Q9WVH3 (FOXO4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Forkhead box protein O4

Alternative name(s):
Afxh
Fork head domain transcription factor AFX1

Gene names

Name:	Foxo4
Synonyms:	Afx, Afx1, Fkhr3, Mllt7

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	505 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.3
Subunit structure	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.
Subcellular location	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.
Tissue specificity	Strongly expressed in brown adipose tissue and weakly in white adipose tissue (at protein level). Expressed in skeletal muscle. Ref.1 Ref.4
Induction	By artery ligation in proliferating neointimal smooth muscle cells. Ref.3
Post-translational modification	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. Phosphorylation by PKB/AKT1 inhibits transcriptional activity and is responsible for cytoplasmic localization. May be phosphorylated at multiple sites by NLK 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.
Sequence similarities	Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
Biological process	Cell cycle Differentiation Myogenesis Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Acetylation Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB cell cycle arrest Inferred from sequence or structural similarity. Source: UniProtKB embryo development Inferred from Biological aspect of Ancestor. Source: RefGenome insulin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB mitotic G2 DNA damage checkpoint Inferred from direct assay PubMed 12048180. Source: MGI muscle organ development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of angiogenesis Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of smooth muscle cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from Biological aspect of Ancestor. Source: RefGenome organ development Inferred from Biological aspect of Ancestor. Source: RefGenome pattern specification process Inferred from Biological aspect of Ancestor. Source: RefGenome positive regulation of transcription from RNA polymerase II promoter Inferred from Biological aspect of Ancestor. Source: RefGenome regulation of sequence-specific DNA binding transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome stem cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB tissue development Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular_component	cytosol Inferred from sequence or structural similarity. Source: UniProtKB transcription factor complex Inferred from Biological aspect of Ancestor. Source: RefGenome
Molecular_function	DNA binding, bending Inferred from Biological aspect of Ancestor. Source: RefGenome RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome double-stranded DNA binding Inferred from Biological aspect of Ancestor. Source: RefGenome protein kinase binding Inferred from Biological aspect of Ancestor. Source: RefGenome sequence-specific DNA binding Inferred from direct assay Ref.1. Source: MGI transcription factor binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 505	505	Forkhead box protein O4		PRO_0000091876
Regions
	DNA binding	100 – 188	89	Fork-head
Amino acid modifications
	Modified residue	32	1	Phosphothreonine; by PKB/AKT1 By similarity
	Modified residue	197	1	Phosphoserine; by PKB/AKT1 By similarity
	Modified residue	200	1	Phosphoserine By similarity
	Modified residue	262	1	Phosphoserine; by PKB/AKT1 By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q9WVH3 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: ABB99B54807C7CE5	FASTA	505	53,649
	10 20 30 40 50 60 MDPENKKSAT GAAAILDLDP DFEPQSRPRS CTWPLPRPDL ATEPHEPSEV EPSLGQKVPT 70 80 90 100 110 120 EGHSEPILLP SRLPEPAGGP QPGILGAVTG PRKGGSRRNA WGNQSYAELI SQAIESAPEK 130 140 150 160 170 180 RLTLAQIYEW MVRTVPYFKD KGDSNSSAGW KNSIRHNLSL HSKFIKVHNE ATGKSSWWML 190 200 210 220 230 240 NPDGGKGGKA PRRRAASMDS SSKLLRGRSK GPKKKPSVLP APPEGATPRS PLGHFAKWSS 250 260 270 280 290 300 SPCPRNREEA DVWTTFRPRS SSNASTVSTR LSPMRPESEV LAEEEMPASA SSYAGGVPPT 310 320 330 340 350 360 LSEDLELLDG LNLASPHSLL SRSGLSGFSL QHPGLAGPLH SYGASLFGPI DGSLSAGEGC 370 380 390 400 410 420 FSSSQSLEAL LTSDTPPPPA DVLMTQVDPI LSQAPTLLLL GGMPSSSKLG TGVSLCPTPL 430 440 450 460 470 480 EGPGPSNLVP NLSVMAPPPV MAGAPIPKVL GTPVLASPTE DSSHDRMPQD LDLDMYMENL 490 500 ECDMDNIISD LMDGEGLDFN FEPDP

References

[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF114260 mRNA. Translation: AAD42108.1. AB032770 mRNA. Translation: BAA86199.1.
IPI	IPI00125978.
RefSeq	NP_061259.1. NM_018789.2.
UniGene	Mm.240299.
3D structure databases
ProteinModelPortal	Q9WVH3.
SMR	Q9WVH3. Positions 97-181.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9WVH3. 1 interaction.
MINT	MINT-4095287.
STRING	10090.ENSMUSP00000059420.
PTM databases
PhosphoSite	Q9WVH3.
Proteomic databases
PaxDb	Q9WVH3.
PRIDE	Q9WVH3.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000062000; ENSMUSP00000059420; ENSMUSG00000042903.
GeneID	54601.
KEGG	mmu:54601.
UCSC	uc009twz.2. mouse.
Organism-specific databases
CTD	4303.
MGI	MGI:1891915. Foxo4.
Phylogenomic databases
eggNOG	COG5025.
GeneTree	ENSGT00390000000589.
HOGENOM	HOG000251635.
HOVERGEN	HBG057789.
InParanoid	Q9WVH3.
KO	K12358.
OrthoDB	EOG441QBC.
Gene expression databases
ArrayExpress	Q9WVH3.
Bgee	Q9WVH3.
CleanEx	MM_FOXO4.
Genevestigator	Q9WVH3.
GermOnline	ENSMUSG00000042903. Mus musculus.
Family and domain databases
Gene3D	1.10.10.10. 1 hit.
InterPro	IPR001766. TF_fork_head. IPR018122. TF_fork_head_CS. IPR011991. WHTH_DNA-bd_dom. [Graphical view]
Pfam	PF00250. Fork_head. 1 hit. [Graphical view]
PRINTS	PR00053. FORKHEAD.
SMART	SM00339. FH. 1 hit. [Graphical view]
PROSITE	PS00657. FORK_HEAD_1. False negative. PS00658. FORK_HEAD_2. 1 hit. PS50039. FORK_HEAD_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	FOXO4. mouse.
NextBio	311392.
SOURCE	Search...

Entry information

Entry name

FOXO4_MOUSE

Accession

Primary (citable) accession number: Q9WVH3

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 11, 2001
Last sequence update:	November 1, 1999
Last modified:	May 29, 2013
This is version 105 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program