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Protein

Forkhead box protein O3

Gene

Foxo3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional activator (PubMed:23805378). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.By similarity1 Publication

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi156 – 25095Fork-headPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  • beta-catenin binding Source: MGI
  • chromatin DNA binding Source: UniProtKB
  • core promoter binding Source: UniProtKB
  • DNA binding Source: MGI
  • protein kinase binding Source: MGI
  • sequence-specific DNA binding Source: MGI
  • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding Source: BHF-UCL
  • transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding Source: MGI
  • transcription factor activity, sequence-specific DNA binding Source: MGI

GO - Biological processi

  • antral ovarian follicle growth Source: MGI
  • brain morphogenesis Source: MGI
  • cellular response to oxidative stress Source: UniProtKB
  • DNA damage response, signal transduction by p53 class mediator Source: MGI
  • extrinsic apoptotic signaling pathway in absence of ligand Source: MGI
  • glucose homeostasis Source: MGI
  • initiation of primordial ovarian follicle growth Source: MGI
  • negative regulation of canonical Wnt signaling pathway Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • neuronal stem cell population maintenance Source: MGI
  • oocyte maturation Source: MGI
  • ovulation from ovarian follicle Source: MGI
  • positive regulation of apoptotic process Source: MGI
  • positive regulation of erythrocyte differentiation Source: MGI
  • positive regulation of neuron apoptotic process Source: MGI
  • positive regulation of transcription, DNA-templated Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • regulation of neural precursor cell proliferation Source: MGI
  • regulation of reactive oxygen species metabolic process Source: MGI
  • regulation of transcription, DNA-templated Source: MGI
  • regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • regulation of translation Source: UniProtKB
  • tumor necrosis factor-mediated signaling pathway Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Apoptosis, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiR-MMU-1181150. Signaling by NODAL.
R-MMU-198693. AKT phosphorylates targets in the nucleus.
R-MMU-5687128. MAPK6/MAPK4 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein O3Curated
Gene namesi
Name:Foxo3Imported
Synonyms:Fkhr21 Publication, Foxo3a1 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1890081. Foxo3.

Subcellular locationi

  • Cytoplasmcytosol By similarity
  • Nucleus By similarity

  • Note: Retention in the cytoplasm contributes to its inactivation. Translocates to the nucleus upon oxidative stress and in the absence of survival factors.By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytosol Source: MGI
  • membrane Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi298 – 2981S → A: Abolishes phosphorylation by CAMK2A. Loss of transcriptional activity. 1 Publication

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 672672Forkhead box protein O3PRO_0000415334Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei32 – 321PhosphothreonineBy similarity
Modified residuei46 – 461N6-methyllysineBy similarity
Modified residuei148 – 1481N6-methyllysineBy similarity
Modified residuei178 – 1781PhosphothreonineBy similarity
Modified residuei208 – 2081PhosphoserineBy similarity
Modified residuei214 – 2141PhosphoserineBy similarity
Modified residuei229 – 2291N6-methyllysineBy similarity
Modified residuei241 – 2411N6-acetyllysineCombined sources
Modified residuei252 – 2521PhosphoserineBy similarity
Modified residuei261 – 2611N6-methyllysineBy similarity
Modified residuei270 – 2701N6-methyllysineBy similarity
Modified residuei279 – 2791PhosphoserineBy similarity
Modified residuei283 – 2831PhosphoserineBy similarity
Modified residuei289 – 2891N6-methyllysineBy similarity
Modified residuei293 – 2931PhosphoserineCombined sources
Modified residuei298 – 2981Phosphoserine; by CaMK2A1 Publication
Modified residuei314 – 3141Phosphoserine; by SGK1By similarity
Modified residuei398 – 3981Phosphoserine; by AMPKBy similarity
Modified residuei412 – 4121Phosphoserine; by AMPKBy similarity
Modified residuei418 – 4181N6-methyllysineBy similarity
Modified residuei420 – 4201PhosphoserineBy similarity
Modified residuei550 – 5501Phosphoserine; by MAPKAPK5By similarity
Modified residuei554 – 5541Phosphoserine; by AMPK and MAPKAPK5By similarity
Modified residuei587 – 5871Phosphoserine; by AMPKBy similarity
Modified residuei625 – 6251Phosphoserine; by AMPKBy similarity
Modified residuei643 – 6431Phosphoserine; by IKKBBy similarity

Post-translational modificationi

Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (By similarity). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress (PubMed:17521387).By similarity1 Publication
In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-252 by AKT1/PKB. This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm. Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis. Although AKT1/PKB doesn't appear to phosphorylate Ser-314 directly, it may activate other kinases that trigger phosphorylation at this residue. Phosphorylated by STK4/MST1 on Ser-208 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation. Phosphorylated by PIM1. Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization. Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation. Phosphorylated by CHUK/IKKA and IKBKB/IKKB. TNF-induced inactivation of FOXO3 requires its phosphorylation at Ser-643 by IKBKB/IKKB which promotes FOXO3 retention in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal degradation (By similarity). May be dephosphorylated by calcineurin A on Ser-298 which abolishes FOXO3 transcriptional activity (PubMed:23805378).By similarity1 Publication
Heavily methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-270. Methylation doesn't affect subcellular location.By similarity
Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation.By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9WVH4.
MaxQBiQ9WVH4.
PaxDbiQ9WVH4.
PeptideAtlasiQ9WVH4.
PRIDEiQ9WVH4.

PTM databases

iPTMnetiQ9WVH4.
PhosphoSiteiQ9WVH4.

Expressioni

Tissue specificityi

Expressed in white and brown adipose tissues (at protein level).1 Publication

Gene expression databases

BgeeiENSMUSG00000048756.
ExpressionAtlasiQ9WVH4. baseline and differential.
GenevisibleiQ9WVH4. MM.

Interactioni

Subunit structurei

Interacts with SIRT2; the interaction occurs independently of SIRT2 deacetylase activity (PubMed:17521387). Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration. Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation. Interacts with PIM1. Interacts with DDIT3/CHOP. Interacts (deacetylated form) with SKP2. Interacts with CHUK and IKBKB (By similarity). Interacts with CAMK2A, CAMK2B and calcineurin A (PubMed:23805378).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
FcorP0DJI62EBI-6127038,EBI-6126630
SETD7Q8WTS65EBI-6127038,EBI-1268586From a different organism.

GO - Molecular functioni

Protein-protein interaction databases

BioGridi208010. 5 interactions.
IntActiQ9WVH4. 2 interactions.
STRINGi10090.ENSMUSP00000050683.

Structurei

3D structure databases

ProteinModelPortaliQ9WVH4.
SMRiQ9WVH4. Positions 157-252.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni299 – 672374Mediates interaction with CHUK/IKKA and IKBKB/IKKBBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi241 – 25818Nuclear localization signalBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi546 – 59550Ser-richAdd
BLAST

Sequence similaritiesi

Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG2294. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00790000123003.
HOGENOMiHOG000169927.
HOVERGENiHBG078744.
InParanoidiQ9WVH4.
KOiK09408.
OMAiWMINPDG.
OrthoDBiEOG091G06K3.
PhylomeDBiQ9WVH4.
TreeFamiTF315583.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR032067. FOXO-TAD.
IPR032068. FOXO_KIX-bd.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF16676. FOXO-TAD. 1 hit.
PF16675. FOXO_KIX_bdg. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9WVH4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAEAPASPVP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE
60 70 80 90 100
TAADSMIPEE DDDEDDEDGG GRASSAMVIG GGVSSTLGSG LLLEDSAMLL
110 120 130 140 150
APGGQDLGSG PASAAGALSG GTPTQLQPQQ PLPQPQPGAA GGSGQPRKCS
160 170 180 190 200
SRRNAWGNLS YADLITRAIE SSPDKRLTLS QIYEWMVRCV PYFKDKGDSN
210 220 230 240 250
SSAGWKNSIR HNLSLHSRFM RVQNEGTGKS SWWIINPDGG KSGKAPRRRA
260 270 280 290 300
VSMDNSNKYT KSRGRAAKKK AALQAAPESA DDSPSQLSKW PGSPTSRSSD
310 320 330 340 350
ELDAWTDFRS RTNSNASTVS GRLSPILAST ELDDVQDDDG PLSPMLYSSS
360 370 380 390 400
ASLSPSVSKP CTVELPRLTD MAGTMNLNDG LAENLMDDLL DNIALPPSQP
410 420 430 440 450
SPPGGLMQRG SSFPYTAKSS GLGSPTGSFN STVFGPSSLN SLRQSPMQTI
460 470 480 490 500
QENRPATFSS VSHYGNQTLQ DLLASDSLSH SDVMMTQSDP LMSQASTAVS
510 520 530 540 550
AQNARRNVML RNDPMMSFAA QPTQGSLVNQ NLLHHQHQTQ GALGGSRALS
560 570 580 590 600
NSVSNMGLSD SSSLGSAKHQ QQSPASQSMQ TLSDSLSGSS LYSASANLPV
610 620 630 640 650
MGHDKFPSDL DLDMFNGSLE CDMESIIRSE LMDADGLDFN FDSLISTQNV
660 670
VGLNVGNFTG AKQASSQSWV PG
Length:672
Mass (Da):71,064
Last modified:November 1, 1999 - v1
Checksum:iEC218D9BA0C1DAC5
GO

Sequence cautioni

The sequence AAH19532 differs from that shown.Contaminating sequence. Potential poly-A sequence.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF114259 mRNA. Translation: AAD42107.1.
AK047413 mRNA. Translation: BAC33049.1.
AC116179 Genomic DNA. No translation available.
AC140402 Genomic DNA. No translation available.
CH466540 Genomic DNA. Translation: EDL04998.1.
BC019532 mRNA. Translation: AAH19532.1. Sequence problems.
CCDSiCCDS23810.1.
RefSeqiNP_062714.1. NM_019740.2.
XP_006512869.1. XM_006512806.1.
UniGeneiMm.338613.
Mm.391700.
Mm.417859.
Mm.466459.

Genome annotation databases

EnsembliENSMUST00000056974; ENSMUSP00000050683; ENSMUSG00000048756.
ENSMUST00000105502; ENSMUSP00000101141; ENSMUSG00000048756.
ENSMUST00000175881; ENSMUSP00000135380; ENSMUSG00000048756.
GeneIDi56484.
KEGGimmu:56484.
UCSCiuc007eyl.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF114259 mRNA. Translation: AAD42107.1.
AK047413 mRNA. Translation: BAC33049.1.
AC116179 Genomic DNA. No translation available.
AC140402 Genomic DNA. No translation available.
CH466540 Genomic DNA. Translation: EDL04998.1.
BC019532 mRNA. Translation: AAH19532.1. Sequence problems.
CCDSiCCDS23810.1.
RefSeqiNP_062714.1. NM_019740.2.
XP_006512869.1. XM_006512806.1.
UniGeneiMm.338613.
Mm.391700.
Mm.417859.
Mm.466459.

3D structure databases

ProteinModelPortaliQ9WVH4.
SMRiQ9WVH4. Positions 157-252.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi208010. 5 interactions.
IntActiQ9WVH4. 2 interactions.
STRINGi10090.ENSMUSP00000050683.

PTM databases

iPTMnetiQ9WVH4.
PhosphoSiteiQ9WVH4.

Proteomic databases

EPDiQ9WVH4.
MaxQBiQ9WVH4.
PaxDbiQ9WVH4.
PeptideAtlasiQ9WVH4.
PRIDEiQ9WVH4.

Protocols and materials databases

DNASUi56484.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000056974; ENSMUSP00000050683; ENSMUSG00000048756.
ENSMUST00000105502; ENSMUSP00000101141; ENSMUSG00000048756.
ENSMUST00000175881; ENSMUSP00000135380; ENSMUSG00000048756.
GeneIDi56484.
KEGGimmu:56484.
UCSCiuc007eyl.1. mouse.

Organism-specific databases

CTDi2309.
MGIiMGI:1890081. Foxo3.

Phylogenomic databases

eggNOGiKOG2294. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00790000123003.
HOGENOMiHOG000169927.
HOVERGENiHBG078744.
InParanoidiQ9WVH4.
KOiK09408.
OMAiWMINPDG.
OrthoDBiEOG091G06K3.
PhylomeDBiQ9WVH4.
TreeFamiTF315583.

Enzyme and pathway databases

ReactomeiR-MMU-1181150. Signaling by NODAL.
R-MMU-198693. AKT phosphorylates targets in the nucleus.
R-MMU-5687128. MAPK6/MAPK4 signaling.

Miscellaneous databases

ChiTaRSiFoxo3. mouse.
PROiQ9WVH4.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000048756.
ExpressionAtlasiQ9WVH4. baseline and differential.
GenevisibleiQ9WVH4. MM.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR032067. FOXO-TAD.
IPR032068. FOXO_KIX-bd.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF16676. FOXO-TAD. 1 hit.
PF16675. FOXO_KIX_bdg. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFOXO3_MOUSE
AccessioniPrimary (citable) accession number: Q9WVH4
Secondary accession number(s): D3Z6Y6, Q05CZ4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 25, 2012
Last sequence update: November 1, 1999
Last modified: September 7, 2016
This is version 147 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.