Q9R1E0 · FOXO1_MOUSE
- ProteinForkhead box protein O1
- GeneFoxo1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids652 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (PubMed:12219087, PubMed:12754525, PubMed:15184386, PubMed:15220471, PubMed:16917544, PubMed:17090532, PubMed:17627282, PubMed:17681146, PubMed:20519497, PubMed:20668652, PubMed:21196578, PubMed:21335550, PubMed:21471200, PubMed:22298775, PubMed:22417654, PubMed:22510882, PubMed:27457971, PubMed:34914893).
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' (PubMed:17090532, PubMed:21335550).
Activity suppressed by insulin (PubMed:12754525, PubMed:17627282).
Main regulator of redox balance and osteoblast numbers and controls bone mass (PubMed:21471200, PubMed:22298775).
Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (PubMed:21471200, PubMed:22298775).
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 (PubMed:32103177).
Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (PubMed:22298775).
Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (PubMed:21471200).
Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (PubMed:12219087, PubMed:27457971).
In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (PubMed:12754525, PubMed:25009184).
Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1 (By similarity).
Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (By similarity).
Promotes neural cell death (By similarity).
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 (PubMed:21196578).
Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (By similarity).
Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity).
Positive regulator of apoptosis in cardiac smooth muscle cells as a result of its transcriptional activation of pro-apoptotic genes (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 (By similarity).
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' (PubMed:17090532, PubMed:21335550).
Activity suppressed by insulin (PubMed:12754525, PubMed:17627282).
Main regulator of redox balance and osteoblast numbers and controls bone mass (PubMed:21471200, PubMed:22298775).
Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (PubMed:21471200, PubMed:22298775).
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 (PubMed:32103177).
Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (PubMed:22298775).
Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (PubMed:21471200).
Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (PubMed:12219087, PubMed:27457971).
In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (PubMed:12754525, PubMed:25009184).
Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1 (By similarity).
Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (By similarity).
Promotes neural cell death (By similarity).
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 (PubMed:21196578).
Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (By similarity).
Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity).
Positive regulator of apoptosis in cardiac smooth muscle cells as a result of its transcriptional activation of pro-apoptotic genes (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 (By similarity).
Miscellaneous
In an animal model of diabetes mellitus type 2 (db/db mice), beta-cell islets exhibit increased levels of PPP2R1A leading to increased dephosphorylation at Thr-24 and Ser-253 and nuclear retention of FOXO1.
Features
Showing features for site, dna binding.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 155 | DNA-binding | ||||
Sequence: N | ||||||
DNA binding | 156-232 | Fork-head | ||||
Sequence: AWGNLSYADLITKAIESSAEKRLTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSS | ||||||
Site | 162 | DNA-binding | ||||
Sequence: Y | ||||||
Site | 222 | DNA-binding | ||||
Sequence: R |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameForkhead box protein O1
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ9R1E0
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Shuttles between the cytoplasm and nucleus (PubMed:32103177).
Largely nuclear in unstimulated cells (By similarity).
In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (PubMed:22298775).
Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (PubMed:32103177).
Insulin-induced phosphorylation at Ser-253 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 (By similarity).
Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation (By similarity).
Phosphorylation by NLK results in nuclear export (PubMed:20061393).
Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (By similarity).
SGK1-mediated phosphorylation also results in nuclear translocation (PubMed:19965929).
Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide (PubMed:21196578).
Methylated form is nuclear (PubMed:18951090).
PPIA/CYPA stimulates its nuclear accumulation (By similarity).
Deacetylation by SIRT6, promotes its translocation into the cytoplasm (PubMed:27457971).
Largely nuclear in unstimulated cells (By similarity).
In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (PubMed:22298775).
Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (PubMed:32103177).
Insulin-induced phosphorylation at Ser-253 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 (By similarity).
Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation (By similarity).
Phosphorylation by NLK results in nuclear export (PubMed:20061393).
Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (By similarity).
SGK1-mediated phosphorylation also results in nuclear translocation (PubMed:19965929).
Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide (PubMed:21196578).
Methylated form is nuclear (PubMed:18951090).
PPIA/CYPA stimulates its nuclear accumulation (By similarity).
Deacetylation by SIRT6, promotes its translocation into the cytoplasm (PubMed:27457971).
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Null mice die around embryonic day 11 and exhibit abnormal angiogenesis. Defects are observed in branchial arches and there is remarkably impaired vascular development of embryos and yolk sacs. Exogeneous VEGF on FOX1-deficient endothelial cells show markedly different morphological response. Active osteocalcin/BGLAP as well as serum insulin and beta-cell and gonadal fat levels were increased, but there is no change in total fat content, lean mass, and body weight. Effect on RUNX2 activity was inhibited. FOXO1 and ATF4 double happlo-insufficient mice exhibit also an increase in insulin levels and beta cell proliferation, but there is an increase in insulin sensitivity demonstrated by an increase in expression of insulin-sensitizing hormone adiponectin. Gonadal fat levels and adipocyte numbers were decreased. Osteocalcin/BGLAP levels were unchanged.
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 24 | Decreases insulin-induced phosphorylation by approximately 30%. Nuclear location but transcriptional activity decreased by about 50%. Abolishes the SIRT1 deacetylase binding and increases acetylation; when associated with A-253; A-316; A-462 and A-463. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with Q-219; Q-242; Q-245; Q-259; Q-262; Q-271 and Q-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with R-219; R-242; R-245; R-259; R-262; R-271 and R-291. | ||||
Sequence: T → A | ||||||
Mutagenesis | 29 | Little change in levels of methylation; when associated with K-147; K-154; K-311 and K-313. | ||||
Sequence: R → K | ||||||
Mutagenesis | 147 | Little change in levels of methylation; when associated with K-29; K-154; K-311 and K-313. | ||||
Sequence: R → K | ||||||
Mutagenesis | 154 | Little change in levels of methylation; when associated with K-29; K-147; K-311 and K-313. | ||||
Sequence: R → K | ||||||
Mutagenesis | 206 | Loss of interaction with CEBPA. | ||||
Sequence: W → G | ||||||
Mutagenesis | 212 | Loss of interaction with CEBPA. | ||||
Sequence: H → P | ||||||
Mutagenesis | 219 | Mimics acetylation. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-242; Q-245; Q-259; Q-262; Q-271 and Q-291. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24; Q-242; Q-245; Q-259; Q-262; Q-271 and Q-291. | ||||
Sequence: K → Q | ||||||
Mutagenesis | 219 | Translocates to the cytoplasm after insulin-stimulation. No change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-242; R-245; R-259; R-262; R-271 and R-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-242; R-245; R-259; R-262; R-271 and R-291. | ||||
Sequence: K → R | ||||||
Mutagenesis | 242 | Mimics acetylation. Cytoplasmic location in absence or presence of insulin. Decreased DNA-binding by about half. Enhanced phosphorylation by PKB/AKT1, no effect on interaction with CEBPA; when associated with either A-245 or Q-245 and either A-262 or Q-262. either A-262 or Q-262. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-219; Q-245; Q-259; Q-262; Q-271 and Q-291. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24; Q-219; Q-245; Q-259; Q-262; Q-271 and Q-291. | ||||
Sequence: K → Q or A | ||||||
Mutagenesis | 242 | Reduced acetylation and transcriptional activity increased by about 1.5 fold. Completely abolishes acetylation, increases interaction with CEBPA and transcriptional activity increased by about 3-fold; when associated with R-245 and R-262. Transcriptional activity not inhibited by FCOR; when associated with R-245; R-259; R-262; R-271 and R-291. Predominantly nuclear and translocates to the cytoplasm on insulin-stimulation. No change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-219; R-245; R-259; R-262; R-271 and R-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-219; R-245; R-259; R-262; R-271 and R-291. | ||||
Sequence: K → R | ||||||
Mutagenesis | 245 | Mimics acetylation. Decreased DNA-binding by about half. Enhanced phosphorylation by PKB/AKT1, no effect on interaction with CEBPA; when associated with either A-242 or Q-242 and either A-262 or Q-262. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-219; Q-242; Q-259; Q-262; Q-271 and Q-291. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24; Q-219; Q-242; Q-259; Q-262; Q-271 and Q-291. | ||||
Sequence: K → Q or A | ||||||
Mutagenesis | 245 | Reduced acetylation and transcriptional activity increased by about 1.5-fold. Completely abolishes acetylation, increases interaction with CEBPA and transcriptional activity increased by about 3-fold; when associated with R-242 and R-262. Transcriptional activity not inhibited by FCOR; when associated with R-242; R-259; R-262; R-271 and R-291. Predominantly nuclear and translocates to the cytoplasm on insulin-stimulation. No change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-219; R-242; R-259; R-262; R-271 and R-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-219; R-242; R-259; R-262; R-271 and R-291. | ||||
Sequence: K → R | ||||||
Mutagenesis | 248 | Some decrease in levels of methylation. Greatly decreased methylation levels; when associated with K-250. | ||||
Sequence: R → K | ||||||
Mutagenesis | 249 | No change in methylation levels. | ||||
Sequence: R → K | ||||||
Mutagenesis | 250 | Some decrease in levels of methylation. Greatly decreased methylation levels; when associated with K-248. | ||||
Sequence: R → K | ||||||
Mutagenesis | 253 | Abolishes insulin-induced phosphorylation when associated with A-463. Nuclear location but transcriptional activity decreased by about 50%. Abolishes the SIRT1 deacetylase binding and increases acetylation; when associated with A-24; A-316; A-462 and A-463. | ||||
Sequence: S → A | ||||||
Mutagenesis | 259 | Mimics acetylation. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-219; Q-242; Q-245; Q-262; Q-271 and Q-291. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24; Q-219; Q-242; Q-245; Q-262; Q-271 and Q-291. | ||||
Sequence: K → Q | ||||||
Mutagenesis | 259 | Transcriptional activity not inhibited by FCOR; when associated with R-242; R-245; R-262; R-271 and R-291. Predominantly nuclear and translocates to the cytoplasm on insulin-stimulation. No change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-219; R-242; R-245; R-262; R-271 and R-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-219; R-242; R-245; R-262; R-271 and R-291. | ||||
Sequence: K → R | ||||||
Mutagenesis | 262 | Mimics acetylation. Decreased DNA-binding by about half and enhanced phosphorylation by PKB/AKT1, no effect on interaction with CEBPA; when associated with either A-242 or Q-242 and either A-245 or Q-245. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-219; Q-242; Q-245; Q-259; Q-271 and Q-291. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24; Q-219; Q-242; Q-245; Q-259; Q-271 and Q-291. | ||||
Sequence: K → Q or A | ||||||
Mutagenesis | 262 | Significant reduction in acetylation and transcriptional activity increased by about 2.0 fold. Completely abolishes acetylation, increases interaction with CEBPA and transcriptional activity increased by about 3-fold; when associated with R-242 and R-245. Transcriptional activity not inhibited by FCOR; when associated with R-242; R-245; R-259; R-271 and R-291. Predominantly nuclear and translocates to the cytoplasm on insulin-stimulation. No change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-219; R-242; R-245; R-259; R-271 and R-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-219; R-242; R-245; R-259; R-271 and R-291. | ||||
Sequence: K → R | ||||||
Mutagenesis | 271 | Mimics acetylation. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-219; Q-242; Q-245; Q-259; Q-262 and Q-291. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24; Q-219; Q-242; Q-245; Q-259; Q-262 and Q-291. | ||||
Sequence: K → Q | ||||||
Mutagenesis | 271 | Transcriptional activity not inhibited by FCOR; when associated with R-242; R-245; R-259; R-262 and R-291. Predominantly nuclear and translocates to the cytoplasm on insulin-stimulation. No inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-219; R-242; R-245; R-259; R-262 and R-291. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-219; R-242; R-245; R-259; R-262 and R-291. | ||||
Sequence: K → R | ||||||
Mutagenesis | 284 | Decreases phosphorylation by NLK; when associated with A-295; A-326; A-380; A-391; A-399; A-413 and A-415. | ||||
Sequence: S → A | ||||||
Mutagenesis | 291 | Mimics acetylation. Cytoplasmic location in absence or presence of insulin, no change on the inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with Q-219; Q-242; Q-245; Q-259; Q-262 and Q-271. Increased insulin-induced phosphorylation at Ser-253 and binding of 14-3-3 proteins; when associated with A-24: Q-219; Q-242; Q-245; Q-259; Q-262 and Q-271. | ||||
Sequence: K → Q | ||||||
Mutagenesis | 291 | Transcriptional activity not inhibited by FCOR; when associated with R-242; R-245; R-259; R-262 and R-271. Predominantly nuclear and translocates to the cytoplasm on insulin-stimulation. No inhibitory effect of oxidative stress on insulin-induced phosphorylations, but no inhibition of these phosphorylations by resveratrol; when associated with R-219; R-242; R-245; R-259; R-262 and R-271. Increased binding of 14-3-3 proteins even with decreased insulin-induced phosphorylation at Ser-253; when associated with A-24; R-219; R-242; R-245; R-259; R-262 and R-271. | ||||
Sequence: K → R | ||||||
Mutagenesis | 295 | Decreases phosphorylation by NLK; when associated with A-284; A-326; A-380; A-391; A-399; A-413 and A-415. | ||||
Sequence: S → A | ||||||
Mutagenesis | 311 | Little change in levels of methylation; when associated with K-29; K-147; K-154 and K-313. | ||||
Sequence: R → K | ||||||
Mutagenesis | 313 | Little change in levels of methylation; when associated with K-29; K-147; K-154 and K-311. | ||||
Sequence: R → K | ||||||
Mutagenesis | 316 | Decreases insulin-induced phosphorylation by approximately 30%. Abolishes the SIRT1 deacetylase binding and increases acetylation; when associated with A-24; A-253; A-462 and A-463. | ||||
Sequence: S → A | ||||||
Mutagenesis | 326 | Decreases phosphorylation by NLK; when associated with A-284; A-295; A-380; A-391; A-399; A-413 and A-415. | ||||
Sequence: S → A | ||||||
Mutagenesis | 380 | Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-391; A-399; A-413 and A-415. | ||||
Sequence: S → A | ||||||
Mutagenesis | 391 | Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-399; A-413 and A-415. | ||||
Sequence: S → A | ||||||
Mutagenesis | 399 | Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-391; A-413 and A-415. | ||||
Sequence: T → A | ||||||
Mutagenesis | 413 | Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-391; A-399 and A-415. | ||||
Sequence: S → A | ||||||
Mutagenesis | 415 | Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-391; A-399 and A-413. | ||||
Sequence: S → A | ||||||
Mutagenesis | 462 | Decreased transcriptional activity by about 2-fold in the absence of serum; when associated with A-463. Nuclear location but transcriptional activity decreased by about 50%. Abolishes the SIRT1 deacetylase binding and increases acetylation; when associated with A-24; A-253; A-316 and A-463. | ||||
Sequence: L → A | ||||||
Mutagenesis | 463 | Decreased transcriptional activity by about 2-fold in the absence of serum; when associated with A-463. Nuclear location but transcriptional activity decreased by about 50%. Abolishes the SIRT1 deacetylase binding and increases acetylation; when associated with A-24; A-253; A-316 and A-462. | ||||
Sequence: L → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 22 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000091873 | 1-652 | Forkhead box protein O1 | |||
Sequence: MAEAPQVVETDPDFEPLPRQRSCTWPLPRPEFNQSNSTTSSPAPSGGAAANPDAAASLASASAVSTDFMSNLSLLEESEDFARAPGCVAVAAAAAASRGLCGDFQGPEAGCVHPAPPQPPPTGPLSQPPPVPPSAAAAAGPLAGQPRKTSSSRRNAWGNLSYADLITKAIESSAEKRLTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSSWWMLNPEGGKSGKSPRRRAASMDNNSKFAKSRGRAAKKKASLQSGQEGPGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGDGDVHSLVYPPSAAKMASTLPSLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGSMMQQTPCYSFAPPNTSLNSPSPNYSKYTYGQSSMSPLPQMPMQTLQDSKSSYGGLNQYNCAPGLLKELLTSDSPPHNDIMSPVDPGVAQPNSRVLGQNVMMGPNSVMPAYGSQASHNKMMNPSSHTHPGHAQQTASVNGRTLPHVVNTMPHTSAMNRLTPVKTPLQVPLSHPMQMSALGSYSSVSSCNGYGRMGVLHQEKLPSDLDGMFIERLDCDMESIIRNDLMDGDTLDFNFDNVLPNQSFPHSVKTTTHSWVSG | ||||||
Modified residue | 24 | Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1 | ||||
Sequence: T | ||||||
Modified residue | 209 | Phosphoserine; by STK4/MST1 | ||||
Sequence: S | ||||||
Modified residue | 215 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 231 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 232 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 242 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 245 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 246 | Phosphoserine; by CDK1 | ||||
Sequence: S | ||||||
Modified residue | 248 | Omega-N-methylarginine; by PRMT1 | ||||
Sequence: R | ||||||
Modified residue | 250 | Omega-N-methylarginine; by PRMT1 | ||||
Sequence: R | ||||||
Modified residue | 253 | Phosphoserine; by PKB/AKT1 and SGK1 | ||||
Sequence: S | ||||||
Modified residue | 259 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 262 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 271 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 284 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 295 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 316 | Phosphoserine; by PKB/AKT1 or PKB/AKT2 | ||||
Sequence: S | ||||||
Modified residue | 319 | Phosphoserine; by CK1 and SGK1 | ||||
Sequence: S | ||||||
Modified residue | 322 | Phosphoserine; by CK1 | ||||
Sequence: S | ||||||
Modified residue | 326 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 330 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 420 | N6-acetyllysine | ||||
Sequence: K |
Post-translational modification
Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-253 and Ser-319 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-253 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-316, permitting phosphorylation of Ser-319 and Ser-322, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-326 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-253 by PP2A in beta-cells under oxidative stress leading to nuclear retention (By similarity).
Phosphorylation of Ser-246 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-209, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export (By similarity).
PPIA/CYPA promotes its dephosphorylation on Ser-253 (By similarity).
Phosphorylation of Ser-246 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-209, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export (By similarity).
PPIA/CYPA promotes its dephosphorylation on Ser-253 (By similarity).
Ubiquitinated by SKP2 (By similarity).
Ubiquitinated, leading to proteasomal degradation (PubMed:28790135).
Ubiquitinated by STUB1/CHIP; when Ser-253 is phosphorylated (By similarity).
Ubiquitinated, leading to proteasomal degradation (PubMed:28790135).
Ubiquitinated by STUB1/CHIP; when Ser-253 is phosphorylated (By similarity).
Methylation inhibits PKB/AKT1-mediated phosphorylation at Ser-253, promoting nuclear retention and increasing the transcriptional activity and cell death. Methylation increased by oxidative stress.
Acetylation at Lys-259 and Lys-271 are necessary for autophagic cell death induction (By similarity).
Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death (By similarity).
Once in the nucleus, acetylated by CREBBP/EP300 (By similarity).
Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-253, and is required for the transcriptional inhibition by FCOR (By similarity).
Deacetylation by SIRT1 results in reactivation of the transcriptional activity (PubMed:15220471, PubMed:16076959, PubMed:17090532).
Acetylation of FOXO1 diminishes its binding to PPARG in adipocytes. Deacetylated by SIRT2; deacetylation of FOXO1 directly increases its repressive binding to PPARG and inhibits adipocyte differentiation (PubMed:17681146, PubMed:19037106, PubMed:20519497, PubMed:21196578).
Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation (By similarity).
By contrast, resveratrol acts independently of acetylation (By similarity).
Acetylated at Lys-420, promoting its localization to the nucleus and transcription factor activity (PubMed:25009184).
Deacetylation at Lys-420 by SIRT6, promotes its translocation into the cytoplasm, preventing its transcription factor activity (PubMed:25009184, PubMed:27457971).
Deacetylation and subsequent inhibition by SIRT6 has different effects depending on cell types: it inhibits gluconeogenesis in hepatocytes, promotes glucose sensing in pancreatic beta-cells and regulates lipid catabolism in brown adipocytes (PubMed:25009184, PubMed:27457971, PubMed:31442424).
Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death (By similarity).
Once in the nucleus, acetylated by CREBBP/EP300 (By similarity).
Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-253, and is required for the transcriptional inhibition by FCOR (By similarity).
Deacetylation by SIRT1 results in reactivation of the transcriptional activity (PubMed:15220471, PubMed:16076959, PubMed:17090532).
Acetylation of FOXO1 diminishes its binding to PPARG in adipocytes. Deacetylated by SIRT2; deacetylation of FOXO1 directly increases its repressive binding to PPARG and inhibits adipocyte differentiation (PubMed:17681146, PubMed:19037106, PubMed:20519497, PubMed:21196578).
Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation (By similarity).
By contrast, resveratrol acts independently of acetylation (By similarity).
Acetylated at Lys-420, promoting its localization to the nucleus and transcription factor activity (PubMed:25009184).
Deacetylation at Lys-420 by SIRT6, promotes its translocation into the cytoplasm, preventing its transcription factor activity (PubMed:25009184, PubMed:27457971).
Deacetylation and subsequent inhibition by SIRT6 has different effects depending on cell types: it inhibits gluconeogenesis in hepatocytes, promotes glucose sensing in pancreatic beta-cells and regulates lipid catabolism in brown adipocytes (PubMed:25009184, PubMed:27457971, PubMed:31442424).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expressed in liver, white and brown adipose tissues (at protein level).
Induction
Expression is regulated by KRIT1 (PubMed:20668652).
Transiently up-regulated during adipogenesis (at protein level) (PubMed:18388859).
Transiently up-regulated during adipogenesis (at protein level) (PubMed:18388859).
Developmental stage
In liver, barely expressed at 14.5 dpc, expression dramatically increases at 18.5 dpc. Abundantly expressed in neonate liver but levels strongly decrease in adult liver (at protein level).
Gene expression databases
Interaction
Subunit
Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteasomal degradation. Interacts with PMRT1; methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus (By similarity).
Interacts (via an N-terminal domain) with FCOR; the interaction is direct, occurs in a forskolin-independent manner and prevents SIRT1 binding to FOXO1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts. Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-253 leading to its nuclear import. Binds to CDK1. Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts. Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. The interaction requires the presence of KRIT1 and is inhibited by FCOR. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (acetylated form) with PPARG (PubMed:12754525, PubMed:15220471, PubMed:16917544, PubMed:17050673, PubMed:17681146, PubMed:19037106, PubMed:20061393, PubMed:20668652, PubMed:21471200, PubMed:22298775, PubMed:22417654, PubMed:22510882).
Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (PubMed:21317886).
Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated (PubMed:17090532, PubMed:17627282).
Interacts with WDFY2 (PubMed:18388859).
Forms a complex with WDFY2 and AKT1 (PubMed:18388859).
Interacts with CRY1 (PubMed:28790135).
Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (By similarity).
Interacts with TOX4; FOXO1 is required for full induction of TOX4-dependent activity and the interaction is inhibited by insulin (PubMed:34914893).
Interacts (when phosphorylated on Ser-253) with STUB1/CHIP (By similarity).
Interacts (via an N-terminal domain) with FCOR; the interaction is direct, occurs in a forskolin-independent manner and prevents SIRT1 binding to FOXO1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts. Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-253 leading to its nuclear import. Binds to CDK1. Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts. Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. The interaction requires the presence of KRIT1 and is inhibited by FCOR. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (acetylated form) with PPARG (PubMed:12754525, PubMed:15220471, PubMed:16917544, PubMed:17050673, PubMed:17681146, PubMed:19037106, PubMed:20061393, PubMed:20668652, PubMed:21471200, PubMed:22298775, PubMed:22417654, PubMed:22510882).
Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (PubMed:21317886).
Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated (PubMed:17090532, PubMed:17627282).
Interacts with WDFY2 (PubMed:18388859).
Forms a complex with WDFY2 and AKT1 (PubMed:18388859).
Interacts with CRY1 (PubMed:28790135).
Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (By similarity).
Interacts with TOX4; FOXO1 is required for full induction of TOX4-dependent activity and the interaction is inhibited by insulin (PubMed:34914893).
Interacts (when phosphorylated on Ser-253) with STUB1/CHIP (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
XENO | Q9R1E0 | AR P10275 | 4 | EBI-1371343, EBI-608057 | |
BINARY | Q9R1E0 | Cebpa P53566 | 5 | EBI-1371343, EBI-2644207 | |
BINARY | Q9R1E0 | Fcor P0DJI6 | 12 | EBI-1371343, EBI-6126630 | |
BINARY | Q9R1E0 | Lrpprc Q6PB66 | 2 | EBI-1371343, EBI-1371262 | |
BINARY | Q9R1E0 | Rorc P51450-2 | 2 | EBI-1371343, EBI-4422078 | |
XENO | Q9R1E0 | SIRT1 Q96EB6 | 2 | EBI-1371343, EBI-1802965 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-62 | Disordered | ||||
Sequence: MAEAPQVVETDPDFEPLPRQRSCTWPLPRPEFNQSNSTTSSPAPSGGAAANPDAAASLASAS | ||||||
Compositional bias | 27-46 | Polar residues | ||||
Sequence: LPRPEFNQSNSTTSSPAPSG | ||||||
Compositional bias | 112-136 | Pro residues | ||||
Sequence: VHPAPPQPPPTGPLSQPPPVPPSAA | ||||||
Region | 112-154 | Disordered | ||||
Sequence: VHPAPPQPPPTGPLSQPPPVPPSAAAAAGPLAGQPRKTSSSRR | ||||||
Region | 208-215 | DNA-binding | ||||
Sequence: NSIRHNLS | ||||||
Region | 231-234 | DNA-binding | ||||
Sequence: SSWW | ||||||
Region | 231-342 | Disordered | ||||
Sequence: SSWWMLNPEGGKSGKSPRRRAASMDNNSKFAKSRGRAAKKKASLQSGQEGPGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGDGDVHS | ||||||
Motif | 248-250 | Nuclear localization signal | ||||
Sequence: RRR | ||||||
Compositional bias | 277-327 | Polar residues | ||||
Sequence: GQEGPGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSP | ||||||
Region | 280-562 | Sufficient for interaction with NLK | ||||
Sequence: GPGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGDGDVHSLVYPPSAAKMASTLPSLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGSMMQQTPCYSFAPPNTSLNSPSPNYSKYTYGQSSMSPLPQMPMQTLQDSKSSYGGLNQYNCAPGLLKELLTSDSPPHNDIMSPVDPGVAQPNSRVLGQNVMMGPNSVMPAYGSQASHNKMMNPSSHTHPGHAQQTASVNGRTLPHVVNTMPHTSAMNRLTPVKTPLQVP | ||||||
Region | 360-456 | Required for interaction with RUNX2 | ||||
Sequence: SEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGSMMQQTPCYSFAPPNTSLNSPSPNYSKYTYGQSSMSPLPQMPMQTLQDSKSSYGGLNQYNCAP | ||||||
Region | 383-410 | Disordered | ||||
Sequence: SLTVSTQSSPGSMMQQTPCYSFAPPNTS | ||||||
Motif | 459-463 | Required for interaction with SIRT1 | ||||
Sequence: LKELL |
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length652
- Mass (Da)69,518
- Last updated2011-07-27 v2
- Checksum3FF58636EA85205F
Features
Showing features for compositional bias, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 27-46 | Polar residues | ||||
Sequence: LPRPEFNQSNSTTSSPAPSG | ||||||
Compositional bias | 112-136 | Pro residues | ||||
Sequence: VHPAPPQPPPTGPLSQPPPVPPSAA | ||||||
Compositional bias | 277-327 | Polar residues | ||||
Sequence: GQEGPGDSPGSQFSKWPASPGSHSNDDFDNWSTFRPRTSSNASTISGRLSP | ||||||
Sequence conflict | 619 | in Ref. 1; AAD40636 | ||||
Sequence: L → P |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF126056 EMBL· GenBank· DDBJ | AAD40636.1 EMBL· GenBank· DDBJ | mRNA | ||
AJ252157 EMBL· GenBank· DDBJ | CAB86873.1 EMBL· GenBank· DDBJ | mRNA | ||
AK137629 EMBL· GenBank· DDBJ | BAE23437.1 EMBL· GenBank· DDBJ | mRNA | ||
AK154041 EMBL· GenBank· DDBJ | BAE32333.1 EMBL· GenBank· DDBJ | mRNA | ||
CH466530 EMBL· GenBank· DDBJ | EDL35224.1 EMBL· GenBank· DDBJ | Genomic DNA |