Protein: Forkhead box protein O3 (Q9WVH4)
Organism: Mus musculus (Mouse)
Function: Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy. Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins. Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (By similarity). 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 (By similarity). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation. Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (By similarity).
Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:18054315, ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:32103177}. Nucleus {ECO:0000269|PubMed:18054315, ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:32103177}. Mitochondrion matrix {ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193}. Mitochondrion outer membrane {ECO:0000269|PubMed:29445193}; Peripheral membrane protein {ECO:0000269|PubMed:29445193}; Cytoplasmic side {ECO:0000269|PubMed:29445193}. Note=Retention in the cytoplasm contributes to its inactivation (By similarity). Translocates to the nucleus upon oxidative stress and in the absence of survival factors (By similarity). Translocates from the cytosol to the nucleus following dephosphorylation in response to autophagy-inducing stimuli (PubMed:18054315). Translocates in a AMPK-dependent manner into the mitochondrion in response to metabolic stress (PubMed:23283301, PubMed:29445193). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (PubMed:32103177). {ECO:0000250|UniProtKB:O43524, ECO:0000269|PubMed:18054315, ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193, ECO:0000269|PubMed:32103177}.
Sequence: MAEAPASPVPLSPLEVELDPEFEPQSRPRSCTWPLQRPELQASPAKPSGETAADSMIPEEDDDEDDEDGGGRASSAMVIGGGVSSTLGSGLLLEDSAMLLAPGGQDLGSGPASAAGALSGGTPTQLQPQQPLPQPQPGAAGGSGQPRKCSSRRNAWGNLSYADLITRAIESSPDKRLTLSQIYEWMVRCVPYFKDKGDSNSSAGWKNSIRHNLSLHSRFMRVQNEGTGKSSWWIINPDGGKSGKAPRRRAVSMDNSNKYTKSRGRAAKKKAALQAAPESADDSPSQLSKWPGSPTSRSSDELDAWTDFRSRTNSNASTVSGRLSPILASTELDDVQDDDGPLSPMLYSSSASLSPSVSKPCTVELPRLTDMAGTMNLNDGLAENLMDDLLDNIALPPSQPSPPGGLMQRGSSFPYTAKSSGLGSPTGSFNSTVFGPSSLNSLRQSPMQTIQENRPATFSSVSHYGNQTLQDLLASDSLSHSDVMMTQSDPLMSQASTAVSAQNARRNVMLRNDPMMSFAAQPTQGSLVNQNLLHHQHQTQGALGGSRALSNSVSNMGLSDSSSLGSAKHQQQSPASQSMQTLSDSLSGSSLYSASANLPVMGHDKFPSDLDLDMFNGSLECDMESIIRSELMDADGLDFNFDSLISTQNVVGLNVGNFTGAKQASSQSWVPG
InterPro domains: - IPR036388: Winged helix-like DNA-binding domain superfamily (homologous_superfamily) [152-242]
- IPR036390: Winged helix DNA-binding domain superfamily (homologous_superfamily) [152-238]
- IPR032068: FOXO protein, KIX-binding domain (domain) [432-510]
- IPR030456: Fork head domain conserved site 2 (conserved_site) [205-211]
- IPR001766: Fork head domain (domain) [154-250]
- IPR032067: FOXO protein, transactivation domain (domain) [603-643]
Interaction partners: - Cyclin-dependent kinase 2
- Catenin beta-1
- NAD-dependent protein deacetylase sirtuin-1
- Hypoxia-inducible factor 1-alpha
- RAC-alpha serine/threonine-protein kinase
- Cyclin-dependent kinase inhibitor 1
- Transcription factor E2F1
- Mothers against decapentaplegic homolog 2
- E3 ubiquitin-protein ligase Mdm2
- Focal adhesion kinase 1
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0140110 (transcription regulator activity), GO:1901363 (heterocyclic compound binding), GO:0003700 (DNA-binding transcription factor activity), GO:0003682 (chromatin binding), GO:0097159 (organic cyclic compound binding), GO:0005515 (protein binding), GO:0008134 (transcription factor binding), GO:0003676 (nucleic acid binding), GO:0001216 (DNA-binding transcription activator activity), GO:0001217 (DNA-binding transcription repressor activity), GO:1990841 (promoter-specific chromatin binding), GO:0031490 (chromatin DNA binding), GO:0019899 (enzyme binding), GO:0000981 (DNA-binding transcription factor activity, RNA polymerase II-specific), GO:0001227 (DNA-binding transcription repressor activity, RNA polymerase II-specific), GO:0001228 (DNA-binding transcription activator activity, RNA polymerase II-specific), GO:0001067 (transcription regulatory region nucleic acid binding), GO:0003677 (DNA binding), GO:0019902 (phosphatase binding), GO:0003690 (double-stranded DNA binding), GO:0043565 (sequence-specific DNA binding), GO:0000976 (transcription cis-regulatory region binding), GO:0019903 (protein phosphatase binding), GO:1990837 (sequence-specific double-stranded DNA binding), GO:0000987 (cis-regulatory region sequence-specific DNA binding), GO:0051721 (protein phosphatase 2A binding), GO:0000977 (RNA polymerase II transcription regulatory region sequence-specific DNA binding), GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0000003 (reproduction), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0042592 (homeostatic process), GO:0022414 (reproductive process), GO:0048519 (negative regulation of biological process), GO:0019953 (sexual reproduction), GO:0048856 (anatomical structure development), GO:0023057 (negative regulation of signaling), GO:0042221 (response to chemical), GO:0032504 (multicellular organism reproduction), GO:0003006 (developmental process involved in reproduction), GO:0009892 (negative regulation of metabolic process), GO:0050793 (regulation of developmental process), GO:0009719 (response to endogenous stimulus), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0051093 (negative regulation of developmental process), GO:0048523 (negative regulation of cellular process), GO:0007165 (signal transduction), GO:0007275 (multicellular organism development), GO:0019222 (regulation of metabolic process), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0048878 (chemical homeostasis), GO:0044237 (cellular metabolic process), GO:0009893 (positive regulation of metabolic process), GO:0006950 (response to stress), GO:0048609 (multicellular organismal reproductive process), GO:0048585 (negative regulation of response to stimulus), GO:0007154 (cell communication), GO:0048522 (positive regulation of cellular process), GO:0009968 (negative regulation of signal transduction), GO:0060548 (negative regulation of cell death), GO:0080134 (regulation of response to stress), GO:0044248 (cellular catabolic process), GO:0048731 (system development), GO:0048513 (animal organ development), GO:0009966 (regulation of signal transduction), GO:0071495 (cellular response to endogenous stimulus), GO:0060255 (regulation of macromolecule metabolic process), GO:0048608 (reproductive structure development), GO:0045137 (development of primary sexual characteristics), GO:0009725 (response to hormone), GO:0006793 (phosphorus metabolic process), GO:0009894 (regulation of catabolic process), GO:0030968 (endoplasmic reticulum unfolded protein response), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0045595 (regulation of cell differentiation), GO:0007166 (cell surface receptor signaling pathway), GO:0007548 (sex differentiation), GO:1901575 (organic substance catabolic process), GO:0008284 (positive regulation of cell population proliferation), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0007276 (gamete generation), GO:0010648 (negative regulation of cell communication), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0006979 (response to oxidative stress), GO:1901700 (response to oxygen-containing compound), GO:0031324 (negative regulation of cellular metabolic process), GO:0010033 (response to organic substance), GO:0009891 (positive regulation of biosynthetic process), GO:0007283 (spermatogenesis), GO:0062013 (positive regulation of small molecule metabolic process), GO:0010941 (regulation of cell death), GO:0009888 (tissue development), GO:0010646 (regulation of cell communication), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0033554 (cellular response to stress), GO:0045596 (negative regulation of cell differentiation), GO:0009889 (regulation of biosynthetic process), GO:0062012 (regulation of small molecule metabolic process), GO:0031323 (regulation of cellular metabolic process), GO:0009890 (negative regulation of biosynthetic process), GO:0080090 (regulation of primary metabolic process), GO:0009896 (positive regulation of catabolic process), GO:0034599 (cellular response to oxidative stress), GO:0045598 (regulation of fat cell differentiation), GO:0031347 (regulation of defense response), GO:0009059 (macromolecule biosynthetic process), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0043069 (negative regulation of programmed cell death), GO:0043067 (regulation of programmed cell death), GO:0008406 (gonad development), GO:0010468 (regulation of gene expression), GO:0006140 (regulation of nucleotide metabolic process), GO:0007399 (nervous system development), GO:1903201 (regulation of oxidative stress-induced cell death), GO:0010508 (positive regulation of autophagy), GO:0002064 (epithelial cell development), GO:0090207 (regulation of triglyceride metabolic process), GO:1902882 (regulation of response to oxidative stress), GO:0031327 (negative regulation of cellular biosynthetic process), GO:0051252 (regulation of RNA metabolic process), GO:0045599 (negative regulation of fat cell differentiation), GO:0048232 (male gamete generation), GO:1901701 (cellular response to oxygen-containing compound), GO:0045934 (negative regulation of nucleobase-containing compound metabolic process), GO:0061458 (reproductive system development), GO:1901215 (negative regulation of neuron death), GO:0007167 (enzyme-linked receptor protein signaling pathway), GO:2000377 (regulation of reactive oxygen species metabolic process), GO:0071310 (cellular response to organic substance), GO:0062197 (cellular response to chemical stress), GO:0010906 (regulation of glucose metabolic process), GO:1901214 (regulation of neuron death), GO:0010628 (positive regulation of gene expression), GO:2001234 (negative regulation of apoptotic signaling pathway), GO:0006796 (phosphate-containing compound metabolic process), GO:1902532 (negative regulation of intracellular signal transduction), GO:2001233 (regulation of apoptotic signaling pathway), GO:2000737 (negative regulation of stem cell differentiation), GO:2000736 (regulation of stem cell differentiation), GO:0030855 (epithelial cell differentiation), GO:0046890 (regulation of lipid biosynthetic process), GO:0010557 (positive regulation of macromolecule biosynthetic process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0043467 (regulation of generation of precursor metabolites and energy), GO:0051254 (positive regulation of RNA metabolic process), GO:0032870 (cellular response to hormone stimulus), GO:0010907 (positive regulation of glucose metabolic process), GO:0010243 (response to organonitrogen compound), GO:0031326 (regulation of cellular biosynthetic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0010558 (negative regulation of macromolecule biosynthetic process), GO:0031331 (positive regulation of cellular catabolic process), GO:0060429 (epithelium development), GO:0031329 (regulation of cellular catabolic process), GO:0048232 (male gamete generation), GO:0051253 (negative regulation of RNA metabolic process), GO:0048232 (male gamete generation), GO:0051253 (negative regulation of RNA metabolic process), GO:0031328 (positive regulation of cellular biosynthetic process), GO:1902531 (regulation of intracellular signal transduction), GO:0051174 (regulation of phosphorus metabolic process), GO:1900542 (regulation of purine nucleotide metabolic process), GO:0006006 (glucose metabolic process), GO:0042981 (regulation of apoptotic process), GO:0008585 (female gonad development), GO:2001141 (regulation of RNA biosynthetic process), GO:0043523 (regulation of neuron apoptotic process), GO:0071345 (cellular response to cytokine stimulus), GO:0016310 (phosphorylation), GO:0043524 (negative regulation of neuron apoptotic process), GO:1902680 (positive regulation of RNA biosynthetic process), GO:1902679 (negative regulation of RNA biosynthetic process), GO:0010498 (proteasomal protein catabolic process), GO:2001242 (regulation of intrinsic apoptotic signaling pathway), GO:0006110 (regulation of glycolytic process), GO:0071375 (cellular response to peptide hormone stimulus), GO:0032868 (response to insulin), GO:0043066 (negative regulation of apoptotic process), GO:0006355 (regulation of DNA-templated transcription), GO:0019220 (regulation of phosphate metabolic process), GO:0071396 (cellular response to lipid), GO:0008584 (male gonad development), GO:0043122 (regulation of I-kappaB kinase/NF-kappaB signaling), GO:2000628 (regulation of miRNA metabolic process), GO:0061136 (regulation of proteasomal protein catabolic process), GO:1902235 (regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway), GO:0045936 (negative regulation of phosphate metabolic process), GO:0016239 (positive regulation of macroautophagy), GO:0001932 (regulation of protein phosphorylation), GO:0045892 (negative regulation of DNA-templated transcription), GO:1903508 (positive regulation of nucleic acid-templated transcription), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0042325 (regulation of phosphorylation), GO:0045893 (positive regulation of DNA-templated transcription), GO:0008286 (insulin receptor signaling pathway), GO:0001539 (cilium or flagellum-dependent cell motility), GO:1903507 (negative regulation of nucleic acid-templated transcription), GO:0045944 (positive regulation of transcription by RNA polymerase II), GO:0000122 (negative regulation of transcription by RNA polymerase II)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0005739 (mitochondrion), GO:0043233 (organelle lumen), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)