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O43524

- FOXO3_HUMAN

UniProt

O43524 - FOXO3_HUMAN

Protein

Forkhead box protein O3

Gene

FOXO3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 158 (01 Oct 2014)
      Sequence version 1 (01 Jun 1998)
      Previous versions | rss
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    Functioni

    Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.3 Publications

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    DNA bindingi157 – 25195Fork-headPROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. chromatin DNA binding Source: UniProtKB
    2. core promoter binding Source: UniProtKB
    3. DNA binding Source: UniProtKB
    4. protein binding Source: UniProtKB
    5. protein kinase binding Source: UniProtKB
    6. sequence-specific DNA binding Source: UniProtKB
    7. sequence-specific DNA binding transcription factor activity Source: MGI

    GO - Biological processi

    1. antral ovarian follicle growth Source: Ensembl
    2. cellular response to oxidative stress Source: UniProtKB
    3. DNA damage response, signal transduction by p53 class mediator Source: Ensembl
    4. epidermal growth factor receptor signaling pathway Source: Reactome
    5. extrinsic apoptotic signaling pathway in absence of ligand Source: Ensembl
    6. Fc-epsilon receptor signaling pathway Source: Reactome
    7. fibroblast growth factor receptor signaling pathway Source: Reactome
    8. glucose homeostasis Source: Ensembl
    9. initiation of primordial ovarian follicle growth Source: Ensembl
    10. innate immune response Source: Reactome
    11. negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    12. neurotrophin TRK receptor signaling pathway Source: Reactome
    13. oocyte maturation Source: Ensembl
    14. ovulation from ovarian follicle Source: Ensembl
    15. phosphatidylinositol-mediated signaling Source: Reactome
    16. positive regulation of erythrocyte differentiation Source: MGI
    17. positive regulation of neuron apoptotic process Source: UniProtKB
    18. positive regulation of transcription, DNA-templated Source: UniProtKB
    19. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    20. regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    21. regulation of translation Source: UniProtKB
    22. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Apoptosis, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_111057. Signaling by NODAL.
    REACT_12442. AKT phosphorylates targets in the nucleus.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    SignaLinkiO43524.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Forkhead box protein O3
    Alternative name(s):
    AF6q21 protein
    Forkhead in rhabdomyosarcoma-like 1
    Gene namesi
    Name:FOXO3
    Synonyms:FKHRL1, FOXO3A
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:3821. FOXO3.

    Subcellular locationi

    Cytoplasmcytosol. Nucleus
    Note: Translocates to the nucleus upon oxidative stress and in the absence of survival factors.

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. cytosol Source: UniProtKB-SubCell
    3. membrane Source: Ensembl
    4. nucleoplasm Source: Reactome
    5. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, 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 keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi32 – 321T → 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
    Mutagenesisi179 – 1791T → 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
    Mutagenesisi209 – 2091S → A: Impairs nuclear translocation upon oxidative stress. 1 Publication
    Mutagenesisi242 – 2421K → A: Slightly decreases DNA affinity. 2 Publications
    Mutagenesisi242 – 2421K → 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
    Mutagenesisi245 – 2451K → A: Decreases DNA affinity. 1 Publication
    Mutagenesisi253 – 2531S → 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
    Mutagenesisi259 – 2591K → 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
    Mutagenesisi269 – 2691K → R: Methylation levels similar to wild-type; when associated with ARG-270. 1 Publication
    Mutagenesisi270 – 2701K → R: Methylation levels similar to wild-type; when associated with ARG-269. 1 Publication
    Mutagenesisi271 – 2711K → R: Methylation levels strongly reduced. 1 Publication
    Mutagenesisi290 – 2901K → 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
    Mutagenesisi315 – 3151S → 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
    Mutagenesisi399 – 3991S → 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
    Mutagenesisi413 – 4131S → 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
    Mutagenesisi555 – 5551S → 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
    Mutagenesisi569 – 5691K → 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
    Mutagenesisi588 – 5881S → 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
    Mutagenesisi626 – 6261S → 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

    Keywords - Diseasei

    Proto-oncogene

    Organism-specific databases

    PharmGKBiPA28239.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 673673Forkhead box protein O3PRO_0000091874Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei32 – 321Phosphothreonine; by PKB/AKT12 Publications
    Modified residuei46 – 461N6-methyllysine1 Publication
    Modified residuei149 – 1491N6-methyllysine1 Publication
    Modified residuei179 – 1791Phosphothreonine; by AMPK2 Publications
    Modified residuei209 – 2091Phosphoserine; by STK4/MST12 Publications
    Modified residuei215 – 2151Phosphoserine; by MAPKAPK52 Publications
    Modified residuei230 – 2301N6-methyllysine1 Publication
    Modified residuei242 – 2421N6-acetyllysineBy similarity
    Modified residuei253 – 2531Phosphoserine; by PKB/AKT1 and MAPKAPK53 Publications
    Modified residuei262 – 2621N6-methyllysine1 Publication
    Modified residuei271 – 2711N6-methyllysine1 Publication
    Modified residuei280 – 2801Phosphoserine3 Publications
    Modified residuei284 – 2841Phosphoserine2 Publications
    Modified residuei290 – 2901N6-methyllysine1 Publication
    Modified residuei315 – 3151Phosphoserine; by SGK13 Publications
    Modified residuei399 – 3991Phosphoserine; by AMPK2 Publications
    Modified residuei413 – 4131Phosphoserine; by AMPK2 Publications
    Modified residuei419 – 4191N6-methyllysine1 Publication
    Modified residuei421 – 4211Phosphoserine2 Publications
    Modified residuei551 – 5511Phosphoserine; by MAPKAPK52 Publications
    Modified residuei555 – 5551Phosphoserine; by AMPK and MAPKAPK53 Publications
    Modified residuei588 – 5881Phosphoserine; by AMPK2 Publications
    Modified residuei626 – 6261Phosphoserine; by AMPK2 Publications

    Post-translational modificationi

    In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB. This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm. Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis. Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue. Phosphorylated by STK4/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation. Phosphorylated by PIM1. Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization. Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.9 Publications
    Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress By similarity. Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation.By similarity1 Publication
    Heavyly 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

    MaxQBiO43524.
    PaxDbiO43524.
    PRIDEiO43524.

    PTM databases

    PhosphoSiteiO43524.

    Expressioni

    Tissue specificityi

    Ubiquitous.1 Publication

    Gene expression databases

    ArrayExpressiO43524.
    BgeeiO43524.
    CleanExiHS_FOXO3.
    GenevestigatoriO43524.

    Organism-specific databases

    HPAiCAB004074.

    Interactioni

    Subunit structurei

    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. Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation. Interacts with PIM1. Interacts with DDIT3/CHOP. Interacts (deacetylated form) with SKP2.By similarity5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    FOXM1Q080502EBI-1644164,EBI-866480
    HCFC1P516102EBI-1644164,EBI-396176
    SIRT1Q96EB65EBI-1644164,EBI-1802965
    SMAD4Q134854EBI-1644164,EBI-347263
    TP53P046372EBI-1644164,EBI-366083

    Protein-protein interaction databases

    BioGridi108598. 42 interactions.
    DIPiDIP-29723N.
    IntActiO43524. 24 interactions.
    MINTiMINT-89098.
    STRINGi9606.ENSP00000339527.

    Structurei

    Secondary structure

    1
    673
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Turni156 – 1583
    Helixi162 – 1698
    Beta strandi172 – 1765
    Helixi180 – 18910
    Beta strandi198 – 2003
    Helixi206 – 21611
    Beta strandi217 – 22913
    Beta strandi233 – 2364
    Beta strandi238 – 2403
    Beta strandi463 – 4653
    Helixi468 – 47710
    Turni478 – 4803
    Helixi621 – 6233
    Helixi624 – 63310

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2K86NMR-A151-251[»]
    2LQHNMR-B461-635[»]
    2LQINMR-B461-635[»]
    2UZKX-ray2.70A/C158-253[»]
    ProteinModelPortaliO43524.
    SMRiO43524. Positions 158-253.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO43524.

    Family & Domainsi

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi242 – 25918Nuclear localization signal1 PublicationAdd
    BLAST

    Sequence similaritiesi

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

    Phylogenomic databases

    eggNOGiCOG5025.
    HOGENOMiHOG000251635.
    HOVERGENiHBG057789.
    InParanoidiO43524.
    KOiK09408.
    OMAiNLPVMGH.
    OrthoDBiEOG7R2BJD.
    PhylomeDBiO43524.
    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]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: O43524-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' 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

    MAEAPASPAP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE    50
    TAADSMIPEE EDDEDDEDGG GRAGSAMAIG GGGGSGTLGS GLLLEDSARV 100
    LAPGGQDPGS GPATAAGGLS GGTQALLQPQ QPLPPPQPGA AGGSGQPRKC 150
    SSRRNAWGNL SYADLITRAI ESSPDKRLTL SQIYEWMVRC VPYFKDKGDS 200
    NSSAGWKNSI RHNLSLHSRF MRVQNEGTGK SSWWIINPDG GKSGKAPRRR 250
    AVSMDNSNKY TKSRGRAAKK KAALQTAPES ADDSPSQLSK WPGSPTSRSS 300
    DELDAWTDFR SRTNSNASTV SGRLSPIMAS TELDEVQDDD APLSPMLYSS 350
    SASLSPSVSK PCTVELPRLT DMAGTMNLND GLTENLMDDL LDNITLPPSQ 400
    PSPTGGLMQR SSSFPYTTKG SGLGSPTSSF NSTVFGPSSL NSLRQSPMQT 450
    IQENKPATFS SMSHYGNQTL QDLLTSDSLS HSDVMMTQSD PLMSQASTAV 500
    SAQNSRRNVM LRNDPMMSFA AQPNQGSLVN QNLLHHQHQT QGALGGSRAL 550
    SNSVSNMGLS ESSSLGSAKH QQQSPVSQSM QTLSDSLSGS SLYSTSANLP 600
    VMGHEKFPSD LDLDMFNGSL ECDMESIIRS ELMDADGLDF NFDSLISTQN 650
    VVGLNVGNFT GAKQASSQSW VPG 673
    Length:673
    Mass (Da):71,277
    Last modified:June 1, 1998 - v1
    Checksum:iE5B4E830665A9982
    GO
    Isoform 2 (identifier: O43524-2) [UniParc]FASTAAdd to Basket

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

    Note: No experimental confirmation available.

    Show »
    Length:453
    Mass (Da):48,406
    Checksum:iE093364532E78AE1
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti156 – 1638AWGNLSYA → WGKPVYS in CAA04860. (PubMed:9345057)Curated
    Sequence conflicti238 – 2469PDGGKSGKA → LMGEERKT in CAA04860. (PubMed:9345057)Curated
    Sequence conflicti253 – 2531S → T in CAA04860. (PubMed:9345057)Curated
    Sequence conflicti271 – 2711Missing in CAA04860. (PubMed:9345057)Curated
    Sequence conflicti292 – 33039PGSPT…PIMAS → AWQPHVNAAVMSWMRGRTSV HAPILTPAQSVAACRPSWQV in CAA04860. (PubMed:9345057)CuratedAdd
    BLAST
    Sequence conflicti345 – 36117PMLYS…SVSKP → AHALQHVSQPVTFSKQA in CAA04860. (PubMed:9345057)CuratedAdd
    BLAST
    Sequence conflicti367 – 3671P → R in CAA04860. (PubMed:9345057)Curated
    Sequence conflicti371 – 3711D → E in CAA04860. (PubMed:9345057)Curated
    Sequence conflicti382 – 3832LT → AD in CAA04860. (PubMed:9345057)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 220220Missing in isoform 2. 1 PublicationVSP_056225Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF032886 mRNA. Translation: AAC39592.1.
    AK301304 mRNA. Translation: BAG62858.1.
    AL096818 Genomic DNA. No translation available.
    AL391646, AL365509 Genomic DNA. Translation: CAI16405.1.
    AL365509, AL391646 Genomic DNA. Translation: CAI16295.1.
    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.
    CCDSiCCDS5068.1.
    RefSeqiNP_001446.1. NM_001455.3.
    NP_963853.1. NM_201559.2.
    XP_005266925.1. XM_005266868.1.
    UniGeneiHs.220950.

    Genome annotation databases

    EnsembliENST00000343882; ENSP00000339527; ENSG00000118689.
    ENST00000406360; ENSP00000385824; ENSG00000118689.
    ENST00000540898; ENSP00000446316; ENSG00000118689.
    GeneIDi2309.
    KEGGihsa:2309.
    UCSCiuc003psk.2. human.

    Keywords - Coding sequence diversityi

    Alternative splicing, 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
    AF032886 mRNA. Translation: AAC39592.1 .
    AK301304 mRNA. Translation: BAG62858.1 .
    AL096818 Genomic DNA. No translation available.
    AL391646 , AL365509 Genomic DNA. Translation: CAI16405.1 .
    AL365509 , AL391646 Genomic DNA. Translation: CAI16295.1 .
    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.
    RefSeqi NP_001446.1. NM_001455.3.
    NP_963853.1. NM_201559.2.
    XP_005266925.1. XM_005266868.1.
    UniGenei Hs.220950.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2K86 NMR - A 151-251 [» ]
    2LQH NMR - B 461-635 [» ]
    2LQI NMR - B 461-635 [» ]
    2UZK X-ray 2.70 A/C 158-253 [» ]
    ProteinModelPortali O43524.
    SMRi O43524. Positions 158-253.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 108598. 42 interactions.
    DIPi DIP-29723N.
    IntActi O43524. 24 interactions.
    MINTi MINT-89098.
    STRINGi 9606.ENSP00000339527.

    Chemistry

    ChEMBLi CHEMBL5778.

    PTM databases

    PhosphoSitei O43524.

    Proteomic databases

    MaxQBi O43524.
    PaxDbi O43524.
    PRIDEi O43524.

    Protocols and materials databases

    DNASUi 2309.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000343882 ; ENSP00000339527 ; ENSG00000118689 .
    ENST00000406360 ; ENSP00000385824 ; ENSG00000118689 .
    ENST00000540898 ; ENSP00000446316 ; ENSG00000118689 .
    GeneIDi 2309.
    KEGGi hsa:2309.
    UCSCi uc003psk.2. human.

    Organism-specific databases

    CTDi 2309.
    GeneCardsi GC06P108881.
    HGNCi HGNC:3821. FOXO3.
    HPAi CAB004074.
    MIMi 602681. gene.
    neXtProti NX_O43524.
    PharmGKBi PA28239.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5025.
    HOGENOMi HOG000251635.
    HOVERGENi HBG057789.
    InParanoidi O43524.
    KOi K09408.
    OMAi NLPVMGH.
    OrthoDBi EOG7R2BJD.
    PhylomeDBi O43524.
    TreeFami TF315583.

    Enzyme and pathway databases

    Reactomei REACT_111057. Signaling by NODAL.
    REACT_12442. AKT phosphorylates targets in the nucleus.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    SignaLinki O43524.

    Miscellaneous databases

    ChiTaRSi FOXO3. human.
    EvolutionaryTracei O43524.
    GeneWikii FOXO3.
    GenomeRNAii 2309.
    NextBioi 9379.
    PROi O43524.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O43524.
    Bgeei O43524.
    CleanExi HS_FOXO3.
    Genevestigatori O43524.

    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. "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] (ISOFORM 1), TISSUE SPECIFICITY.
      Tissue: Rhabdomyosarcoma.
    2. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
      Tissue: Stomach.
    3. "The DNA sequence and analysis of human chromosome 6."
      Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D.
      , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
      Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    4. 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] (ISOFORM 1).
      Tissue: Muscle and Placenta.
    6. "AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily."
      Hillion J., Le Coniat M., Jonveaux P., Berger R., Bernard O.A.
      Blood 90:3714-3719(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-383 (ISOFORM 1), INVOLVEMENT IN SECONDARY ACUTE LEUKEMIAS.
    7. "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor."
      Brunet A., Bonni A., Zigmond M.J., Lin M.Z., Juo P., Hu L.S., Anderson M.J., Arden K.C., Blenis J., Greenberg M.E.
      Cell 96:857-868(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-32; SER-253 AND SER-315, MUTAGENESIS OF THR-32; SER-253 AND SER-315.
    8. "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)."
      Brunet A., Park J., Tran H., Hu L.S., Hemmings B.A., Greenberg M.E.
      Mol. Cell. Biol. 21:952-965(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-315.
    9. "A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span."
      Lehtinen M.K., Yuan Z., Boag P.R., Yang Y., Villen J., Becker E.B.E., DiBacco S., de la Iglesia N., Gygi S.P., Blackwell T.K., Bonni A.
      Cell 125:987-1001(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT SER-209, INTERACTION WITH STK4/MST1 AND YWHAB, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-209.
    10. "The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor."
      Greer E.L., Oskoui P.R., Banko M.R., Maniar J.M., Gygi M.P., Gygi S.P., Brunet A.
      J. Biol. Chem. 282:30107-30119(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-179; SER-399; SER-413; SER-555; SER-588 AND SER-626, MUTAGENESIS OF THR-179; SER-399; SER-413; SER-555; SER-588 AND SER-626, SUBCELLULAR LOCATION.
    11. "Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels."
      Morishita D., Katayama R., Sekimizu K., Tsuruo T., Fujita N.
      Cancer Res. 68:5076-5085(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PIM1, PHOSPHORYLATION.
    12. "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
      Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
      J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    13. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-280 AND SER-284, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    14. "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].
    15. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-280, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    16. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    17. "The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis."
      Kress T.R., Cannell I.G., Brenkman A.B., Samans B., Gaestel M., Roepman P., Burgering B.M., Bushell M., Rosenwald A., Eilers M.
      Mol. Cell 41:445-457(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, DNA-BINDING, PHOSPHORYLATION AT SER-215; SER-253; SER-551 AND SER-555.
    18. "Methylation by Set9 modulates FoxO3 stability and transcriptional activity."
      Calnan D.R., Webb A.E., White J.L., Stowe T.R., Goswami T., Shi X., Espejo A., Bedford M.T., Gozani O., Gygi S.P., Brunet A.
      Aging (Albany NY) 4:462-479(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: METHYLATION AT LYS-46; LYS-149; LYS-230; LYS-262; LYS-271; LYS-290 AND LYS-419, MUTAGENESIS OF LYS-269; LYS-270 AND LYS-271.
    19. "Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation."
      Wang F., Chan C.H., Chen K., Guan X., Lin H.K., Tong Q.
      Oncogene 31:1546-1557(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION, DEACETYLATION BY SIRT2, INTERACTION WITH SKP2, UBIQUITINATION BY SKP2, MUTAGENESIS OF LYS-242; LYS-259; LYS-290 AND LYS-569.
    20. "CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress."
      Ghosh A.P., Klocke B.J., Ballestas M.E., Roth K.A.
      PLoS ONE 7:E39586-E39586(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH DDIT3, SUBCELLULAR LOCATION.
    21. "Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification."
      Tsai K.-L., Sun Y.-J., Huang C.-Y., Yang J.-Y., Hung M.-C., Hsiao C.-D.
      Nucleic Acids Res. 35:6984-6994(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 158-253 IN COMPLEX WITH DNA, MUTAGENESIS OF LYS-242 AND LYS-245, NUCLEAR LOCALIZATION SIGNAL.

    Entry informationi

    Entry nameiFOXO3_HUMAN
    AccessioniPrimary (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: October 1, 2014
    This is version 158 of the entry and version 1 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 6
      Human chromosome 6: 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