FOXO3

Functionⁱ

Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). 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 (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity).By similarity4 Publications

Regions

Feature key	Position(s)	DescriptionActions	Graphical view	Length
DNA bindingⁱ	157 – 251	Fork-headPROSITE-ProRule annotationAdd BLAST		95

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

GO - Biological processⁱ

Complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	Activator, DNA-binding
Biological process	Apoptosis, Transcription, Transcription regulation

Enzyme and pathway databases

Reactomeⁱ	R-HSA-1181150 Signaling by NODAL R-HSA-198693 AKT phosphorylates targets in the nucleus R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer R-HSA-5687128 MAPK6/MAPK4 signaling R-HSA-6785807 Interleukin-4 and Interleukin-13 signaling R-HSA-8862803 Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models R-HSA-8952158 RUNX3 regulates BCL2L11 (BIM) transcription R-HSA-9614399 Regulation of localization of FOXO transcription factors R-HSA-9614657 FOXO-mediated transcription of cell death genes R-HSA-9615017 FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes R-HSA-9617629 Regulation of FOXO transcriptional activity by acetylation R-HSA-9617828 FOXO-mediated transcription of cell cycle genes R-HSA-9634638 Estrogen-dependent nuclear events downstream of ESR-membrane signaling
SignaLinkⁱ	O43524
SIGNORⁱ	O43524

Names & Taxonomyⁱ

Protein namesⁱ	Recommended name: Forkhead box protein O3Curated Alternative name(s): AF6q21 protein1 Publication Forkhead in rhabdomyosarcoma-like 11 Publication
Gene namesⁱ	Name:FOXO3Imported Synonyms:FKHRL11 Publication, FOXO3A1 Publication
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome 6

Organism-specific databases

EuPathDBⁱ	HostDB:ENSG00000118689.14
Human Gene Nomenclature Database More...HGNCⁱ	HGNC:3821 FOXO3
MIMⁱ	602681 gene
neXtProtⁱ	NX_O43524

Keywords - Cellular componentⁱ

Cytoplasm, Membrane, Mitochondrion, Mitochondrion outer membrane, Nucleus

Pathology & Biotechⁱ

Involvement in diseaseⁱ

A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	2 – 148	Missing : Loss of localization to the mitochondrion outer membrane and loss of translocation into the mitochondrion following metabolic stress. 1 PublicationAdd BLAST	147
Mutagenesisⁱ	2 – 30	Missing : Loss of translocation into the mitochondrion following metabolic stress. 1 PublicationAdd BLAST	29
Mutagenesisⁱ	12	S → A in normal cells, no defect in mitochondrion import following metabolic stress. In cancer cells, defective mitochondrion import following metabolic stress and abolition of ERK-mediated phosphorylation. 1 Publication	1
Mutagenesisⁱ	30	S → A: Abolishes phosphorylation. Loss of localization to the mitochondrion outer membrane and loss of translocation into the mitochondrion following metabolic stress. 1 Publication	1
Mutagenesisⁱ	32	T → A: Abolishes YWHAZ-binding; when associated with A-253. Exclusively nuclear, induces transcription and promotes apoptosis; when associated with A-253 and A-315. 1 Publication	1
Mutagenesisⁱ	80 – 108	Missing : Loss of translocation into the mitochondrion following metabolic stress. 1 PublicationAdd BLAST	29
Mutagenesisⁱ	179	T → A: Decreased phosphorylation by AMPK and impaired ability to transactivate a reporter gene; when associated with A-399; A-413; A-555; A-588 and A-626. 1 Publication	1
Mutagenesisⁱ	209	S → A: Impairs nuclear translocation upon oxidative stress. 1 Publication	1
Mutagenesisⁱ	242 – 271	Missing : Loss of nuclear import. 1 PublicationAdd BLAST	30
Mutagenesisⁱ	242	K → A: Slightly decreases DNA affinity. 2 Publications	1
Mutagenesisⁱ	242	K → R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-259; R-290 and R-569. 2 Publications	1
Mutagenesisⁱ	245	K → A: Decreases DNA affinity. 1 Publication	1
Mutagenesisⁱ	253	S → A: Abolishes YWHAZ-binding; when associated with A-32. Exclusively nuclear, induces transcription and promotes apoptosis; when associated with A-32 and A-315. 1 Publication	1
Mutagenesisⁱ	259	K → R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-242; R-290 and R-569. 1 Publication	1
Mutagenesisⁱ	269	K → R: Methylation levels similar to wild-type; when associated with ARG-270. 1 Publication	1
Mutagenesisⁱ	270	K → R: Methylation levels similar to wild-type; when associated with ARG-269. 1 Publication	1
Mutagenesisⁱ	271	K → R: Methylation levels strongly reduced. 1 Publication	1
Mutagenesisⁱ	290	K → R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-242; R-259 and R-569. 1 Publication	1
Mutagenesisⁱ	315	S → A: No effect on YWHAZ-binding. Promotes nuclear translocation. Exclusively nuclear, induces transcription and promotes apoptosis; when associated with A-32 and A-253. 1 Publication	1
Mutagenesisⁱ	399	S → A: Decreased phosphorylation by AMPK and impaired ability to transactivate a reporter gene; when associated with A-179; A-413; A-555; A-588 and A-626. 1 Publication	1
Mutagenesisⁱ	413	S → A: Decreased phosphorylation by AMPK and impaired ability to transactivate a reporter gene; when associated with A-179; A-399; A-555; A-588 and A-626. 1 Publication	1
Mutagenesisⁱ	555	S → A: Decreased phosphorylation by AMPK and impaired ability to transactivate a reporter gene; when associated with A-179; A-399; A-413; A-588 and A-626. 1 Publication	1
Mutagenesisⁱ	569	K → R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-242; R-259 and R-290. 1 Publication	1
Mutagenesisⁱ	588	S → A: Decreased phosphorylation by AMPK and impaired ability to transactivate a reporter gene; when associated with A-179; A-399; A-413; A-555 and A-626. 1 Publication	1
Mutagenesisⁱ	626	S → A: Decreased phosphorylation by AMPK and impaired ability to transactivate a reporter gene; when associated with A-179; A-399; A-413; A-555 and A-588. 1 Publication	1
Mutagenesisⁱ	644	S → A: Loss of phosphorylation by IKKB. 1 Publication	1

Keywords - Diseaseⁱ

Proto-oncogene

Organism-specific databases

DisGeNET More...DisGeNETⁱ	2309
Open Targets More...OpenTargetsⁱ	ENSG00000118689
PharmGKBⁱ	PA28239

Miscellaneous databases

Pharosⁱ	O43524 Tbio

Pharosⁱ

O43524 Tbio

Chemistry databases

ChEMBLⁱ	CHEMBL5778

ChEMBLⁱ

CHEMBL5778

Polymorphism and mutation databases

BioMutaⁱ	FOXO3

BioMutaⁱ

FOXO3

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Graphical view	Length
ChainⁱPRO_0000091874	1 – 673	Forkhead box protein O3Add BLAST		673

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Modified residueⁱ	30	Phosphoserine; by AMPK1 Publication	1
Modified residueⁱ	32	Phosphothreonine; by PKB/AKT11 Publication	1
Modified residueⁱ	46	N6-methyllysine1 Publication	1
Modified residueⁱ	149	N6-methyllysine1 Publication	1
Modified residueⁱ	179	Phosphothreonine; by AMPK1 Publication	1
Modified residueⁱ	209	Phosphoserine; by STK4/MST11 Publication	1
Modified residueⁱ	215	Phosphoserine; by MAPKAPK51 Publication	1
Modified residueⁱ	230	N6-methyllysine1 Publication	1
Modified residueⁱ	242	N6-acetyllysineBy similarity	1
Modified residueⁱ	253	Phosphoserine; by PKB/AKT1 and MAPKAPK52 Publications	1
Modified residueⁱ	262	N6-methyllysine1 Publication	1
Modified residueⁱ	271	N6-methyllysine1 Publication	1
Modified residueⁱ	280	PhosphoserineCombined sources	1
Modified residueⁱ	284	PhosphoserineCombined sources	1
Modified residueⁱ	290	N6-methyllysine1 Publication	1
Modified residueⁱ	294	PhosphoserineBy similarity	1
Modified residueⁱ	299	Phosphoserine; by CaMK2ACombined sources1 Publication	1
Modified residueⁱ	311	PhosphoserineCombined sources	1
Modified residueⁱ	315	Phosphoserine; by SGK12 Publications	1
Modified residueⁱ	399	Phosphoserine; by AMPK1 Publication	1
Modified residueⁱ	413	Phosphoserine; by AMPKCombined sources1 Publication	1
Modified residueⁱ	419	N6-methyllysine1 Publication	1
Modified residueⁱ	421	PhosphoserineCombined sources	1
Modified residueⁱ	551	Phosphoserine; by MAPKAPK5Combined sources1 Publication	1
Modified residueⁱ	555	Phosphoserine; by AMPK and MAPKAPK52 Publications	1
Modified residueⁱ	588	Phosphoserine; by AMPK1 Publication	1
Modified residueⁱ	626	Phosphoserine; by AMPK1 Publication	1
Modified residueⁱ	644	Phosphoserine; by IKKB1 Publication	1

Post-translational modificationⁱ

In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB (PubMed:10102273). This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm (PubMed:10102273). Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis (PubMed:10102273). Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue (PubMed:10102273, PubMed:11154281). Phosphorylated by STK4/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation (PubMed:16751106). Phosphorylated by PIM1 (PubMed:18593906). Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization (PubMed:17711846). In response to metabolic stress, phosphorylated by AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation (PubMed:29445193). 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 (PubMed:21329882). Phosphorylated by CHUK/IKKA and IKBKB/IKKB (PubMed:15084260). TNF-induced inactivation of FOXO3 requires its phosphorylation at Ser-644 by IKBKB/IKKB which promotes FOXO3 retention in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:15084260). May be dephosphorylated by calcineurin A on Ser-299 which abolishes FOXO3 transcriptional activity (By similarity). In cancer cells, ERK mediated-phosphorylation of Ser-12 is required for mitochondrial translocation of FOXO3 in response to metabolic stress or chemotherapeutic agents (PubMed:29445193).By similarity8 Publications

Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (PubMed:21841822). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress (By similarity). Deacetylated by SIRT3 (PubMed:23283301). Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA transcriptional activity in response to metabolic stress (PubMed:23283301).By similarity2 Publications

Heavily methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location.1 Publication

Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation.1 Publication

Keywords - PTMⁱ

Acetylation, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDⁱ	O43524
jPOSTⁱ	O43524
MassIVEⁱ	O43524
MaxQB - The MaxQuant DataBase More...MaxQBⁱ	O43524
PaxDbⁱ	O43524
PeptideAtlas More...PeptideAtlasⁱ	O43524
PRIDEⁱ	O43524
ProteomicsDBⁱ	49029 [O43524-1] 5304

PTM databases

GlyConnectⁱ	1253
iPTMnetⁱ	O43524
PhosphoSitePlusⁱ	O43524

Expressionⁱ

Tissue specificityⁱ

Ubiquitous.1 Publication

Gene expression databases

Bgeeⁱ	ENSG00000118689 Expressed in trabecular bone tissue and 235 other tissues
Genevisibleⁱ	O43524 HS

Organism-specific databases

Human Protein Atlas More...HPAⁱ	ENSG00000118689 Low tissue specificity

HPAⁱ

ENSG00000118689 Low tissue specificity

Interactionⁱ

Subunit structureⁱ

Upon metabolic stress, forms a complex composed of FOXO3, SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited to mtDNA in a SIRT3-dependent manner (PubMed:23283301). Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT (PubMed:29445193).

Interacts with SIRT2; the interaction occurs independently of SIRT2 deacetylase activity (By similarity).

Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration (PubMed:16751106). Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation (PubMed:16751106).

Interacts with PIM1 (PubMed:18593906).

Interacts with DDIT3/CHOP (PubMed:22761832).

Interacts (deacetylated form) with SKP2 (PubMed:21841822).

Interacts with CHUK and IKBKB (PubMed:15084260, PubMed:22313691).

Interacts with CAMK2A, CAMK2B and calcineurin A (By similarity). Interacts FOXO3; this interaction represses FOXO3 transactivation (PubMed:20181828).

By similarity9 Publications

Binary interactionsⁱ

Hide details

O43524

With	#Exp.	IntAct
AKT1 [P31749]	3	EBI-1644164,EBI-296087
ARHGEF2 [Q92974]	2	EBI-1644164,EBI-302405
CDC27 [P30260]	2	EBI-1644164,EBI-994813
CREBBP [Q92793]	3	EBI-1644164,EBI-81215
ESR1 [P03372]	7	EBI-1644164,EBI-78473
ESR2 [Q92731]	4	EBI-1644164,EBI-78505
FOXK1 [P85037]	2	EBI-1644164,EBI-2509974
FOXM1 [Q08050]	2	EBI-1644164,EBI-866480
HCFC1 [P51610]	2	EBI-1644164,EBI-396176
MYC [P01106]	3	EBI-1644164,EBI-447544
PIM1 - isoform 1 [P11309-1]	2	EBI-1644164,EBI-1018629
PNKP [Q96T60]	2	EBI-1644164,EBI-1045072
RB1 [P06400]	2	EBI-1644164,EBI-491274
RBL1 [P28749]	3	EBI-1644164,EBI-971402
SIRT1 [Q96EB6]	5	EBI-1644164,EBI-1802965
SMAD3 [P84022]	5	EBI-1644164,EBI-347161
SMAD4 [Q13485]	9	EBI-1644164,EBI-347263
TAF5L [O75529]	2	EBI-1644164,EBI-1785876
TP53 [P04637]	2	EBI-1644164,EBI-366083
YWHAZ [P63104]	3	EBI-1644164,EBI-347088
Foxg1 [Q60987] from Mus musculus.	5	EBI-1644164,EBI-11166131
Ywhaz [P63101] from Mus musculus.	2	EBI-1644164,EBI-354751

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGRIDⁱ	108598, 73 interactors
ComplexPortalⁱ	CPX-1123 FOXO3-MYC complex CPX-1147 FOXO3-YWHAZ complex
CORUMⁱ	O43524
Database of interacting proteins More...DIPⁱ	DIP-29723N
IntActⁱ	O43524, 51 interactors
Molecular INTeraction database More...MINTⁱ	O43524
STRINGⁱ	9606.ENSP00000385824

Chemistry databases

BindingDBⁱ

O43524

Miscellaneous databases

RNActⁱ	O43524 protein

RNActⁱ

O43524 protein

Structureⁱ

Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area

Feature key	Position(s)	DescriptionActions	Length
Turnⁱ	156 – 158	Combined sources	3
Helixⁱ	162 – 169	Combined sources	8
Beta strandⁱ	172 – 176	Combined sources	5
Helixⁱ	180 – 189	Combined sources	10
Beta strandⁱ	198 – 200	Combined sources	3
Helixⁱ	206 – 216	Combined sources	11
Beta strandⁱ	217 – 229	Combined sources	13
Beta strandⁱ	233 – 236	Combined sources	4
Beta strandⁱ	238 – 240	Combined sources	3
Beta strandⁱ	463 – 465	Combined sources	3
Helixⁱ	468 – 477	Combined sources	10
Turnⁱ	478 – 480	Combined sources	3

Show more details

3D structure databases

SMRⁱ	O43524
ModBaseⁱ	Search...
PDBe-KBⁱ	Search...

Miscellaneous databases

EvolutionaryTraceⁱ	O43524

EvolutionaryTraceⁱ

O43524

Family & Domainsⁱ

Region

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Regionⁱ	80 – 108	Required for mitochondrial import1 PublicationAdd BLAST		29
Regionⁱ	300 – 673	Mediates interaction with CHUK/IKKA and IKBKB/IKKB1 PublicationAdd BLAST		374

Motif

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Motifⁱ	242 – 259	Nuclear localization signal2 PublicationsAdd BLAST		18

Phylogenomic databases

eggNOGⁱ	KOG2294 Eukaryota COG5025 LUCA
Ensembl GeneTree More...GeneTreeⁱ	ENSGT00940000159826
HOGENOMⁱ	CLU_023456_1_0_1
InParanoidⁱ	O43524
KEGG Orthology (KO) More...KOⁱ	K09408
OMAⁱ	DPVMTFG
Database of Orthologous Groups More...OrthoDBⁱ	1160384at2759
PhylomeDBⁱ	O43524
TreeFamⁱ	TF315583

Family and domain databases

Conserved Domains Database More...CDDⁱ	cd00059 FH, 1 hit
Gene3Dⁱ	1.10.10.10, 1 hit
IDEALⁱ	IID00433
InterProⁱ	View protein in InterPro IPR001766 Fork_head_dom IPR032067 FOXO-TAD IPR032068 FOXO_KIX-bd IPR030456 TF_fork_head_CS_2 IPR036388 WH-like_DNA-bd_sf IPR036390 WH_DNA-bd_sf
Pfam protein domain database More...Pfamⁱ	View protein in Pfam PF00250 Forkhead, 1 hit PF16676 FOXO-TAD, 1 hit PF16675 FOXO_KIX_bdg, 1 hit
PRINTSⁱ	PR00053 FORKHEAD
SMARTⁱ	View protein in SMART SM00339 FH, 1 hit
SUPFAMⁱ	SSF46785 SSF46785, 1 hit
PROSITEⁱ	View protein in PROSITE PS00658 FORK_HEAD_2, 1 hit PS50039 FORK_HEAD_3, 1 hit

Sequences (2)ⁱ

Sequence statusⁱ: Complete.

This entry describes 2 isoformsⁱ produced by alternative splicing. Align Add to basket

Isoform 1 (identifier: O43524-1) [UniParc]FASTA Add to basket

This isoform has been chosen as the canonicalⁱ sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAEAPASPAP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE 
        60         70         80         90        100
TAADSMIPEE EDDEDDEDGG GRAGSAMAIG GGGGSGTLGS GLLLEDSARV 
       110        120        130        140        150
LAPGGQDPGS GPATAAGGLS GGTQALLQPQ QPLPPPQPGA AGGSGQPRKC 
       160        170        180        190        200
SSRRNAWGNL SYADLITRAI ESSPDKRLTL SQIYEWMVRC VPYFKDKGDS 
       210        220        230        240        250
NSSAGWKNSI RHNLSLHSRF MRVQNEGTGK SSWWIINPDG GKSGKAPRRR 
       260        270        280        290        300
AVSMDNSNKY TKSRGRAAKK KAALQTAPES ADDSPSQLSK WPGSPTSRSS 
       310        320        330        340        350
DELDAWTDFR SRTNSNASTV SGRLSPIMAS TELDEVQDDD APLSPMLYSS 
       360        370        380        390        400
SASLSPSVSK PCTVELPRLT DMAGTMNLND GLTENLMDDL LDNITLPPSQ 
       410        420        430        440        450
PSPTGGLMQR SSSFPYTTKG SGLGSPTSSF NSTVFGPSSL NSLRQSPMQT 
       460        470        480        490        500
IQENKPATFS SMSHYGNQTL QDLLTSDSLS HSDVMMTQSD PLMSQASTAV 
       510        520        530        540        550
SAQNSRRNVM LRNDPMMSFA AQPNQGSLVN QNLLHHQHQT QGALGGSRAL 
       560        570        580        590        600
SNSVSNMGLS ESSSLGSAKH QQQSPVSQSM QTLSDSLSGS SLYSTSANLP 
       610        620        630        640        650
VMGHEKFPSD LDLDMFNGSL ECDMESIIRS ELMDADGLDF NFDSLISTQN 
       660        670 
VVGLNVGNFT GAKQASSQSW VPG

Length:673

Mass (Da):71,277

Last modified:June 1, 1998 - v1

Checksum:ⁱE5B4E830665A9982

GO

Isoform 2 (identifier: O43524-2) [UniParc]FASTA Add to basket

The sequence of this isoform differs from the canonical sequence as follows:
1-220: Missing.

« Hide

        10         20         30         40         50
MRVQNEGTGK SSWWIINPDG GKSGKAPRRR AVSMDNSNKY TKSRGRAAKK 
        60         70         80         90        100
KAALQTAPES ADDSPSQLSK WPGSPTSRSS DELDAWTDFR SRTNSNASTV 
       110        120        130        140        150
SGRLSPIMAS TELDEVQDDD APLSPMLYSS SASLSPSVSK PCTVELPRLT 
       160        170        180        190        200
DMAGTMNLND GLTENLMDDL LDNITLPPSQ PSPTGGLMQR SSSFPYTTKG 
       210        220        230        240        250
SGLGSPTSSF NSTVFGPSSL NSLRQSPMQT IQENKPATFS SMSHYGNQTL 
       260        270        280        290        300
QDLLTSDSLS HSDVMMTQSD PLMSQASTAV SAQNSRRNVM LRNDPMMSFA 
       310        320        330        340        350
AQPNQGSLVN QNLLHHQHQT QGALGGSRAL SNSVSNMGLS ESSSLGSAKH 
       360        370        380        390        400
QQQSPVSQSM QTLSDSLSGS SLYSTSANLP VMGHEKFPSD LDLDMFNGSL 
       410        420        430        440        450
ECDMESIIRS ELMDADGLDF NFDSLISTQN VVGLNVGNFT GAKQASSQSW 

VPG

Show »

Length:453

Mass (Da):48,406

Checksum:ⁱE093364532E78AE1

GO

Experimental Info

Feature key	Position(s)	DescriptionActions	Length
Sequence conflictⁱ	156 – 163	AWGNLSYA → WGKPVYS in CAA04860 (PubMed:9345057).Curated	8
Sequence conflictⁱ	238 – 246	PDGGKSGKA → LMGEERKT in CAA04860 (PubMed:9345057).Curated	9
Sequence conflictⁱ	253	S → T in CAA04860 (PubMed:9345057).Curated	1
Sequence conflictⁱ	271	Missing in CAA04860 (PubMed:9345057).Curated	1
Sequence conflictⁱ	292 – 330	PGSPT…PIMAS → AWQPHVNAAVMSWMRGRTSV HAPILTPAQSVAACRPSWQV in CAA04860 (PubMed:9345057).CuratedAdd BLAST	39
Sequence conflictⁱ	345 – 361	PMLYS…SVSKP → AHALQHVSQPVTFSKQA in CAA04860 (PubMed:9345057).CuratedAdd BLAST	17
Sequence conflictⁱ	367	P → R in CAA04860 (PubMed:9345057).Curated	1
Sequence conflictⁱ	371	D → E in CAA04860 (PubMed:9345057).Curated	1
Sequence conflictⁱ	382 – 383	LT → AD in CAA04860 (PubMed:9345057).Curated	2

Alternative sequence

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Alternative sequenceⁱVSP_056225	1 – 220	Missing in isoform 2. 1 PublicationAdd BLAST		220

Sequence databases

Select the link destinations: EMBLⁱ GenBankⁱ DDBJⁱ Links Updated	AF032886 mRNA Translation: AAC39592.1 AK301304 mRNA Translation: BAG62858.1 AL096818 Genomic DNA No translation available. AL391646 Genomic DNA No translation available. AL365509 Genomic DNA No translation available. CH471051 Genomic DNA Translation: EAW48373.1 CH471051 Genomic DNA Translation: EAW48374.1 BC020227 mRNA Translation: AAH20227.1 BC021224 mRNA Translation: AAH21224.1 BC068552 mRNA Translation: AAH68552.1 AJ001589 mRNA Translation: CAA04860.1 AJ001590 Genomic DNA Translation: CAA04861.1
The Consensus CDS (CCDS) project More...CCDSⁱ	CCDS5068.1 [O43524-1]
NCBI Reference Sequences More...RefSeqⁱ	NP_001446.1, NM_001455.3 [O43524-1] NP_963853.1, NM_201559.2 [O43524-1] XP_005266925.1, XM_005266868.3 [O43524-2] XP_011533930.1, XM_011535628.2 [O43524-2] XP_011533931.1, XM_011535629.2 [O43524-2] XP_016866075.1, XM_017010586.1 [O43524-2]

Genome annotation databases

Ensemblⁱ	ENST00000343882; ENSP00000339527; ENSG00000118689 [O43524-1] ENST00000406360; ENSP00000385824; ENSG00000118689 [O43524-1] ENST00000540898; ENSP00000446316; ENSG00000118689 [O43524-2]
GeneIDⁱ	2309
KEGGⁱ	hsa:2309
UCSC genome browser More...UCSCⁱ	uc003psk.3 human [O43524-1]

Keywords - Coding sequence diversityⁱ

Alternative splicing, Chromosomal rearrangement

Similar proteinsⁱ

100% Identity
90% Identity
50% Identity

Protein	Similar proteins		Species	Score	Length	Source
O43524-2	FOXO3 isoform 3		PONAB		453	UniRef100_A0A2J8U1Q1
FOXO3 isoform 3		PANTR		453
UPI00136234DF		HYLML		734
UPI0013622D45		HYLML		672

Protein	Similar proteins		Species	Score	Length	Source
O43524	Fork-head domain-containing protein		RABIT		675	UniRef90_O43524
Forkhead box O3		GORGO		674
Forkhead box O3		PANTR		673
Forkhead box protein O3		MACMU		672
Forkhead box O3		CALJA		672
+22

Protein	Similar proteins		Species	Score	Length	Source
O43524	Forkhead box protein O3		XENLA		657	UniRef50_O43524
Fork-head domain-containing protein		RABIT		675
Forkhead box O3		GORGO		674
Forkhead box O3		PANTR		673
FOXO3 isoform 1		PONAB		672
+109

Cross-referencesⁱ

Web resourcesⁱ

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations: EMBLⁱ GenBankⁱ DDBJⁱ Links Updated	AF032886 mRNA Translation: AAC39592.1 AK301304 mRNA Translation: BAG62858.1 AL096818 Genomic DNA No translation available. AL391646 Genomic DNA No translation available. AL365509 Genomic DNA No translation available. CH471051 Genomic DNA Translation: EAW48373.1 CH471051 Genomic DNA Translation: EAW48374.1 BC020227 mRNA Translation: AAH20227.1 BC021224 mRNA Translation: AAH21224.1 BC068552 mRNA Translation: AAH68552.1 AJ001589 mRNA Translation: CAA04860.1 AJ001590 Genomic DNA Translation: CAA04861.1
CCDSⁱ	CCDS5068.1 [O43524-1]
RefSeqⁱ	NP_001446.1, NM_001455.3 [O43524-1] NP_963853.1, NM_201559.2 [O43524-1] XP_005266925.1, XM_005266868.3 [O43524-2] XP_011533930.1, XM_011535628.2 [O43524-2] XP_011533931.1, XM_011535629.2 [O43524-2] XP_016866075.1, XM_017010586.1 [O43524-2]

3D structure databases

Select the link destinations: Protein Data Bank Europe More...PDBeⁱ Protein Data Bank RCSB More...RCSB PDBⁱ Protein Data Bank Japan More...PDBjⁱ Links Updated	PDB entry	Method	Resolution (Å)	Chain	Positions	PDBsum
	2K86	NMR	-	A	151-251	[»]
	2LQH	NMR	-	B	461-483	[»]
	2LQI	NMR	-	B	461-483	[»]
	2UZK	X-ray	2.70	A/C	158-253	[»]
	6MNL	NMR	-	A	237-252	[»]
SMRⁱ	O43524
ModBaseⁱ	Search...
PDBe-KBⁱ	Search...

Protein-protein interaction databases

BioGRIDⁱ	108598, 73 interactors
ComplexPortalⁱ	CPX-1123 FOXO3-MYC complex CPX-1147 FOXO3-YWHAZ complex
CORUMⁱ	O43524
DIPⁱ	DIP-29723N
IntActⁱ	O43524, 51 interactors
MINTⁱ	O43524
STRINGⁱ	9606.ENSP00000385824

Chemistry databases

BindingDBⁱ	O43524
ChEMBLⁱ	CHEMBL5778

PTM databases

GlyConnectⁱ	1253
iPTMnetⁱ	O43524
PhosphoSitePlusⁱ	O43524

Polymorphism and mutation databases

BioMutaⁱ	FOXO3

BioMutaⁱ

FOXO3

Proteomic databases

EPDⁱ	O43524
jPOSTⁱ	O43524
MassIVEⁱ	O43524
MaxQBⁱ	O43524
PaxDbⁱ	O43524
PeptideAtlasⁱ	O43524
PRIDEⁱ	O43524
ProteomicsDBⁱ	49029 [O43524-1] 5304

Protocols and materials databases

Antibodypediaⁱ	3419 1125 antibodies
The DNASU plasmid repository More...DNASUⁱ	2309

Genome annotation databases

Ensemblⁱ	ENST00000343882; ENSP00000339527; ENSG00000118689 [O43524-1] ENST00000406360; ENSP00000385824; ENSG00000118689 [O43524-1] ENST00000540898; ENSP00000446316; ENSG00000118689 [O43524-2]
GeneIDⁱ	2309
KEGGⁱ	hsa:2309
UCSCⁱ	uc003psk.3 human [O43524-1]

Organism-specific databases

CTDⁱ	2309
DisGeNETⁱ	2309
EuPathDBⁱ	HostDB:ENSG00000118689.14
GeneCardsⁱ	FOXO3
HGNCⁱ	HGNC:3821 FOXO3
HPAⁱ	ENSG00000118689 Low tissue specificity
MIMⁱ	602681 gene
neXtProtⁱ	NX_O43524
OpenTargetsⁱ	ENSG00000118689
PharmGKBⁱ	PA28239
GenAtlas: human gene database More...GenAtlasⁱ	Search...

Phylogenomic databases

eggNOGⁱ	KOG2294 Eukaryota COG5025 LUCA
GeneTreeⁱ	ENSGT00940000159826
HOGENOMⁱ	CLU_023456_1_0_1
InParanoidⁱ	O43524
KOⁱ	K09408
OMAⁱ	DPVMTFG
OrthoDBⁱ	1160384at2759
PhylomeDBⁱ	O43524
TreeFamⁱ	TF315583

Enzyme and pathway databases

Reactomeⁱ	R-HSA-1181150 Signaling by NODAL R-HSA-198693 AKT phosphorylates targets in the nucleus R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer R-HSA-5687128 MAPK6/MAPK4 signaling R-HSA-6785807 Interleukin-4 and Interleukin-13 signaling R-HSA-8862803 Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models R-HSA-8952158 RUNX3 regulates BCL2L11 (BIM) transcription R-HSA-9614399 Regulation of localization of FOXO transcription factors R-HSA-9614657 FOXO-mediated transcription of cell death genes R-HSA-9615017 FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes R-HSA-9617629 Regulation of FOXO transcriptional activity by acetylation R-HSA-9617828 FOXO-mediated transcription of cell cycle genes R-HSA-9634638 Estrogen-dependent nuclear events downstream of ESR-membrane signaling
SignaLinkⁱ	O43524
SIGNORⁱ	O43524

Miscellaneous databases

BioGRID-ORCSⁱ	2309 5 hits in 801 CRISPR screens
ChiTaRSⁱ	FOXO3 human
EvolutionaryTraceⁱ	O43524
GeneWikiⁱ	FOXO3
GenomeRNAiⁱ	2309
Pharosⁱ	O43524 Tbio
Protein Ontology More...PROⁱ	PR:O43524
RNActⁱ	O43524 protein
SOURCEⁱ	Search...

Gene expression databases

Bgeeⁱ	ENSG00000118689 Expressed in trabecular bone tissue and 235 other tissues
Genevisibleⁱ	O43524 HS

Family and domain databases

CDDⁱ	cd00059 FH, 1 hit
Gene3Dⁱ	1.10.10.10, 1 hit
IDEALⁱ	IID00433
InterProⁱ	View protein in InterPro IPR001766 Fork_head_dom IPR032067 FOXO-TAD IPR032068 FOXO_KIX-bd IPR030456 TF_fork_head_CS_2 IPR036388 WH-like_DNA-bd_sf IPR036390 WH_DNA-bd_sf
Pfamⁱ	View protein in Pfam PF00250 Forkhead, 1 hit PF16676 FOXO-TAD, 1 hit PF16675 FOXO_KIX_bdg, 1 hit
PRINTSⁱ	PR00053 FORKHEAD
SMARTⁱ	View protein in SMART SM00339 FH, 1 hit
SUPFAMⁱ	SSF46785 SSF46785, 1 hit
PROSITEⁱ	View protein in PROSITE PS00658 FORK_HEAD_2, 1 hit PS50039 FORK_HEAD_3, 1 hit
ProtoNetⁱ	Search...
MobiDBⁱ	Search...

Entry informationⁱ

Entry nameⁱ	FOXO3_HUMAN
Accessionⁱ	O43524Primary (citable) accession number: O43524 Secondary accession number(s): B4DVZ6 , E1P5E6, O15171, Q5T2I7, Q9BZ04
Entry historyⁱ	Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
	Last sequence update:	June 1, 1998
	Last modified:	June 17, 2020
	This is version 217 of the entry and version 1 of the sequence. See complete history.
Entry statusⁱ	Reviewed (UniProtKB/Swiss-Prot)
Annotation program	Chordata Protein Annotation Program
Disclaimer	Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousⁱ

Keywords - Technical termⁱ

3D-structure, Reference proteome

Documents

PDB cross-references
Index of Protein Data Bank (PDB) cross-references
MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
Human chromosome 6
Human chromosome 6: entries, gene names and cross-references to MIM

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UniProtKB - O43524 (FOXO3_HUMAN)

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Forkhead box protein O3

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<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Regions

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

Enzyme and pathway databases

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

Organism-specific databases

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Cytosol

Mitochondrion

Nucleus

Cytosol

Mitochondrion

Nucleus

Other locations

Keywords - Cellular componenti

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

Mutagenesis

Keywords - Diseasei

Organism-specific databases

Miscellaneous databases

Chemistry databases

Polymorphism and mutation databases

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Amino acid modifications

Keywords - PTMi

Proteomic databases

PTM databases

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

Gene expression databases

Organism-specific databases

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

O43524

GO - Molecular functioni

Protein-protein interaction databases

Chemistry databases

Miscellaneous databases

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

3D structure databases

Miscellaneous databases

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

Region

Motif

Phylogenomic databases

Family and domain databases

Experimental Info

Alternative sequence

Sequence databases

Genome annotation databases

Keywords - Coding sequence diversityi

<p>This section is used to point to information related to entries and found in data collections other than UniProtKB.<p><a href='/help/cross_references_section' target='_top'>More...</a></p>Cross-referencesi

<p>This subsection of the <a href="http://www.uniprot.org/manual/cross%5Freferences%5Fsection">Cross-references</a> section provides links to various web resources that are relevant for a specific protein.<p><a href='/help/web_resource' target='_top'>More...</a></p>Web resourcesi

Sequence databases

3D structure databases

Protein-protein interaction databases

Chemistry databases

PTM databases

Polymorphism and mutation databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Miscellaneous databases

Gene expression databases

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Functionⁱ

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Keywords - Cellular componentⁱ

Pathology & Biotechⁱ

Keywords - Diseaseⁱ

PTM / Processingⁱ

Keywords - PTMⁱ

Expressionⁱ

Interactionⁱ

GO - Molecular functionⁱ

Structureⁱ

Family & Domainsⁱ

Keywords - Coding sequence diversityⁱ

Cross-referencesⁱ

Web resourcesⁱ

Entry informationⁱ

Miscellaneousⁱ

Keywords - Technical termⁱ