Q9WVH4 (FOXO3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Forkhead box protein O3

Gene names

Name:	Foxo3
Synonyms:	Fkhr2, Foxo3a

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	672 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transcriptional activator which 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 similarity.
Subunit structure	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 By similarity. Interacts with DDIT3/CHOP By similarity.
Subcellular location	Cytoplasm › cytosol By similarity. Nucleus By similarity. Note: Translocates to the nucleus upon oxidative stress and in the absence of survival factors By similarity.
Tissue specificity	Expressed in white and brown adipose tissues (at protein level). Ref.6
Post-translational modification	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 By similarity. Heavyly 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.
Sequence similarities	Contains 1 fork-head DNA-binding domain.
Sequence caution	The sequence AAH19532.1 differs from that shown. Reason: Contaminating sequence. Potential poly-A sequence.

Ontologies

Keywords
Biological process	Apoptosis Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Disease	Proto-oncogene
Ligand	DNA-binding
Molecular function	Activator
PTM	Acetylation Methylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA damage response, signal transduction by p53 class mediator Inferred from direct assay PubMed 15383658. Source: MGI antral ovarian follicle growth Inferred from mutant phenotype PubMed 14978268. Source: MGI apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW embryo development Inferred from Biological aspect of Ancestor. Source: RefGenome glucose homeostasis Inferred from mutant phenotype PubMed 12855809. Source: MGI induction of apoptosis Inferred from mutant phenotype PubMed 12431371. Source: MGI initiation of primordial ovarian follicle growth Inferred from mutant phenotype PubMed 12855809. Source: MGI insulin receptor signaling pathway Inferred from Biological aspect of Ancestor. Source: RefGenome negative regulation of transcription from RNA polymerase II promoter Inferred from Biological aspect of Ancestor. Source: RefGenome oocyte maturation Inferred from mutant phenotype PubMed 12855809. Source: MGI ovulation from ovarian follicle Inferred from mutant phenotype PubMed 12855809. Source: MGI pattern specification process Inferred from Biological aspect of Ancestor. Source: RefGenome positive regulation of erythrocyte differentiation 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 cell proliferation 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 regulation of translation Inferred from sequence or structural similarity. Source: UniProtKB tissue development Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular_component	cytosol Inferred from Biological aspect of Ancestor. Source: RefGenome membrane Inferred from direct assay PubMed 15383658. Source: MGI 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 Biological aspect of Ancestor. Source: RefGenome
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Fcor	P0DJI6	2	EBI-6127038,EBI-6126630

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 672	671	Forkhead box protein O3		PRO_0000415334
Regions
	DNA binding	156 – 250	95	Fork-head
	Motif	241 – 258	18	Nuclear localization signal By similarity
	Compositional bias	546 – 595	50	Ser-rich
Amino acid modifications
	Modified residue	2	1	N-acetylalanine By similarity
	Modified residue	7	1	Phosphoserine By similarity
	Modified residue	12	1	Phosphoserine By similarity
	Modified residue	32	1	Phosphothreonine; by PKB/AKT1 By similarity
	Modified residue	46	1	N6-methyllysine By similarity
	Modified residue	148	1	N6-methyllysine By similarity
	Modified residue	178	1	Phosphothreonine; by AMPK By similarity
	Modified residue	208	1	Phosphoserine; by STK4/MST1 By similarity
	Modified residue	214	1	Phosphoserine; by MAPKAPK5 By similarity
	Modified residue	229	1	N6-methyllysine By similarity
	Modified residue	252	1	Phosphoserine; by PKB/AKT1 and MAPKAPK5 By similarity
	Modified residue	261	1	N6-methyllysine By similarity
	Modified residue	270	1	N6-methyllysine By similarity
	Modified residue	279	1	Phosphoserine By similarity
	Modified residue	283	1	Phosphoserine By similarity
	Modified residue	289	1	N6-methyllysine By similarity
	Modified residue	314	1	Phosphoserine; by SGK1 By similarity
	Modified residue	398	1	Phosphoserine; by AMPK By similarity
	Modified residue	412	1	Phosphoserine; by AMPK By similarity
	Modified residue	418	1	N6-methyllysine By similarity
	Modified residue	420	1	Phosphoserine By similarity
	Modified residue	550	1	Phosphoserine; by MAPKAPK5 By similarity
	Modified residue	554	1	Phosphoserine; by AMPK and MAPKAPK5 By similarity
	Modified residue	587	1	Phosphoserine; by AMPK By similarity
	Modified residue	625	1	Phosphoserine; by AMPK By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q9WVH4 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: EC218D9BA0C1DAC5	FASTA	672	71,064
	10 20 30 40 50 60 MAEAPASPVP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE TAADSMIPEE 70 80 90 100 110 120 DDDEDDEDGG GRASSAMVIG GGVSSTLGSG LLLEDSAMLL APGGQDLGSG PASAAGALSG 130 140 150 160 170 180 GTPTQLQPQQ PLPQPQPGAA GGSGQPRKCS SRRNAWGNLS YADLITRAIE SSPDKRLTLS 190 200 210 220 230 240 QIYEWMVRCV PYFKDKGDSN SSAGWKNSIR HNLSLHSRFM RVQNEGTGKS SWWIINPDGG 250 260 270 280 290 300 KSGKAPRRRA VSMDNSNKYT KSRGRAAKKK AALQAAPESA DDSPSQLSKW PGSPTSRSSD 310 320 330 340 350 360 ELDAWTDFRS RTNSNASTVS GRLSPILAST ELDDVQDDDG PLSPMLYSSS ASLSPSVSKP 370 380 390 400 410 420 CTVELPRLTD MAGTMNLNDG LAENLMDDLL DNIALPPSQP SPPGGLMQRG SSFPYTAKSS 430 440 450 460 470 480 GLGSPTGSFN STVFGPSSLN SLRQSPMQTI QENRPATFSS VSHYGNQTLQ DLLASDSLSH 490 500 510 520 530 540 SDVMMTQSDP LMSQASTAVS AQNARRNVML RNDPMMSFAA QPTQGSLVNQ NLLHHQHQTQ 550 560 570 580 590 600 GALGGSRALS NSVSNMGLSD SSSLGSAKHQ QQSPASQSMQ TLSDSLSGSS LYSASANLPV 610 620 630 640 650 660 MGHDKFPSDL DLDMFNGSLE CDMESIIRSE LMDADGLDFN FDSLISTQNV VGLNVGNFTG 670 AKQASSQSWV PG

References

	« Hide 'large scale' referencesShow 'large scale' 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].
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Cerebellum.
[3]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[4]	Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-255.
[6]	"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	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.
IPI	IPI00125980.
RefSeq	NP_062714.1. NM_019740.2.
UniGene	Mm.338613. Mm.391700. Mm.417859. Mm.466459.
3D structure databases
HSSP	HSSP built from PDB template 1E17 based on UniProtKB P98177.
ProteinModelPortal	Q9WVH4.
SMR	Q9WVH4. Positions 157-252.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9WVH4. 1 interaction.
STRING	10090.ENSMUSP00000101141.
PTM databases
PhosphoSite	Q9WVH4.
Proteomic databases
PRIDE	Q9WVH4.
Protocols and materials databases
DNASU	56484.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000056974; ENSMUSP00000050683; ENSMUSG00000048756. ENSMUST00000105502; ENSMUSP00000101141; ENSMUSG00000048756. ENSMUST00000175881; ENSMUSP00000135380; ENSMUSG00000048756.
GeneID	56484.
KEGG	mmu:56484.
UCSC	uc007eyl.1. mouse.
Organism-specific databases
CTD	2309.
MGI	MGI:1890081. Foxo3.
Phylogenomic databases
eggNOG	COG5025.
GeneTree	ENSGT00390000000589.
HOGENOM	HOG000251635.
HOVERGEN	HBG078744.
InParanoid	Q9WVH4.
KO	K09408.
OMA	NLPVMGH.
OrthoDB	EOG4N8R4G.
Gene expression databases
ArrayExpress	Q9WVH4.
Bgee	Q9WVH4.
Genevestigator	Q9WVH4.
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	FOXO3. mouse.
NextBio	312750.
SOURCE	Search...

Entry information

Entry name

FOXO3_MOUSE

Accession

Primary (citable) accession number: Q9WVH4
Secondary accession number(s): D3Z6Y6, Q05CZ4

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 25, 2012
Last sequence update:	November 1, 1999
Last modified:	May 1, 2013
This is version 112 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program