G0 to G1 transition; ISS:UniProtKB.
DR   GO; GO:0051151; P:negative regulation of smooth muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:MGI.
DR   GO; GO:0014911; P:positive regulation of smooth muscle cell migration; ISO:MGI.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR   GO; GO:0006979; P:response to oxidative stress; ISO:MGI.
DR   GO; GO:1990785; P:response to water-immersion restraint stress; IEA:Ensembl.
DR   GO; GO:0048863; P:stem cell differentiation; ISS:UniProtKB.
DR   CDD; cd20062; FH_FOXO4; 1.
DR   Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1.
DR   InterPro; IPR047409; FH_FOXO4.
DR   InterPro; IPR001766; Fork_head_dom.
DR   InterPro; IPR032067; FOXO-TAD.
DR   InterPro; IPR030456; TF_fork_head_CS_2.
DR   InterPro; IPR036388; WH-like_DNA-bd_sf.
DR   InterPro; IPR036390; WH_DNA-bd_sf.
DR   PANTHER; PTHR45767; FORKHEAD BOX PROTEIN O; 1.
DR   PANTHER; PTHR45767:SF3; FORKHEAD BOX PROTEIN O4; 1.
DR   Pfam; PF00250; Forkhead; 1.
DR   Pfam; PF16676; FOXO-TAD; 1.
DR   PRINTS; PR00053; FORKHEAD.
DR   SMART; SM00339; FH; 1.
DR   SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1.
DR   PROSITE; PS00658; FORK_HEAD_2; 1.
DR   PROSITE; PS50039; FORK_HEAD_3; 1.
DR   Genevisible; Q9WVH3; MM.
PE   1: Evidence at protein level;
KW   Acetylation; Activator; Cell cycle; Cytoplasm; Developmental protein;
KW   Differentiation; DNA-binding; Myogenesis; Nucleus; Phosphoprotein;
KW   Reference proteome; Transcription; Transcription regulation;
KW   Ubl conjugation.
FT   CHAIN           1..505
FT                   /note="Forkhead box protein O4"
FT                   /id="PRO_0000091876"
FT   DNA_BIND        100..188
FT                   /note="Fork-head"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT   REGION          1..66
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          97..215
FT                   /note="Required for interaction with FOXK1"
FT                   /evidence="ECO:0000269|PubMed:22956541"
FT   REGION          175..244
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          257..276
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        257..273
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         32
FT                   /note="Phosphothreonine; by PKB/AKT1"
FT                   /evidence="ECO:0000250|UniProtKB:P98177"
FT   MOD_RES         197
FT                   /note="Phosphoserine; by PKB/AKT1"
FT                   /evidence="ECO:0000250|UniProtKB:P98177"
FT   MOD_RES         262
FT                   /note="Phosphoserine; by PKB/AKT1"
FT                   /evidence="ECO:0000250|UniProtKB:P98177"
SQ   SEQUENCE   505 AA;  53649 MW;  ABB99B54807C7CE5 CRC64;
     MDPENKKSAT GAAAILDLDP DFEPQSRPRS CTWPLPRPDL ATEPHEPSEV EPSLGQKVPT
     EGHSEPILLP SRLPEPAGGP QPGILGAVTG PRKGGSRRNA WGNQSYAELI SQAIESAPEK
     RLTLAQIYEW MVRTVPYFKD KGDSNSSAGW KNSIRHNLSL HSKFIKVHNE ATGKSSWWML
     NPDGGKGGKA PRRRAASMDS SSKLLRGRSK GPKKKPSVLP APPEGATPRS PLGHFAKWSS
     SPCPRNREEA DVWTTFRPRS SSNASTVSTR LSPMRPESEV LAEEEMPASA SSYAGGVPPT
     LSEDLELLDG LNLASPHSLL SRSGLSGFSL QHPGLAGPLH SYGASLFGPI DGSLSAGEGC
     FSSSQSLEAL LTSDTPPPPA DVLMTQVDPI LSQAPTLLLL GGMPSSSKLG TGVSLCPTPL
     EGPGPSNLVP NLSVMAPPPV MAGAPIPKVL GTPVLASPTE DSSHDRMPQD LDLDMYMENL
     ECDMDNIISD LMDGEGLDFN FEPDP
//