FOXO3
entrez
2309
canonical
uniprot
O43524
canonical
ensembl
ENSG00000118689
resolver
ensp
ENSP00000339527
resolver
ensp
ENSP00000385824
resolver
ensp
ENSP00000446316
resolver
ensp
ENSP00000791233
resolver
genesymbol
FOXO3
resolver
genesymbol
FOXO3A
resolver
genesymbol_syn
FKHRL1
resolver
genesymbol_syn
FOXO3A
resolver
hgnc
HGNC:3821
resolver
uniprot
A0A856PRE8
resolver
uniprot
B4DVZ6
resolver
uniprot
E1P5E6
resolver
uniprot
O15171
resolver
uniprot
Q5T2I7
resolver
uniprot
Q9BZ04
resolver
uniprot_entry
A0A856PRE8_HUMAN
resolver
uniprot_entry
FOXO3_HUMAN
resolver
uniprot_sec
B4DVZ6
resolver
uniprot_sec
E1P5E6
resolver
uniprot_sec
O15171
resolver
uniprot_sec
Q5T2I7
resolver
uniprot_sec
Q9BZ04
resolver
amino_acid_sequence
MAEAPASPAPLSPLEVELDPEFEPQSRPRSCTWPLQRPELQASPAKPSGETAADSMIPEEEDDEDDEDGGGRAGSAMAIGGGGGSGTLGSGLLLEDSARVLAPGGQDPGSGPATAAGGLSGGTQALLQPQQPLPPPQPGAAGGSGQPRKCSSRRNAWGNLSYADLITRAIESSPDKRLTLSQIYEWMVRCVPYFKDKGDSNSSAGWKNSIRHNLSLHSRFMRVQNEGTGKSSWWIINPDGGKSGKAPRRRAVSMDNSNKYTKSRGRAAKKKAALQTAPESADDSPSQLSKWPGSPTSRSSDELDAWTDFRSRTNSNASTVSGRLSPIMASTELDEVQDDDAPLSPMLYSSSASLSPSVSKPCTVELPRLTDMAGTMNLNDGLTENLMDDLLDNITLPPSQPSPTGGLMQRSSSFPYTTKGSGLGSPTSSFNSTVFGPSSLNSLRQSPMQTIQENKPATFSSMSHYGNQTLQDLLTSDSLSHSDVMMTQSDPLMSQASTAVSAQNSRRNVMLRNDPMMSFAAQPNQGSLVNQNLLHHQHQTQGALGGSRALSNSVSNMGLSESSSLGSAKHQQQSPVSQSMQTLSDSLSGSSLYSTSANLPVMGHEKFPSDLDLDMFNGSLECDMESIIRSELMDADGLDFNFDSLISTQNVVGLNVGNFTGAKQASSQSWVPG
uniprot
proteins
disease_involvement
DISEASE: Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.
uniprot
proteins
function
FUNCTION: 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, PubMed:30513302). 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). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302). {ECO:0000250|UniProtKB:Q9WVH4, ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:30513302}.
uniprot
proteins
mass_dalton
71277
uniprot
proteins
mutagenesis
MUTAGEN 2..148; /note="Missing: Loss of localization to the mitochondrion outer membrane and loss of translocation into the mitochondrion following metabolic stress."; /evidence="ECO:0000269|PubMed:29445193"; MUTAGEN 2..30; /note="Missing: Loss of translocation into the mitochondrion following metabolic stress."; /evidence="ECO:0000269|PubMed:29445193"; MUTAGEN 12; /note="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."; /evidence="ECO:0000269|PubMed:29445193"; MUTAGEN 30; /note="S->A: Abolishes phosphorylation. Loss of localization to the mitochondrion outer membrane and loss of translocation into the mitochondrion following metabolic stress."; /evidence="ECO:0000269|PubMed:29445193"; MUTAGEN 32; /note="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."; /evidence="ECO:0000269|PubMed:10102273"; MUTAGEN 80..108; /note="Missing: Loss of translocation into the mitochondrion following metabolic stress."; /evidence="ECO:0000269|PubMed:29445193"; MUTAGEN 179; /note="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."; /evidence="ECO:0000269|PubMed:17711846"; MUTAGEN 209; /note="S->A: Impairs nuclear translocation upon oxidative stress."; /evidence="ECO:0000269|PubMed:16751106"; MUTAGEN 242..271; /note="Missing: Loss of nuclear import."; /evidence="ECO:0000269|PubMed:29445193"; MUTAGEN 242; /note="K->A: Slightly decreases DNA affinity."; /evidence="ECO:0000269|PubMed:17940099, ECO:0000269|PubMed:21841822"; MUTAGEN 242; /note="K->R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-259; R-290 and R-569."; /evidence="ECO:0000269|PubMed:17940099, ECO:0000269|PubMed:21841822"; MUTAGEN 245; /note="K->A: Decreases DNA affinity."; /evidence="ECO:0000269|PubMed:17940099"; MUTAGEN 253; /note="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."; /evidence="ECO:0000269|PubMed:10102273"; MUTAGEN 259; /note="K->R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-242; R-290 and R-569."; /evidence="ECO:0000269|PubMed:21841822"; MUTAGEN 269; /note="K->R: Methylation levels similar to wild-type; when associated with Arg-270."; /evidence="ECO:0000269|PubMed:22820736"; MUTAGEN 270; /note="K->R: Methylation levels similar to wild-type; when associated with Arg-269."; /evidence="ECO:0000269|PubMed:22820736"; MUTAGEN 271; /note="K->R: Methylation levels strongly reduced."; /evidence="ECO:0000269|PubMed:22820736"; MUTAGEN 290; /note="K->R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-242; R-259 and R-569."; /evidence="ECO:0000269|PubMed:21841822"; MUTAGEN 315; /note="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."; /evidence="ECO:0000269|PubMed:10102273"; MUTAGEN 399; /note="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."; /evidence="ECO:0000269|PubMed:17711846"; MUTAGEN 413; /note="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."; /evidence="ECO:0000269|PubMed:17711846"; MUTAGEN 555; /note="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."; /evidence="ECO:0000269|PubMed:17711846"; MUTAGEN 569; /note="K->R: Reduces acetylation, increases interaction with SKP2 and inhibits FOXO3 ubiquitination and degradation; when associated with R-242; R-259 and R-290."; /evidence="ECO:0000269|PubMed:21841822"; MUTAGEN 588; /note="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."; /evidence="ECO:0000269|PubMed:17711846"; MUTAGEN 626; /note="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."; /evidence="ECO:0000269|PubMed:17711846"; MUTAGEN 644; /note="S->A: Loss of phosphorylation by IKKB."; /evidence="ECO:0000269|PubMed:15084260
uniprot
proteins
post_translational_modification
PTM: In the presence of survival factors such as IGF1, 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). Phosphorylation at Ser-253 promotes its degradation by the proteasome (PubMed:30513302). Dephosphorylation at Ser-253 by protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:30513302). Dephosphorylated at Ser-253 by CTDSPL2 (PubMed:28851713). {ECO:0000250|UniProtKB:Q9WVH4, ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:11154281, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:28851713, ECO:0000269|PubMed:29445193, ECO:0000269|PubMed:30513302}.; PTM: 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). {ECO:0000250|UniProtKB:Q9WVH4, ECO:0000269|PubMed:21841822, ECO:0000269|PubMed:23283301}.; PTM: 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. {ECO:0000269|PubMed:22820736}.; PTM: Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation. {ECO:0000269|PubMed:21841822}.; PTM: The N-terminus is cleaved following import into the mitochondrion. {ECO:0000269|PubMed:29445193}.
uniprot
proteins
pubmed
10102273
uniprot
proteins
pubmed
11154281
uniprot
proteins
pubmed
14574404
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15084260
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16751106
uniprot
proteins
pubmed
17711846
uniprot
proteins
pubmed
17940099
uniprot
proteins
pubmed
18220336
uniprot
proteins
pubmed
18593906
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
20181828
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21329882
uniprot
proteins
pubmed
21841822
uniprot
proteins
pubmed
22313691
uniprot
proteins
pubmed
22761832
uniprot
proteins
pubmed
22820736
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23283301
uniprot
proteins
pubmed
23805378
uniprot
proteins
pubmed
28851713
uniprot
proteins
pubmed
29445193
uniprot
proteins
pubmed
30513302
uniprot
proteins
pubmed
9345057
uniprot
proteins
pubmed
9479491
uniprot
proteins
sequence_length
673
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:22313691, ECO:0000269|PubMed:22761832, ECO:0000269|PubMed:23283301}. Nucleus {ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:22313691, ECO:0000269|PubMed:22761832, ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:28851713, ECO:0000269|PubMed:29445193}. Mitochondrion matrix {ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193}. Mitochondrion outer membrane {ECO:0000269|PubMed:29445193}; Peripheral membrane protein {ECO:0000269|PubMed:29445193}; Cytoplasmic side {ECO:0000269|PubMed:29445193}. Note=Retention in the cytoplasm contributes to its inactivation (PubMed:10102273, PubMed:15084260, PubMed:16751106). Translocates to the nucleus upon oxidative stress and in the absence of survival factors (PubMed:10102273, PubMed:16751106). Translocates from the cytosol to the nucleus following dephosphorylation in response to autophagy-inducing stimuli (By similarity). Translocates in a AMPK-dependent manner into the mitochondrion in response to metabolic stress (PubMed:23283301, PubMed:29445193). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (By similarity). {ECO:0000250|UniProtKB:Q9WVH4, ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193}.
uniprot
proteins