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Q12778

- FOXO1_HUMAN

UniProt

Q12778 - FOXO1_HUMAN

Protein

Forkhead box protein O1

Gene

FOXO1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 155 (01 Oct 2014)
      Sequence version 2 (17 Oct 2006)
      Previous versions | rss
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    Functioni

    Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. 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'. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. Acts syngernistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A to activate the expression of genes such as IGFBP1, G6PC and PPCK1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and SKT4/MST1. Promotes neural cell death. Mediates insulin action on adipose. 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. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells. Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner.8 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei158 – 1581DNA-binding
    Sitei165 – 1651DNA-binding
    Sitei225 – 2251DNA-binding

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    DNA bindingi159 – 23577Fork-headPROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. chromatin binding Source: UniProtKB
    2. protein binding Source: UniProtKB
    3. protein phosphatase 2A binding Source: UniProtKB
    4. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription Source: Ensembl
    5. sequence-specific DNA binding Source: UniProtKB
    6. ubiquitin protein ligase binding Source: UniProtKB

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. blood vessel development Source: Ensembl
    3. cellular glucose homeostasis Source: UniProtKB
    4. cellular response to cold Source: UniProtKB
    5. cellular response to DNA damage stimulus Source: UniProtKB
    6. cellular response to hyperoxia Source: UniProtKB
    7. cellular response to insulin stimulus Source: UniProtKB
    8. cellular response to nitric oxide Source: UniProtKB
    9. cellular response to oxidative stress Source: UniProtKB
    10. cellular response to starvation Source: UniProtKB
    11. endocrine pancreas development Source: Reactome
    12. epidermal growth factor receptor signaling pathway Source: Reactome
    13. fat cell differentiation Source: UniProtKB
    14. Fc-epsilon receptor signaling pathway Source: Reactome
    15. fibroblast growth factor receptor signaling pathway Source: Reactome
    16. innate immune response Source: Reactome
    17. insulin receptor signaling pathway Source: UniProtKB
    18. negative regulation of apoptotic process Source: UniProtKB
    19. negative regulation of fat cell differentiation Source: UniProtKB
    20. negative regulation of stress-activated MAPK cascade Source: BHF-UCL
    21. negative regulation of transcription, DNA-templated Source: UniProtKB
    22. neurotrophin TRK receptor signaling pathway Source: Reactome
    23. phosphatidylinositol-mediated signaling Source: Reactome
    24. positive regulation of apoptotic process Source: UniProtKB
    25. positive regulation of autophagy Source: UniProtKB
    26. positive regulation of gluconeogenesis Source: Ensembl
    27. positive regulation of protein catabolic process Source: UniProtKB
    28. positive regulation of transcription, DNA-templated Source: UniProtKB
    29. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    30. protein acetylation Source: UniProtKB
    31. regulation of cell proliferation Source: Ensembl
    32. regulation of energy homeostasis Source: UniProtKB
    33. regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter Source: Ensembl
    34. temperature homeostasis Source: UniProtKB

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Apoptosis, Autophagy, Differentiation, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_12442. AKT phosphorylates targets in the nucleus.
    REACT_13655. AKT-mediated inactivation of FOXO1A.
    REACT_13819. Regulation of gene expression in beta cells.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    SignaLinkiQ12778.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Forkhead box protein O1
    Alternative name(s):
    Forkhead box protein O1A
    Forkhead in rhabdomyosarcoma
    Gene namesi
    Name:FOXO1
    Synonyms:FKHR, FOXO1A
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 13

    Organism-specific databases

    HGNCiHGNC:3819. FOXO1.

    Subcellular locationi

    Cytoplasm. Nucleus
    Note: Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells. In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus 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-proteosomal pathway. Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation. Phosphorylation by NLK results in nuclear export. Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1. SGK1-mediated phosphorylation also results in nuclear translocation. Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide. Retained in the nucleus on methylation.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. cytosol Source: UniProtKB
    3. mitochondrion Source: UniProtKB
    4. nucleoplasm Source: Reactome
    5. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    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.

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi24 – 241T → 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. 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. Targeted to the nucleus and enhances transactivation; when associated with A-319. 2 Publications
    Mutagenesisi212 – 2121S → A: Abolishes STK4/MST1-mediated phosphorylation. 1 Publication
    Mutagenesisi245 – 2451K → A: Disrupts DNA-binding; when associated with A-248.
    Mutagenesisi248 – 2481K → A: Disrupts DNA-binding; when associated with A-245.
    Mutagenesisi249 – 2491S → A: Impaired phosphorylation by CDK1. 2 Publications
    Mutagenesisi249 – 2491S → E: No effect on DNA-binding. 2 Publications
    Mutagenesisi251 – 2533RRR → SAS: No targeting to the nucleus and disruption of DNA-binding.
    Mutagenesisi256 – 2561S → 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. Enhances transactivation; when associated with A-24 and A-319. 3 Publications
    Mutagenesisi256 – 2561S → 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. 3 Publications
    Mutagenesisi262 – 2621K → R: Inhibits interaction with ATG7 and FOXO1-acetylation-induced autophagic cell death; when associated with R-265 and R-274.
    Mutagenesisi265 – 2651K → R: Inhibits interaction with ATG7 and FOXO1-acetylation-induced autophagic cell death; when associated with R-262 and R-274.
    Mutagenesisi274 – 2741K → R: Inhibits interaction with ATG7 and FOXO1-acetylation-induced autophagic cell death; when associated with R-262 and R-265.
    Mutagenesisi319 – 3191S → 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. 2 Publications
    Mutagenesisi329 – 3291S → A: Targeted to the nucleus and enhances transactivation. 1 Publication

    Keywords - Diseasei

    Proto-oncogene

    Organism-specific databases

    MIMi268220. phenotype.
    Orphaneti99756. Alveolar rhabdomyosarcoma.
    PharmGKBiPA28237.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 655655Forkhead box protein O1PRO_0000091872Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei24 – 241Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK14 Publications
    Modified residuei212 – 2121Phosphoserine; by STK4/MST14 Publications
    Modified residuei218 – 2181Phosphoserine; by STK4/MST12 Publications
    Modified residuei234 – 2341Phosphoserine; by STK4/MST12 Publications
    Modified residuei235 – 2351Phosphoserine; by STK4/MST12 Publications
    Modified residuei245 – 2451N6-acetyllysineBy similarity
    Modified residuei248 – 2481N6-acetyllysineBy similarity
    Modified residuei249 – 2491Phosphoserine; by CDK12 Publications
    Modified residuei251 – 2511Omega-N-methylarginine; by PRMT1By similarity
    Modified residuei253 – 2531Omega-N-methylarginine; by PRMT1By similarity
    Modified residuei256 – 2561Phosphoserine; by PKB/AKT1 and SGK15 Publications
    Modified residuei262 – 2621N6-acetyllysine1 Publication
    Modified residuei265 – 2651N6-acetyllysine1 Publication
    Modified residuei274 – 2741N6-acetyllysine1 Publication
    Modified residuei287 – 2871Phosphoserine4 Publications
    Modified residuei319 – 3191Phosphoserine; by PKB/AKT14 Publications
    Modified residuei322 – 3221Phosphoserine; by CK1 and SGK12 Publications
    Modified residuei325 – 3251Phosphoserine; by CK12 Publications
    Modified residuei329 – 3291Phosphoserine; by DYRK1A3 Publications
    Modified residuei467 – 4671PhosphothreonineBy similarity
    Modified residuei468 – 4681PhosphoserineBy similarity

    Post-translational modificationi

    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.By similarity9 Publications
    Acetylated. Acetylation at Lys-262, Lys-265 and Lys-274 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death.1 Publication
    Ubiquitinated by SRT2. Ubiquitination leads to proteasomal degradation.1 Publication
    Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress.By similarity
    Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-256. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation.4 Publications

    Keywords - PTMi

    Acetylation, Methylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ12778.
    PaxDbiQ12778.
    PRIDEiQ12778.

    PTM databases

    PhosphoSiteiQ12778.

    Expressioni

    Tissue specificityi

    Ubiquitous.1 Publication

    Inductioni

    Expression is regulated by KRIT1. Levels of expression also regulated by FOXC1 which binds to a conserved element in the FOXO1 promoter.1 Publication

    Gene expression databases

    BgeeiQ12778.
    CleanExiHS_FOXO1.
    GenevestigatoriQ12778.

    Organism-specific databases

    HPAiCAB022326.
    HPA001252.

    Interactioni

    Subunit structurei

    Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-256 leading to its nuclear import. Interacts (acetylated form) with PPARG By similarity. Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteosomal degradation. The interaction requires the presence of KRIT1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death.By similarity7 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    CCNB1P146352EBI-1108782,EBI-495332
    CDK1P064935EBI-1108782,EBI-444308
    CREBBPQ927932EBI-1108782,EBI-81215
    ESR1P033722EBI-1108782,EBI-78473
    FHL2Q141928EBI-1108782,EBI-701903
    SETQ011055EBI-1108782,EBI-1053182
    SIRT1Q96EB63EBI-1108782,EBI-1802965
    Sirt1Q923E42EBI-1108782,EBI-1802585From a different organism.

    Protein-protein interaction databases

    BioGridi108597. 31 interactions.
    DIPiDIP-35654N.
    IntActiQ12778. 13 interactions.
    STRINGi9606.ENSP00000368880.

    Structurei

    Secondary structure

    1
    655
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi156 – 1583
    Helixi165 – 17511
    Beta strandi176 – 1794
    Helixi183 – 19311
    Helixi195 – 1973
    Helixi203 – 21917
    Beta strandi223 – 2264
    Turni230 – 2323
    Beta strandi236 – 2394

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3CO6X-ray2.10C151-249[»]
    3CO7X-ray2.91C/F151-266[»]
    3COAX-ray2.20C/F151-266[»]
    ProteinModelPortaliQ12778.
    SMRiQ12778. Positions 154-269.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ12778.

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni211 – 2188DNA-binding
    Regioni234 – 2374DNA-binding
    Regioni283 – 563281Sufficient for interaction with NLKBy similarityAdd
    BLAST
    Regioni363 – 45997Required for interaction with RUNX2By similarityAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi251 – 2533Nuclear localization signal
    Motifi462 – 4665Required for interaction with SIRT1By similarity

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi91 – 10212Poly-AlaAdd
    BLAST
    Compositional biasi120 – 13011Poly-ProAdd
    BLAST
    Compositional biasi152 – 1554Poly-Ser

    Sequence similaritiesi

    Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG5025.
    HOGENOMiHOG000251635.
    HOVERGENiHBG057789.
    InParanoidiQ12778.
    KOiK07201.
    OMAiGVKTTTH.
    OrthoDBiEOG7SJD45.
    PhylomeDBiQ12778.
    TreeFamiTF315583.

    Family and domain databases

    Gene3Di1.10.10.10. 1 hit.
    InterProiIPR001766. TF_fork_head.
    IPR018122. TF_fork_head_CS.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view]
    PfamiPF00250. Fork_head. 1 hit.
    [Graphical view]
    PRINTSiPR00053. FORKHEAD.
    SMARTiSM00339. FH. 1 hit.
    [Graphical view]
    PROSITEiPS00658. FORK_HEAD_2. 1 hit.
    PS50039. FORK_HEAD_3. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q12778-1 [UniParc]FASTAAdd to Basket

    « Hide

    MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGSAAA    50
    NPDAAAGLPS ASAAAVSADF MSNLSLLEES EDFPQAPGSV AAAVAAAAAA 100
    AATGGLCGDF QGPEAGCLHP APPQPPPPGP LSQHPPVPPA AAGPLAGQPR 150
    KSSSSRRNAW GNLSYADLIT KAIESSAEKR LTLSQIYEWM VKSVPYFKDK 200
    GDSNSSAGWK NSIRHNLSLH SKFIRVQNEG TGKSSWWMLN PEGGKSGKSP 250
    RRRAASMDNN SKFAKSRSRA AKKKASLQSG QEGAGDSPGS QFSKWPASPG 300
    SHSNDDFDNW STFRPRTSSN ASTISGRLSP IMTEQDDLGE GDVHSMVYPP 350
    SAAKMASTLP SLSEISNPEN MENLLDNLNL LSSPTSLTVS TQSSPGTMMQ 400
    QTPCYSFAPP NTSLNSPSPN YQKYTYGQSS MSPLPQMPIQ TLQDNKSSYG 450
    GMSQYNCAPG LLKELLTSDS PPHNDIMTPV DPGVAQPNSR VLGQNVMMGP 500
    NSVMSTYGSQ ASHNKMMNPS SHTHPGHAQQ TSAVNGRPLP HTVSTMPHTS 550
    GMNRLTQVKT PVQVPLPHPM QMSALGGYSS VSSCNGYGRM GLLHQEKLPS 600
    DLDGMFIERL DCDMESIIRN DLMDGDTLDF NFDNVLPNQS FPHSVKTTTH 650
    SWVSG 655
    Length:655
    Mass (Da):69,662
    Last modified:October 17, 2006 - v2
    Checksum:i6DEF6C994BDFDBAB
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti131 – 1311L → V in AAA03629. (PubMed:8275086)Curated
    Sequence conflicti343 – 3431V → M in AAH70065. (PubMed:15489334)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U02310 mRNA. Translation: AAA03629.1.
    AF032885 mRNA. Translation: AAC39591.1.
    BT007455 mRNA. Translation: AAP36123.1.
    AL355132, AL133318 Genomic DNA. Translation: CAH70978.1.
    AL133318, AL355132 Genomic DNA. Translation: CAI16970.1.
    BC021981 mRNA. Translation: AAH21981.1.
    BC070065 mRNA. Translation: AAH70065.3.
    CCDSiCCDS9371.1.
    PIRiS40521.
    RefSeqiNP_002006.2. NM_002015.3.
    UniGeneiHs.370666.

    Genome annotation databases

    EnsembliENST00000379561; ENSP00000368880; ENSG00000150907.
    GeneIDi2308.
    KEGGihsa:2308.
    UCSCiuc001uxl.4. human.

    Polymorphism databases

    DMDMi116241368.

    Keywords - Coding sequence diversityi

    Chromosomal rearrangement

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U02310 mRNA. Translation: AAA03629.1 .
    AF032885 mRNA. Translation: AAC39591.1 .
    BT007455 mRNA. Translation: AAP36123.1 .
    AL355132 , AL133318 Genomic DNA. Translation: CAH70978.1 .
    AL133318 , AL355132 Genomic DNA. Translation: CAI16970.1 .
    BC021981 mRNA. Translation: AAH21981.1 .
    BC070065 mRNA. Translation: AAH70065.3 .
    CCDSi CCDS9371.1.
    PIRi S40521.
    RefSeqi NP_002006.2. NM_002015.3.
    UniGenei Hs.370666.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3CO6 X-ray 2.10 C 151-249 [» ]
    3CO7 X-ray 2.91 C/F 151-266 [» ]
    3COA X-ray 2.20 C/F 151-266 [» ]
    ProteinModelPortali Q12778.
    SMRi Q12778. Positions 154-269.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 108597. 31 interactions.
    DIPi DIP-35654N.
    IntActi Q12778. 13 interactions.
    STRINGi 9606.ENSP00000368880.

    Chemistry

    BindingDBi Q12778.
    ChEMBLi CHEMBL5294.

    PTM databases

    PhosphoSitei Q12778.

    Polymorphism databases

    DMDMi 116241368.

    Proteomic databases

    MaxQBi Q12778.
    PaxDbi Q12778.
    PRIDEi Q12778.

    Protocols and materials databases

    DNASUi 2308.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000379561 ; ENSP00000368880 ; ENSG00000150907 .
    GeneIDi 2308.
    KEGGi hsa:2308.
    UCSCi uc001uxl.4. human.

    Organism-specific databases

    CTDi 2308.
    GeneCardsi GC13M041129.
    HGNCi HGNC:3819. FOXO1.
    HPAi CAB022326.
    HPA001252.
    MIMi 136533. gene.
    268220. phenotype.
    neXtProti NX_Q12778.
    Orphaneti 99756. Alveolar rhabdomyosarcoma.
    PharmGKBi PA28237.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5025.
    HOGENOMi HOG000251635.
    HOVERGENi HBG057789.
    InParanoidi Q12778.
    KOi K07201.
    OMAi GVKTTTH.
    OrthoDBi EOG7SJD45.
    PhylomeDBi Q12778.
    TreeFami TF315583.

    Enzyme and pathway databases

    Reactomei REACT_12442. AKT phosphorylates targets in the nucleus.
    REACT_13655. AKT-mediated inactivation of FOXO1A.
    REACT_13819. Regulation of gene expression in beta cells.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    SignaLinki Q12778.

    Miscellaneous databases

    ChiTaRSi FOXO1. human.
    EvolutionaryTracei Q12778.
    GeneWikii FOXO1.
    GenomeRNAii 2308.
    NextBioi 9375.
    PROi Q12778.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q12778.
    CleanExi HS_FOXO1.
    Genevestigatori Q12778.

    Family and domain databases

    Gene3Di 1.10.10.10. 1 hit.
    InterProi IPR001766. TF_fork_head.
    IPR018122. TF_fork_head_CS.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view ]
    Pfami PF00250. Fork_head. 1 hit.
    [Graphical view ]
    PRINTSi PR00053. FORKHEAD.
    SMARTi SM00339. FH. 1 hit.
    [Graphical view ]
    PROSITEi PS00658. FORK_HEAD_2. 1 hit.
    PS50039. FORK_HEAD_3. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma."
      Galili N., Davis R.J., Fredericks W.J., Mukhopadhyay S., Rauscher F.J. III, Emanuel B.S., Rovera G., Barr F.G.
      Nat. Genet. 5:230-235(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH PAX3.
    2. "Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily."
      Anderson M.J., Viars C.S., Czekay S., Cavenee W.K., Arden K.C.
      Genomics 47:187-199(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
      Tissue: Rhabdomyosarcoma.
    3. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
      Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
      Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    4. "The DNA sequence and analysis of human chromosome 13."
      Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.
      , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.
      Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract]
      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].
      Tissue: Lymph and Placenta.
    6. "Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma."
      Davis R.J., D'Cruz C.M., Lovell M.A., Biegel J.A., Barr F.G.
      Cancer Res. 54:2869-2872(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHROMOSOMAL TRANSLOCATION WITH PAX7.
    7. "Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B."
      Rena G., Guo S., Cichy S.C., Unterman T.G., Cohen P.
      J. Biol. Chem. 274:17179-17183(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-24; SER-256 AND SER-319.
    8. "Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence."
      Guo S., Rena G., Cichy S., He X., Cohen P., Unterman T.
      J. Biol. Chem. 274:17184-17192(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: DNA-BINDING, PHOSPHORYLATION AT SER-256, FUNCTION.
    9. "The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site."
      Woods Y.L., Rena G., Morrice N., Barthel A., Becker W., Guo S., Unterman T.G., Cohen P.
      Biochem. J. 355:597-607(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-329, MUTAGENESIS OF SER-329.
    10. "Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting."
      Rena G., Prescott A.R., Guo S., Cohen P., Unterman T.G.
      Biochem. J. 354:605-612(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH YWHAG AND YWHAZ, PHOSPHORYLATION AT THR-24; SER-256 AND SER-319, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-24; SER-256 AND SER-319.
    11. "Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion."
      Rena G., Woods Y.L., Prescott A.R., Peggie M., Unterman T.G., Williams M.R., Cohen P.
      EMBO J. 21:2263-2271(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-24; SER-256; SER-319; SER-322; SER-325 AND SER-329.
    12. "Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding."
      Zhang X., Gan L., Pan H., Guo S., He X., Olson S.T., Mesecar A., Adam S., Unterman T.G.
      J. Biol. Chem. 277:45276-45284(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-24; SER-256 AND SER-319.
    13. "Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity."
      Daitoku H., Hatta M., Matsuzaki H., Aratani S., Ohshima T., Miyagishi M., Nakajima T., Fukamizu A.
      Proc. Natl. Acad. Sci. U.S.A. 101:10042-10047(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CREBBP AND SIRT1, ACETYLATION, DEACETYLATION, FUNCTION.
    14. "The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription."
      Perrot V., Rechler M.M.
      Mol. Endocrinol. 19:2283-2298(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH EP300, ACETYLATION, SUBCELLULAR LOCATION, PHOSPHORYLATION, FUNCTION.
    15. "Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation."
      Huang H., Regan K.M., Wang F., Wang D., Smith D.I., van Deursen J.M., Tindall D.J.
      Proc. Natl. Acad. Sci. U.S.A. 102:1649-1654(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SKP2, UBIQUITINATION, MUTAGENESIS OF SER-256.
    16. "Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt."
      Yamagata K., Daitoku H., Takahashi Y., Namiki K., Hisatake K., Kako K., Mukai H., Kasuya Y., Fukamizu A.
      Mol. Cell 32:221-231(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PRMT1.
    17. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    18. "Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons."
      Yuan Z., Becker E.B.E., Merlo P., Yamada T., DiBacco S., Konishi Y., Schaefer E.M., Bonni A.
      Science 319:1665-1668(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT SER-249 BY CDK1, INTERACTION WITH CDK1 AND 14-3-3 PROTEINS, MUTAGENESIS OF SER-249.
    19. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
      Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
      Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    20. "Regulation of neuronal cell death by MST1-FOXO1 signaling."
      Yuan Z., Lehtinen M.K., Merlo P., Villen J., Gygi S., Bonni A.
      J. Biol. Chem. 284:11285-11292(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-212, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF SER-212.
    21. "Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity."
      Zhao Y., Yang J., Liao W., Liu X., Zhang H., Wang S., Wang D., Feng J., Yu L., Zhu W.G.
      Nat. Cell Biol. 12:665-675(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION AT LYS-262; LYS-265 AND LYS-274, DEACETYLATION BY SIRT2, FUNCTION IN AUTOPHAGY, INTERACTION WITH SIRT2 AND ATG7.
    22. "KRIT1 regulates the homeostasis of intracellular reactive oxygen species."
      Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P., Retta S.F.
      PLoS ONE 5:E11786-E11786(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION.
    23. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    24. "Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner."
      Valis K., Prochazka L., Boura E., Chladova J., Obsil T., Rohlena J., Truksa J., Dong L.F., Ralph S.J., Neuzil J.
      Cancer Res. 71:946-954(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-212.
    25. "System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
      Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
      Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    26. "Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification."
      Brent M.M., Anand R., Marmorstein R.
      Structure 16:1407-1416(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 151-266, DNA-BINDING, PHOSPHORYLATION AT SER-212; SER-218; SER-234 AND SER-235, ACETYLATION, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF SER-249.

    Entry informationi

    Entry nameiFOXO1_HUMAN
    AccessioniPrimary (citable) accession number: Q12778
    Secondary accession number(s): O43523, Q5VYC7, Q6NSK6
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1997
    Last sequence update: October 17, 2006
    Last modified: October 1, 2014
    This is version 155 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny 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, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 13
      Human chromosome 13: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3