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Q9WVH3

- FOXO4_MOUSE

UniProt

Q9WVH3 - FOXO4_MOUSE

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Protein

Forkhead box protein O4

Gene

Foxo4

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

Functioni

Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity (By similarity). Represses smooth muscle cell differentiation by inhibiting the transcriptional coactivator activity of myocardin.By similarity1 Publication

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi100 – 18889Fork-headPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  1. DNA binding Source: UniProtKB
  2. enzyme binding Source: UniProtKB
  3. sequence-specific DNA binding Source: MGI
  4. sequence-specific DNA binding transcription factor activity Source: UniProtKB
  5. transcription factor binding Source: UniProtKB

GO - Biological processi

  1. cell cycle arrest Source: UniProtKB
  2. insulin receptor signaling pathway Source: UniProtKB
  3. mitotic G2 DNA damage checkpoint Source: MGI
  4. muscle organ development Source: UniProtKB-KW
  5. negative regulation of angiogenesis Source: UniProtKB
  6. negative regulation of cell proliferation Source: UniProtKB
  7. negative regulation of G0 to G1 transition Source: UniProtKB
  8. negative regulation of smooth muscle cell differentiation Source: UniProtKB
  9. positive regulation of transcription, DNA-templated Source: MGI
  10. regulation of transcription, DNA-templated Source: UniProtKB
  11. stem cell differentiation Source: UniProtKB
  12. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator, Developmental protein

Keywords - Biological processi

Cell cycle, Differentiation, Myogenesis, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiREACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
REACT_218211. AKT phosphorylates targets in the nucleus.

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein O4
Alternative name(s):
Afxh
Fork head domain transcription factor AFX1
Gene namesi
Name:Foxo4
Synonyms:Afx, Afx1, Fkhr3, Mllt7
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome X

Organism-specific databases

MGIiMGI:1891915. Foxo4.

Subcellular locationi

Cytoplasm. Nucleus
Note: When phosphorylated, translocated from nucleus to cytoplasm. Dephosphorylation triggers nuclear translocation. Monoubiquitination increases nuclear localization. When deubiquitinated, translocated from nucleus to cytoplasm (By similarity).By similarity

GO - Cellular componenti

  1. cytosol Source: UniProtKB
  2. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 505505Forkhead box protein O4PRO_0000091876Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei32 – 321Phosphothreonine; by PKB/AKT1By similarity
Modified residuei197 – 1971Phosphoserine; by PKB/AKT1By similarity
Modified residuei200 – 2001PhosphoserineBy similarity
Modified residuei262 – 2621Phosphoserine; by PKB/AKT1By similarity

Post-translational modificationi

Acetylation by CREBBP/CBP is induced by oxidative stress and inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-dependent and stimulates transcriptional activity (By similarity).By similarity
Phosphorylation by PKB/AKT1 inhibits transcriptional activity and is responsible for cytoplasmic localization. May be phosphorylated at multiple sites by NLK (By similarity).By similarity
Monoubiquitinated; monoubiquitination is induced by oxidative stress and reduced by deacetylase inhibitors; results in its relocalization to the nucleus and its increased transcriptional activity. Deubiquitinated by USP7; deubiquitination is induced by oxidative stress; enhances its interaction with USP7 and consequently, deubiquitination; increases its translocation to the cytoplasm and inhibits its transcriptional activity. Hydrogene-peroxide-induced ubiquitination and USP7-mediated deubiquitination have no major effect on its protein stability (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ9WVH3.
PRIDEiQ9WVH3.

PTM databases

PhosphoSiteiQ9WVH3.

Expressioni

Tissue specificityi

Strongly expressed in brown adipose tissue and weakly in white adipose tissue (at protein level). Expressed in skeletal muscle.2 Publications

Inductioni

By artery ligation in proliferating neointimal smooth muscle cells.1 Publication

Gene expression databases

BgeeiQ9WVH3.
CleanExiMM_FOXO4.
ExpressionAtlasiQ9WVH3. baseline and differential.
GenevestigatoriQ9WVH3.

Interactioni

Subunit structurei

Interacts with CREBBP/CBP, MYOCD, SIRT1, SRF and YWHAZ. Acetylated by CREBBP/CBP and deacetylated by SIRT1. Binding of YWHAZ inhibits DNA-binding. Interacts with USP7; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of TP53. Interacts with NLK, and this inhibits monoubiquitination and transcriptional activity (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
OgtP565582EBI-4567305,EBI-7614183From a different organism.

Protein-protein interaction databases

IntActiQ9WVH3. 3 interactions.
MINTiMINT-4095287.
STRINGi10090.ENSMUSP00000059420.

Structurei

3D structure databases

ProteinModelPortaliQ9WVH3.
SMRiQ9WVH3. Positions 97-181.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00390000000589.
HOGENOMiHOG000251635.
HOVERGENiHBG057789.
InParanoidiQ9WVH3.
KOiK12358.
OMAiFSLQHPG.
OrthoDBiEOG7SFHZ8.
PhylomeDBiQ9WVH3.
TreeFamiTF315583.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Fork_head. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9WVH3-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MDPENKKSAT GAAAILDLDP DFEPQSRPRS CTWPLPRPDL ATEPHEPSEV
60 70 80 90 100
EPSLGQKVPT EGHSEPILLP SRLPEPAGGP QPGILGAVTG PRKGGSRRNA
110 120 130 140 150
WGNQSYAELI SQAIESAPEK RLTLAQIYEW MVRTVPYFKD KGDSNSSAGW
160 170 180 190 200
KNSIRHNLSL HSKFIKVHNE ATGKSSWWML NPDGGKGGKA PRRRAASMDS
210 220 230 240 250
SSKLLRGRSK GPKKKPSVLP APPEGATPRS PLGHFAKWSS SPCPRNREEA
260 270 280 290 300
DVWTTFRPRS SSNASTVSTR LSPMRPESEV LAEEEMPASA SSYAGGVPPT
310 320 330 340 350
LSEDLELLDG LNLASPHSLL SRSGLSGFSL QHPGLAGPLH SYGASLFGPI
360 370 380 390 400
DGSLSAGEGC FSSSQSLEAL LTSDTPPPPA DVLMTQVDPI LSQAPTLLLL
410 420 430 440 450
GGMPSSSKLG TGVSLCPTPL EGPGPSNLVP NLSVMAPPPV MAGAPIPKVL
460 470 480 490 500
GTPVLASPTE DSSHDRMPQD LDLDMYMENL ECDMDNIISD LMDGEGLDFN

FEPDP
Length:505
Mass (Da):53,649
Last modified:November 1, 1999 - v1
Checksum:iABB99B54807C7CE5
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF114260 mRNA. Translation: AAD42108.1.
AB032770 mRNA. Translation: BAA86199.1.
CCDSiCCDS41077.1.
RefSeqiNP_061259.1. NM_018789.2.
UniGeneiMm.240299.

Genome annotation databases

EnsembliENSMUST00000062000; ENSMUSP00000059420; ENSMUSG00000042903.
GeneIDi54601.
KEGGimmu:54601.
UCSCiuc009twz.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF114260 mRNA. Translation: AAD42108.1 .
AB032770 mRNA. Translation: BAA86199.1 .
CCDSi CCDS41077.1.
RefSeqi NP_061259.1. NM_018789.2.
UniGenei Mm.240299.

3D structure databases

ProteinModelPortali Q9WVH3.
SMRi Q9WVH3. Positions 97-181.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

IntActi Q9WVH3. 3 interactions.
MINTi MINT-4095287.
STRINGi 10090.ENSMUSP00000059420.

PTM databases

PhosphoSitei Q9WVH3.

Proteomic databases

PaxDbi Q9WVH3.
PRIDEi Q9WVH3.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000062000 ; ENSMUSP00000059420 ; ENSMUSG00000042903 .
GeneIDi 54601.
KEGGi mmu:54601.
UCSCi uc009twz.2. mouse.

Organism-specific databases

CTDi 4303.
MGIi MGI:1891915. Foxo4.

Phylogenomic databases

eggNOGi COG5025.
GeneTreei ENSGT00390000000589.
HOGENOMi HOG000251635.
HOVERGENi HBG057789.
InParanoidi Q9WVH3.
KOi K12358.
OMAi FSLQHPG.
OrthoDBi EOG7SFHZ8.
PhylomeDBi Q9WVH3.
TreeFami TF315583.

Enzyme and pathway databases

Reactomei REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
REACT_218211. AKT phosphorylates targets in the nucleus.

Miscellaneous databases

ChiTaRSi Foxo4. mouse.
NextBioi 311392.
PROi Q9WVH3.
SOURCEi Search...

Gene expression databases

Bgeei Q9WVH3.
CleanExi MM_FOXO4.
ExpressionAtlasi Q9WVH3. baseline and differential.
Genevestigatori Q9WVH3.

Family and domain databases

Gene3Di 1.10.10.10. 1 hit.
InterProi IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view ]
Pfami PF00250. Fork_head. 1 hit.
[Graphical view ]
PRINTSi PR00053. FORKHEAD.
SMARTi SM00339. FH. 1 hit.
[Graphical view ]
PROSITEi PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse."
    Biggs W.H. III, Cavenee W.K., Arden K.C.
    Mamm. Genome 12:416-425(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
    Tissue: Embryo.
  2. "Mouse AFX, a forkhead type transcription factor."
    Furuyama T., Nakazawa T., Mori N.
    Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. "Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin."
    Liu Z.-P., Wang Z., Yanagisawa H., Olson E.N.
    Dev. Cell 9:261-270(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  4. "Novel repressor regulates insulin sensitivity through interaction with Foxo1."
    Nakae J., Cao Y., Hakuno F., Takemori H., Kawano Y., Sekioka R., Abe T., Kiyonari H., Tanaka T., Sakai J., Takahashi S., Itoh H.
    EMBO J. 31:2275-2295(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.

Entry informationi

Entry nameiFOXO4_MOUSE
AccessioniPrimary (citable) accession number: Q9WVH3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: November 1, 1999
Last modified: November 26, 2014
This is version 117 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

External Data

Dasty 3