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MGP001088

UniProt Annotations

Entry Information
Gene Nameforkhead box O3
Protein EntryFOXO3_HUMAN
UniProt IDO43524
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=O43524-1; Sequence=Displayed; Name=2; IsoId=O43524-2; Sequence=VSP_056225; Note=No experimental confirmation available.;
DiseaseNote=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.
FunctionTranscriptional 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. {ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:21329882}.
InteractionQ08050:FOXM1; NbExp=2; IntAct=EBI-1644164, EBI-866480; P51610:HCFC1; NbExp=2; IntAct=EBI-1644164, EBI-396176; Q96EB6:SIRT1; NbExp=5; IntAct=EBI-1644164, EBI-1802965; Q13485:SMAD4; NbExp=4; IntAct=EBI-1644164, EBI-347263; P04637:TP53; NbExp=2; IntAct=EBI-1644164, EBI-366083;
PtmDeacetylation 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. {ECO:0000250, ECO:0000269|PubMed:21841822}.
PtmHeavyly methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location. {ECO:0000269|PubMed:22820736}.
PtmIn 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. {ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:11154281, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18220336, ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:19690332, ECO:0000269|PubMed:21329882}.
PtmPolyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation. {ECO:0000269|PubMed:21841822}.
SimilarityContains 1 fork-head DNA-binding domain. {ECO:0000255|PROSITE-ProRule:PRU00089}.
Subcellular LocationCytoplasm, cytosol. Nucleus. Note=Translocates to the nucleus upon oxidative stress and in the absence of survival factors.
SubunitInteracts 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. {ECO:0000250, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:17940099, ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:21841822, ECO:0000269|PubMed:22761832}.
Tissue SpecificityUbiquitous. {ECO:0000269|PubMed:9479491}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/AF6q21ID125.html";
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