Protein: Forkhead box protein O1 (Forkhead box protein O1A) (Forkhead in rhabdomyosarcoma) (Q12778)
Organism: Homo sapiens (Human)
Function: 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 (By similarity). Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (By similarity). 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 (By similarity). Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (By similarity). Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (By similarity). Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (By similarity). In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By similarity). Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1. Promotes neural cell death. Mediates insulin action on adipose tissue (By similarity). 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 (By similarity). Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells (By similarity). Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner. Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity). Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis.
Subcellular location: Cytoplasm {ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}. Nucleus {ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}. Note=Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells (PubMed:11311120, PubMed:12228231, PubMed:19221179, PubMed:20543840, PubMed:21245099, PubMed:25009184). In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (By similarity). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (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-proteasomal pathway (PubMed:11237865, PubMed:12228231). Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation (PubMed:18356527). Phosphorylation by NLK results in nuclear export (By similarity). Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (PubMed:19221179, PubMed:21245099). SGK1-mediated phosphorylation also results in nuclear translocation (By similarity). Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide (By similarity). Retained in the nucleus on methylation (By similarity). PPIA/CYPA stimulates its nuclear accumulation (PubMed:31063815). Deacetylation by SIRT6, promotes its translocation into the cytoplasm (PubMed:25009184). {ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}.
InterPro domains:
- IPR032067: FOXO protein, transactivation domain (domain) [595-634]
- IPR036390: Winged helix DNA-binding domain superfamily (homologous_superfamily) [156-242]
- IPR047408: Forkhead box protein O1, forkhead domain (domain) [151-249]
- IPR032068: FOXO protein, KIX-binding domain (domain) [423-504]
- IPR030456: Fork head domain conserved site 2 (conserved_site) [209-215]
- IPR001766: Fork head domain (domain) [158-254]
- IPR036388: Winged helix-like DNA-binding domain superfamily (homologous_superfamily) [156-246]
Sequence:
MAEAPQVVEIDPDFEPLPRPRSCTWPLPRPEFSQSNSATSSPAPSGSAAANPDAAAGLPSASAAAVSADFMSNLSLLEESEDFPQAPGSVAAAVAAAAAAAATGGLCGDFQGPEAGCLHPAPPQPPPPGPLSQHPPVPPAAAGPLAGQPRKSSSSRRNAWGNLSYADLITKAIESSAEKRLTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSSWWMLNPEGGKSGKSPRRRAASMDNNSKFAKSRSRAAKKKASLQSGQEGAGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGEGDVHSMVYPPSAAKMASTLPSLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGTMMQQTPCYSFAPPNTSLNSPSPNYQKYTYGQSSMSPLPQMPIQTLQDNKSSYGGMSQYNCAPGLLKELLTSDSPPHNDIMTPVDPGVAQPNSRVLGQNVMMGPNSVMSTYGSQASHNKMMNPSSHTHPGHAQQTSAVNGRPLPHTVSTMPHTSGMNRLTQVKTPVQVPLPHPMQMSALGGYSSVSSCNGYGRMGLLHQEKLPSDLDGMFIERLDCDMESIIRNDLMDGDTLDFNFDNVLPNQSFPHSVKTTTHSWVSG
Predicted GO terms:
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:0097159 (organic cyclic compound binding), GO:0005515 (protein binding), GO:0008013 (beta-catenin binding), GO:0003676 (nucleic acid binding), GO:0001217 (DNA-binding transcription repressor activity), 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:0003677 (DNA binding), GO:0019900 (kinase binding), GO:0003690 (double-stranded DNA binding), GO:0043565 (sequence-specific DNA binding), GO:0019901 (protein kinase binding), GO:1990837 (sequence-specific double-stranded 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:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0048869 (cellular developmental process), GO:0042221 (response to chemical), GO:0019222 (regulation of metabolic process), GO:0051241 (negative regulation of multicellular organismal process), GO:0051239 (regulation of multicellular organismal process), GO:0050793 (regulation of developmental process), GO:0048522 (positive regulation of cellular process), GO:0009719 (response to endogenous stimulus), GO:0050794 (regulation of cellular process), GO:0009893 (positive regulation of metabolic process), GO:0051716 (cellular response to stimulus), GO:0051093 (negative regulation of developmental process), GO:0048523 (negative regulation of cellular process), GO:0007154 (cell communication), GO:0007165 (signal transduction), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0030154 (cell differentiation), GO:0008285 (negative regulation of cell population proliferation), GO:0071495 (cellular response to endogenous stimulus), GO:0060255 (regulation of macromolecule metabolic process), GO:1901700 (response to oxygen-containing compound), GO:0010948 (negative regulation of cell cycle process), GO:1901343 (negative regulation of vasculature development), GO:0010033 (response to organic substance), GO:0009725 (response to hormone), GO:0009891 (positive regulation of biosynthetic process), GO:0051726 (regulation of cell cycle), GO:2000026 (regulation of multicellular organismal development), GO:0042127 (regulation of cell population proliferation), GO:1901698 (response to nitrogen compound), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0045596 (negative regulation of cell differentiation), GO:0009889 (regulation of biosynthetic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0022603 (regulation of anatomical structure morphogenesis), GO:0045595 (regulation of cell differentiation), GO:0007166 (cell surface receptor signaling pathway), GO:0031323 (regulation of cellular metabolic process), GO:0045786 (negative regulation of cell cycle), GO:0080090 (regulation of primary metabolic process), GO:0010564 (regulation of cell cycle process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:1901652 (response to peptide), GO:0071417 (cellular response to organonitrogen compound), GO:0007167 (enzyme-linked receptor protein signaling pathway), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0071310 (cellular response to organic substance), GO:1901342 (regulation of vasculature development), GO:1901699 (cellular response to nitrogen compound), GO:0051148 (negative regulation of muscle cell differentiation), GO:0051147 (regulation of muscle cell differentiation), GO:0010468 (regulation of gene expression), GO:0043434 (response to peptide hormone), GO:0010557 (positive regulation of macromolecule biosynthetic process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0048863 (stem cell differentiation), GO:0051254 (positive regulation of RNA metabolic process), GO:0032870 (cellular response to hormone stimulus), GO:0010243 (response to organonitrogen compound), GO:0031326 (regulation of cellular biosynthetic process), GO:0070316 (regulation of G0 to G1 transition), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0045765 (regulation of angiogenesis), GO:0051252 (regulation of RNA metabolic process), GO:1901701 (cellular response to oxygen-containing compound), GO:0031328 (positive regulation of cellular biosynthetic process), GO:2000181 (negative regulation of blood vessel morphogenesis), GO:0016525 (negative regulation of angiogenesis), GO:0071375 (cellular response to peptide hormone stimulus), GO:0032868 (response to insulin), GO:2001141 (regulation of RNA biosynthetic process), GO:0006355 (regulation of DNA-templated transcription), GO:0051151 (negative regulation of smooth muscle cell differentiation), GO:1901653 (cellular response to peptide), GO:0051150 (regulation of smooth muscle cell differentiation), GO:0007169 (transmembrane receptor protein tyrosine kinase signaling pathway), GO:1902680 (positive regulation of RNA biosynthetic process), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0045893 (positive regulation of DNA-templated transcription), GO:0008286 (insulin receptor signaling pathway), GO:0032869 (cellular response to insulin stimulus), GO:1903508 (positive regulation of nucleic acid-templated transcription), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0045944 (positive 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:0005829 (cytosol), GO:0005737 (cytoplasm), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), 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)