FOXO1
entrez
2308
canonical
uniprot
Q12778
canonical
ensembl
ENSG00000150907
resolver
ensp
ENSP00000368880
resolver
ensp
ENSP00000579834
resolver
ensp
ENSP00000632421
resolver
enst
ENST00000379561
resolver
enst
ENST00000909775
resolver
enst
ENST00000962362
resolver
genesymbol
FOXO1
resolver
genesymbol_syn
FKHR
resolver
genesymbol_syn
FOXO1A
resolver
hgnc
HGNC:3819
resolver
uniprot
O43523
resolver
uniprot
Q5VYC7
resolver
uniprot
Q6NSK6
resolver
uniprot_entry
FOXO1_HUMAN
resolver
uniprot_sec
O43523
resolver
uniprot_sec
Q5VYC7
resolver
uniprot_sec
Q6NSK6
resolver
amino_acid_sequence
MAEAPQVVEIDPDFEPLPRPRSCTWPLPRPEFSQSNSATSSPAPSGSAAANPDAAAGLPSASAAAVSADFMSNLSLLEESEDFPQAPGSVAAAVAAAAAAAATGGLCGDFQGPEAGCLHPAPPQPPPPGPLSQHPPVPPAAAGPLAGQPRKSSSSRRNAWGNLSYADLITKAIESSAEKRLTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSSWWMLNPEGGKSGKSPRRRAASMDNNSKFAKSRSRAAKKKASLQSGQEGAGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGEGDVHSMVYPPSAAKMASTLPSLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGTMMQQTPCYSFAPPNTSLNSPSPNYQKYTYGQSSMSPLPQMPIQTLQDNKSSYGGMSQYNCAPGLLKELLTSDSPPHNDIMTPVDPGVAQPNSRVLGQNVMMGPNSVMSTYGSQASHNKMMNPSSHTHPGHAQQTSAVNGRPLPHTVSTMPHTSGMNRLTQVKTPVQVPLPHPMQMSALGGYSSVSSCNGYGRMGLLHQEKLPSDLDGMFIERLDCDMESIIRNDLMDGDTLDFNFDNVLPNQSFPHSVKTTTHSWVSG
uniprot
proteins
disease_involvement
DISEASE: Rhabdomyosarcoma 2 (RMS2) [MIM:268220]: A form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchymal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. Note=The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator. {ECO:0000269|PubMed:8275086}.
uniprot
proteins
function
FUNCTION: Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (PubMed:10358076, PubMed:12228231, PubMed:15220471, PubMed:15890677, PubMed:18356527, PubMed:19221179, PubMed:20543840, PubMed:21245099). Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3' (PubMed:10358076). Activity suppressed by insulin (PubMed:10358076). Main regulator of redox balance and osteoblast numbers and controls bone mass (By similarity). Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (By similarity). 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). Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (By similarity). Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (By similarity). Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (By similarity). In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By similarity). Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1 (PubMed:17024043). Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (PubMed:18356527, PubMed:19221179). Promotes neural cell death (PubMed:18356527). Mediates insulin action on adipose tissue (By similarity). Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake (By similarity). Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells (By similarity). Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (PubMed:20543840). Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity). Positive regulator of apoptosis in cardiac smooth muscle cells as a result of its transcriptional activation of pro-apoptotic genes (PubMed:19483080). Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815). {ECO:0000250|UniProtKB:A4L7N3, ECO:0000250|UniProtKB:G3V7R4, ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:10358076, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:15220471, ECO:0000269|PubMed:15890677, ECO:0000269|PubMed:17024043, ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:19483080, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:31063815}.
uniprot
proteins
mass_dalton
69662
uniprot
proteins
mutagenesis
MUTAGEN 24; /note="T->A: Abolishes PKB/AKT1-mediated phosphorylation but does not prevent phosphorylation of Ser-256 or Ser-319. Also inhibits binding of 14-3-3 proteins. Nuclear in unstimulated cells, and little export to cytoplasm on IGF1 stimulation. Targeted to the nucleus and enhances transactivation; when associated with A-319. No effect on interaction with STUB1. Inhibits the PKB/AKT1-mediated activity towards other substrates but does not block the IGF1-activated 'T-308' of phosphorylation of PKB/AKT1; when associated with A-256 and A-319."; /evidence="ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:19483080"; MUTAGEN 212; /note="S->A: Abolishes STK4/MST1-mediated phosphorylation."; /evidence="ECO:0000269|PubMed:19221179"; MUTAGEN 245; /note="K->A: Disrupts DNA-binding; when associated with A-248."; /evidence="ECO:0000269|PubMed:12228231"; MUTAGEN 248; /note="K->A: Disrupts DNA-binding; when associated with A-245."; /evidence="ECO:0000269|PubMed:12228231"; MUTAGEN 249; /note="S->A: Impaired phosphorylation by CDK1."; /evidence="ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:18786403"; MUTAGEN 249; /note="S->E: No effect on DNA-binding."; /evidence="ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:18786403"; MUTAGEN 251..253; /note="RRR->SAS: No targeting to the nucleus and disruption of DNA-binding."; /evidence="ECO:0000269|PubMed:12228231"; MUTAGEN 256; /note="S->A: Completely abolishes PKB/AKT1-mediated phosphorylation at all three sites, and inhibits binding of 14-3-3 proteins. Inhibits the PKB/AKT1-mediated activity towards other substrates but does not block the IGF1-activated 'T-308' of phosphorylation of PKB/AKT1; when associated with or without A-24 and A-319. Nuclear in unstimulated cells, and little export to cytoplasm on IGF1 stimulation. Abolishes the ability of IGF1 to suppress transactivation. Prevents T-24 and S-319 phosphorylation. Abolishes interaction with and ubiquitination by STUB1. Enhances transactivation; when associated with A-24 and A-319."; /evidence="ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:15668399, ECO:0000269|PubMed:19483080"; MUTAGEN 256; /note="S->D: Reduces DNA binding, promotes nuclear exclusion and partially promotes T-24 and S-319 phosphorylation. Reduces DNA binding, does not promote nuclear exclusion but reduces transactivation; when associated with A-24 and A-319."; /evidence="ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:15668399"; MUTAGEN 262; /note="K->R: Inhibits interaction with ATG7 and FOXO1-acetylation-induced autophagic cell death; when associated with R-265 and R-274."; /evidence="ECO:0000269|PubMed:12228231"; MUTAGEN 265; /note="K->R: Inhibits interaction with ATG7 and FOXO1-acetylation-induced autophagic cell death; when associated with R-262 and R-274."; /evidence="ECO:0000269|PubMed:12228231"; MUTAGEN 274; /note="K->R: Inhibits interaction with ATG7 and FOXO1-acetylation-induced autophagic cell death; when associated with R-262 and R-265."; /evidence="ECO:0000269|PubMed:12228231"; MUTAGEN 319; /note="S->A: Abolishes PKB/AKT1-mediated phosphorylation but does not prevent phosphorylation of Ser-24 or Ser-256. Inhibits the PKB/AKT1-mediated activity towards other substrates but does not block the IGF1-activated 'T-308' of phosphorylation of PKB/AKT1; when associated with A-24 and A-256. Targeted to the nucleus and enhances transactivation; when associated with A-24. No effect on interaction with STUB1."; /evidence="ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:19483080"; MUTAGEN 329; /note="S->A: Targeted to the nucleus and enhances transactivation."; /evidence="ECO:0000269|PubMed:11311120"; MUTAGEN 423; /note="K->R: Abolished deacetylation by SIRT6."; /evidence="ECO:0000269|PubMed:25009184"; MUTAGEN 446; /note="K->R: Does not affect deacetylation by SIRT6."; /evidence="ECO:0000269|PubMed:25009184"; MUTAGEN 463; /note="K->R: Does not affect deacetylation by SIRT6."; /evidence="ECO:0000269|PubMed:25009184"; MUTAGEN 515; /note="K->R: Does not affect deacetylation by SIRT6."; /evidence="ECO:0000269|PubMed:25009184
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta-cells under oxidative stress leading to nuclear retention (By similarity). Phosphorylation of Ser-249 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. PPIA/CYPA promotes its dephosphorylation on Ser-256 (PubMed:31063815). Dephosphorylated at Ser-256 by CTDSPL2 (PubMed:28851713). {ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:10358075, ECO:0000269|PubMed:10358076, ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:11980723, ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:18786403, ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:28851713, ECO:0000269|PubMed:31063815}.; PTM: Ubiquitinated by SKP2 (PubMed:15668399). Ubiquitination leads to proteasomal degradation (PubMed:19483080). Ubiquitinated by STUB1/CHIP; when Ser-256 is phosphorylated (PubMed:19483080). {ECO:0000269|PubMed:15668399, ECO:0000269|PubMed:19483080}.; PTM: Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress. {ECO:0000250|UniProtKB:Q9R1E0}.; PTM: Acetylated (PubMed:15220471, PubMed:15890677, PubMed:18786403, PubMed:20543840). Acetylation at Lys-262, Lys-265 and Lys-274 are necessary for autophagic cell death induction (PubMed:20543840). Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death (PubMed:20543840). Once in the nucleus, acetylated by CREBBP/EP300 (PubMed:15220471, PubMed:15890677, PubMed:18786403). Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-256 (PubMed:15220471, PubMed:15890677, PubMed:18786403). Deacetylation by SIRT1 results in reactivation of the transcriptional activity (PubMed:15220471, PubMed:15890677, PubMed:18786403). Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation (PubMed:15220471, PubMed:15890677, PubMed:18786403). By contrast, resveratrol acts independently of acetylation (PubMed:15220471, PubMed:15890677, PubMed:18786403). Acetylated at Lys-423, promoting its localization to the nucleus and transcription factor activity (PubMed:25009184). Deacetylation at Lys-423 by SIRT6, promotes its translocation into the cytoplasm, preventing its transcription factor activity (PubMed:25009184). Deacetylation and subsequent inhibition by SIRT6 has different effects depending on cell types: it inhibits gluconeogenesis in hepatocytes, promotes glucose sensing in pancreatic beta-cells and regulates lipid catabolism in brown adipocytes (By similarity). {ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:15220471, ECO:0000269|PubMed:15890677, ECO:0000269|PubMed:18786403, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:25009184}.
uniprot
proteins
pubmed
10358075
uniprot
proteins
pubmed
10358076
uniprot
proteins
pubmed
11237865
uniprot
proteins
pubmed
11311120
uniprot
proteins
pubmed
11980723
uniprot
proteins
pubmed
12228231
uniprot
proteins
pubmed
15057823
uniprot
proteins
pubmed
15220471
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15668399
uniprot
proteins
pubmed
15890677
uniprot
proteins
pubmed
17024043
uniprot
proteins
pubmed
18356527
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18786403
uniprot
proteins
pubmed
18951090
uniprot
proteins
pubmed
19221179
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19483080
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20543840
uniprot
proteins
pubmed
20668652
uniprot
proteins
pubmed
21245099
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
25009184
uniprot
proteins
pubmed
28851713
uniprot
proteins
pubmed
31063815
uniprot
proteins
pubmed
8187070
uniprot
proteins
pubmed
8275086
uniprot
proteins
pubmed
9479491
uniprot
proteins
sequence_length
655
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}. Nucleus {ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:28851713, ECO:0000269|PubMed:31063815}. Note=Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells (PubMed:11311120, PubMed:12228231, PubMed:19221179, PubMed:20543840, PubMed:21245099, PubMed:25009184). In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (By similarity). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (By similarity). Insulin-induced phosphorylation at Ser-256 by PKB/AKT1 leads, via stimulation of Thr-24 phosphorylation, to binding of 14-3-3 proteins and nuclear export to the cytoplasm where it is degraded by the ubiquitin-proteasomal pathway (PubMed:11237865, PubMed:12228231). Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation (PubMed:18356527). Phosphorylation by NLK results in nuclear export (By similarity). Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (PubMed:19221179, PubMed:21245099). SGK1-mediated phosphorylation also results in nuclear translocation (By similarity). Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide (By similarity). Retained in the nucleus on methylation (By similarity). PPIA/CYPA stimulates its nuclear accumulation (PubMed:31063815). Deacetylation by SIRT6, promotes its translocation into the cytoplasm (PubMed:25009184). {ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}.
uniprot
proteins