FOXO4_MOUSE
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 03-AUG-2022, entry version 172.
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; Q9WVH3; -.
DR PRIDE; Q9WVH3; -.
DR ProteomicsDB; 271715; -.
DR Antibodypedia; 6096; 1051 antibodies from 46 providers.
DR DNASU; 54601; -.
DR Ensembl; ENSMUST00000062000; ENSMUSP00000059420; ENSMUSG00000042903.
DR GeneID; 54601; -.
DR KEGG; mmu:54601; -.
DR UCSC; uc009twz.2; mouse.
DR CTD; 4303; -.
DR MGI; MGI:1891915; Foxo4.
DR VEuPathDB; HostDB:ENSMUSG00000042903; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000159334; -.
DR InParanoid; Q9WVH3; -.
DR OMA; GKWGVNS; -.
DR OrthoDB; 1160384at2759; -.
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 77 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 195 other tissues.
DR ExpressionAtlas; Q9WVH3; baseline and differential.
DR Genevisible; Q9WVH3; MM.
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: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:0007568; P:aging; IEA:Ensembl.
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: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:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
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; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
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 Pfam; PF00250; Forkhead; 1.
DR Pfam; PF16676; FOXO-TAD; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
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
