Reviewed,
UniProtKB/Swiss-Prot O43524 (FOXO3_HUMAN)
Last modified
June 16, 2009.
Version 98.
History...
Clusters with 100%,
90%,
50% identity |
Documents (4) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Forkhead box protein O3 Alternative name(s): Forkhead in rhabdomyosarcoma-like 1 AF6q21 protein | ||||
| Gene names |
| ||||
| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 673 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | 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'. Ref.5 Ref.7 |
| Subunit structure | 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, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation. Ref.7 |
| Subcellular location | Cytoplasm › cytosol. Nucleus. Note: Translocates to the nucleus upon oxidative stress and in the absence of survival factors. Ref.5 Ref.7 |
| Tissue specificity | Ubiquitous. Ref.1 |
| Post-translational modification | 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 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation. Ref.5 Ref.7 Ref.6 Ref.8 Ref.9 |
| Involvement in disease | A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX. |
| Sequence similarities | Contains 1 fork-head DNA-binding domain. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| FOXM1 | Q08050 | 1 | EBI-1644164,EBI-866480 | |
| SIRT3 | Q9NTG7 | 1 | EBI-1644164,EBI-724621 |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | |||||||||||||||||||
Molecule processing | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 673 | 673 | Forkhead box protein O3 | PRO_0000091874 | ||||||||||||||||||||
Regions | ||||||||||||||||||||||||
| DNA binding | 157 – 251 | 95 | Fork-head | |||||||||||||||||||||
| Motif | 242 – 259 | 18 | Nuclear localization signal Ref.11 | |||||||||||||||||||||
Amino acid modifications | ||||||||||||||||||||||||
| Modified residue | 32 | 1 | Phosphothreonine; by PKB/AKT1 Ref.5 | |||||||||||||||||||||
| Modified residue | 209 | 1 | Phosphoserine; by STK4 Ref.7 | |||||||||||||||||||||
| Modified residue | 253 | 1 | Phosphoserine; by PKB/AKT1 Ref.5 | |||||||||||||||||||||
| Modified residue | 280 | 1 | Phosphoserine Ref.9 | |||||||||||||||||||||
| Modified residue | 284 | 1 | Phosphoserine Ref.9 | |||||||||||||||||||||
| Modified residue | 315 | 1 | Phosphoserine; by SGK Ref.5 Ref.6 | |||||||||||||||||||||
| Modified residue | 421 | 1 | Phosphoserine Ref.8 | |||||||||||||||||||||
| Modified residue | 427 | 1 | Phosphothreonine Ref.8 | |||||||||||||||||||||
Experimental info | ||||||||||||||||||||||||
| Mutagenesis | 32 | 1 | 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. Ref.5 | |||||||||||||||||||||
| Mutagenesis | 209 | 1 | S → A: Impairs nuclear translocation upon oxidative stress. Ref.7 | |||||||||||||||||||||
| Mutagenesis | 242 | 1 | K → A: Slightly decreases DNA affinity. Ref.11 | |||||||||||||||||||||
| Mutagenesis | 245 | 1 | K → A: Decreases DNA affinity. Ref.11 | |||||||||||||||||||||
| Mutagenesis | 253 | 1 | 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. Ref.5 | |||||||||||||||||||||
| Mutagenesis | 315 | 1 | 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. Ref.5 | |||||||||||||||||||||
| Sequence conflict | 156 – 163 | 8 | AWGNLSYA → WGKPVYS in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 238 – 246 | 9 | PDGGKSGKA → LMGEERKT in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 253 | 1 | S → T in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 271 | 1 | Missing in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 292 – 330 | 39 | PGSPT…PIMAS → AWQPHVNAAVMSWMRGRTSV HAPILTPAQSVAACRPSWQV in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 345 – 361 | 17 | PMLYS…SVSKP → AHALQHVSQPVTFSKQA in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 367 | 1 | P → R in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 371 | 1 | D → E in CAA04860. Ref.4 | |||||||||||||||||||||
| Sequence conflict | 382 – 383 | 2 | LT → AD in CAA04860. Ref.4 | |||||||||||||||||||||
Secondary structure | ||||||||||||||||||||||||
Helix Strand Turn | ||||||||||||||||||||||||
| Helix | 162 – 169 | 8 | ||||||||||||||||||||||
| Beta strand | 172 – 176 | 5 | ||||||||||||||||||||||
| Helix | 180 – 189 | 10 | ||||||||||||||||||||||
| Beta strand | 198 – 200 | 3 | ||||||||||||||||||||||
| Helix | 206 – 216 | 11 | ||||||||||||||||||||||
| Beta strand | 217 – 223 | 7 | ||||||||||||||||||||||
| Beta strand | 226 – 229 | 4 | ||||||||||||||||||||||
| Beta strand | 233 – 236 | 4 | ||||||||||||||||||||||
Sequences
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References
| « Hide 'large scale' references | |
| [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: 9479491] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Rhabdomyosarcoma. |
| [2] | "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. Beck S.Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. |
| [3] | "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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Muscle and Placenta. |
| [4] | "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: 9345057] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-383, INVOLVEMENT IN SECONDARY ACUTE LEUKEMIAS. |
| [5] | "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: 10102273] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-32; SER-253 AND SER-315, MUTAGENESIS OF THR-32; SER-253 AND SER-315. |
| [6] | "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: 11154281] [Abstract] Cited for: PHOSPHORYLATION AT SER-315. |
| [7] | "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: 16751106] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-209, INTERACTION WITH STK4 AND YWHAB, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-209. |
| [8] | "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: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421 AND THR-427, MASS SPECTROMETRY. |
| [9] | "A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-280 AND SER-284, MASS SPECTROMETRY. |
| [10] | Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY. |
| [11] | "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: 17940099] [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. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AF032886 mRNA. Translation: AAC39592.1. AL391646, AL365509 Genomic DNA. Translation: CAI16405.1. AL365509, AL391646 Genomic DNA. Translation: CAI16295.1. 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. | |||||||||||||||||||
| IPI | IPI00012856. | ||||||||||||||||||
| RefSeq | NP_001446.1. NP_963853.1. | ||||||||||||||||||
| UniGene | Hs.220950 | ||||||||||||||||||
3D structure databases | |||||||||||||||||||
| |||||||||||||||||||
| SMR | O43524. Positions 152-241. | ||||||||||||||||||
| ModBase | Search... | ||||||||||||||||||
Protein-protein interaction databases | |||||||||||||||||||
| IntAct | O43524. 10 interactions. | ||||||||||||||||||
PTM databases | |||||||||||||||||||
| PhosphoSite | O43524. | ||||||||||||||||||
Proteomic databases | |||||||||||||||||||
| PRIDE | O43524. | ||||||||||||||||||
Genome annotation databases | |||||||||||||||||||
| Ensembl | ENSG00000118689. Homo sapiens. [Contig view] | ||||||||||||||||||
| GeneID | 2309. | ||||||||||||||||||
| KEGG | hsa:2309. | ||||||||||||||||||
Organism-specific databases | |||||||||||||||||||
| GeneCards | GC06P108988. | ||||||||||||||||||
| H-InvDB | HIX0006119. | ||||||||||||||||||
| HGNC | HGNC:3821. FOXO3. | ||||||||||||||||||
| HPA | CAB004074. | ||||||||||||||||||
| MIM | 602681. gene. | ||||||||||||||||||
| PharmGKB | PA28239. | ||||||||||||||||||
| GenAtlas | Search... | ||||||||||||||||||
Phylogenomic databases | |||||||||||||||||||
| HOGENOM | O43524. | ||||||||||||||||||
| HOVERGEN | O43524. | ||||||||||||||||||
| OMA | O43524. RSDPMMS. | ||||||||||||||||||
Enzyme and pathway databases | |||||||||||||||||||
| Pathway_Interaction_DB | pi3kcipathway. Class I PI3K signaling events. pi3kciaktpathway. Class I PI3K signaling events mediated by Akt. foxopathway. FoxO family signaling. il2_pi3kpathway. IL2 signaling events mediated by PI3K. insulin_pathway. Insulin Pathway. smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling. hdac_classiii_pathway. Signaling events mediated by HDAC Class III. kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit). pi3kplctrkpathway. Trk receptor signaling mediated by PI3K and PLC-gamma. | ||||||||||||||||||
| Reactome | REACT_11061. Signalling by NGF. | ||||||||||||||||||
Gene expression databases | |||||||||||||||||||
| ArrayExpress | O43524. | ||||||||||||||||||
| Bgee | O43524. | ||||||||||||||||||
| CleanEx | HS_FOXO3. | ||||||||||||||||||
| GermOnline | ENSG00000118689. Homo sapiens. | ||||||||||||||||||
Family and domain databases | |||||||||||||||||||
| InterPro | IPR001766. TF_fork_head. IPR018122. TF_fork_head_CS. IPR011991. Wing_hlx_DNA_bd. [Graphical view] | ||||||||||||||||||
| Gene3D | G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 1 hit. | ||||||||||||||||||
| PANTHER | PTHR11829. Fork_box_protein. 1 hit. | ||||||||||||||||||
| Pfam | PF00250. Fork_head. 1 hit. [Graphical view] | ||||||||||||||||||
| PRINTS | PR00053. FORKHEAD. | ||||||||||||||||||
| ProDom | PD000425. TF_Fork_head. 1 hit. [Graphical view] [Entries sharing at least one domain] | ||||||||||||||||||
| SMART | SM00339. FH. 1 hit. [Graphical view] | ||||||||||||||||||
| PROSITE | PS00657. FORK_HEAD_1. False negative. PS00658. FORK_HEAD_2. 1 hit. PS50039. FORK_HEAD_3. 1 hit. [Graphical view] | ||||||||||||||||||
| ProtoNet | Search... | ||||||||||||||||||
Other Resources | |||||||||||||||||||
| NextBio | 9379. | ||||||||||||||||||
| SOURCE | Search... | ||||||||||||||||||
Entry information
| Entry name | FOXO3_HUMAN | ||||||||
| Accession | Primary (citable) accession number: O43524 Secondary accession number(s): O15171, Q5T2I7, Q9BZ04 | ||||||||
| Entry history |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
Relevant documents
| Human chromosome 6 Human chromosome 6: entries, gene names and cross-references to MIM |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PDB cross-references Index of Protein Data Bank (PDB) cross-references |
| SIMILARITY comments Index of protein domains and families |

Clusters with


