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Q9R1E0 (FOXO1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 129. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Forkhead box protein O1
Alternative name(s):
Forkhead box protein O1A
Forkhead in rhabdomyosarcoma
Gene names
Name:Foxo1
Synonyms:Fkhr, Foxo1a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length652 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. Acts syngernistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A to activate the expression of genes such as IGFBP1, G6PC and PPCK1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and SKT4/MST1. Promotes neural cell death. Mediates insulin action on adipose. 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. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells. Ref.5 Ref.6 Ref.7 Ref.10 Ref.14 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22

Subunit structure

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 proteosomal 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. Ref.5 Ref.7 Ref.9 Ref.10 Ref.13 Ref.16 Ref.19 Ref.20 Ref.21 Ref.22

Subcellular location

Cytoplasm. Nucleus. Note: Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells. In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus By similarity. 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-proteosomal pathway. Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation. Phosphorylation by NLK results in nuclear export. Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1. SGK1-mediated phosphorylation also results in nuclear translocation. Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide. Methylated form is nuclear. Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.17 Ref.18 Ref.22

Tissue specificity

Expressed in white and brown adipose tissues (at protein level). Ref.21

Induction

Expression is regulated by KRIT1. Ref.16

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. Ref.1 Ref.5 Ref.8 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.20

Ubiquitinated by SRT2. Ubiquitination leads to proteasomal degradation 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. Ref.12

Once in the nucleus, acetylated by CREBBP/EP300. 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. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation. Ref.7 Ref.8 Ref.14 Ref.17

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. Ref.6 Ref.22

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.

Sequence similarities

Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
   Biological processApoptosis
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   LigandDNA-binding
   Molecular functionActivator
   PTMAcetylation
Methylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

blood vessel development

Inferred from mutant phenotype PubMed 14978268Ref.6. Source: MGI

cellular response to DNA damage stimulus

Inferred from direct assay Ref.17. Source: UniProtKB

cellular response to insulin stimulus

Inferred from direct assay PubMed 17681146. Source: UniProtKB

cellular response to nitric oxide

Inferred from direct assay Ref.17. Source: UniProtKB

cellular response to oxidative stress

Inferred from direct assay Ref.20. Source: UniProtKB

endocrine pancreas development

Traceable author statement. Source: Reactome

glucose homeostasis

Inferred from direct assay PubMed 21317886. Source: MGI

insulin receptor signaling pathway

Inferred from mutant phenotype PubMed 12488434. Source: MGI

negative regulation of apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of fat cell differentiation

Inferred from mutant phenotype PubMed 17681146. Source: UniProtKB

negative regulation of stress-activated MAPK cascade

Inferred from Biological aspect of Ancestor. Source: RefGenome

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 17950246. Source: GOC

pattern specification process

Inferred from Biological aspect of Ancestor. Source: RefGenome

positive regulation of gluconeogenesis

Inferred from mutant phenotype PubMed 12783775. Source: MGI

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cell proliferation

Inferred from mutant phenotype PubMed 12488434. Source: MGI

regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter

Inferred from mutant phenotype PubMed 18497885. Source: MGI

regulation of transcription, DNA-templated

Inferred from direct assay PubMed 12488434. Source: MGI

tissue development

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 17681146PubMed 19037106. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 17681146PubMed 19037106. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from direct assay PubMed 12488434. Source: MGI

DNA binding, bending

Inferred from Biological aspect of Ancestor. Source: RefGenome

RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription

Inferred from direct assay PubMed 17950246. Source: MGI

protein binding

Inferred from physical interaction PubMed 19037106Ref.19Ref.21. Source: UniProtKB

protein phosphatase 2A binding

Inferred from direct assay Ref.20. Source: UniProtKB

sequence-specific DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 12488434. Source: MGI

transcription factor binding transcription factor activity

Inferred from physical interaction PubMed 23906066. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ARP102754EBI-1371343,EBI-608057From a different organism.
CebpaP535665EBI-1371343,EBI-2644207
FcorP0DJI612EBI-1371343,EBI-6126630
LrpprcQ6PB662EBI-1371343,EBI-1371262
SIRT1Q96EB62EBI-1371343,EBI-1802965From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 652652Forkhead box protein O1
PRO_0000091873

Regions

DNA binding156 – 23277Fork-head Ref.8 Ref.18
Region208 – 2158DNA-binding By similarity
Region231 – 2344DNA-binding By similarity
Region280 – 562283Sufficient for interaction with NLK
Region360 – 45697Required for interaction with RUNX2
Motif248 – 2503Nuclear localization signal By similarity
Motif459 – 4635Required for interaction with SIRT1
Compositional bias89 – 968Poly-Ala
Compositional bias135 – 1395Poly-Ala
Compositional bias149 – 1524Poly-Ser

Sites

Site1551DNA-binding By similarity
Site1621DNA-binding By similarity
Site2221DNA-binding By similarity

Amino acid modifications

Modified residue241Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1 Ref.1 Ref.14 Ref.15 Ref.20
Modified residue2091Phosphoserine; by STK4/MST1 By similarity
Modified residue2151Phosphoserine By similarity
Modified residue2311Phosphoserine By similarity
Modified residue2321Phosphoserine By similarity
Modified residue2421N6-acetyllysine Ref.7 Ref.8
Modified residue2451N6-acetyllysine Ref.7 Ref.8
Modified residue2461Phosphoserine; by CDK1 By similarity
Modified residue2481Omega-N-methylarginine; by PRMT1 Ref.12
Modified residue2501Omega-N-methylarginine; by PRMT1 Ref.12
Modified residue2531Phosphoserine; by PKB/AKT1 and SGK1 Ref.1 Ref.8 Ref.14 Ref.15 Ref.20
Modified residue2621N6-acetyllysine Ref.7 Ref.8
Modified residue2841Phosphoserine By similarity
Modified residue3161Phosphoserine; by PKB/AKT1 or PKB/AKT2 Ref.1
Modified residue3191Phosphoserine; by CK1 and SGK1 Ref.15
Modified residue3221Phosphoserine; by CK1 By similarity
Modified residue3261Phosphoserine; by DYRK1A By similarity
Modified residue4641Phosphothreonine
Modified residue4651Phosphoserine

Experimental info

Mutagenesis241T → A: 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. Ref.1 Ref.10 Ref.14
Mutagenesis291R → K: Little change in levels of methylation; when associated with K-147; K-154; K-311 and K-313. Ref.12
Mutagenesis1471R → K: Little change in levels of methylation; when associated with K-29; K-154; K-311 and K-313. Ref.12
Mutagenesis1541R → K: Little change in levels of methylation; when associated with K-29; K-147; K-311 and K-313. Ref.12
Mutagenesis2191K → Q: 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. Ref.14
Mutagenesis2191K → R: 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. Ref.14
Mutagenesis2421K → Q: Mimics acetylation. Cytoplasmic location in absence or presence of insulin. Decreased DNA-binding by about half. Enhanced phosphorylation by PKB/AKT1; 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. Ref.7 Ref.8 Ref.14 Ref.21
Mutagenesis2421K → R: Reduced acetylation and transcriptional activity increased by about 1.5 fold. Completely abolishes acetylation 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. Ref.7 Ref.8 Ref.14 Ref.21
Mutagenesis2451K → Q: Mimics acetylation. Decreased DNA-binding by about half. Enhanced phosphorylation by PKB/AKT1; 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. Ref.7 Ref.8 Ref.14 Ref.21
Mutagenesis2451K → R: Reduced acetylation and transciptional activity increased by about 1.5-fold. Completely abolishes acetylation 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. Ref.7 Ref.8 Ref.14 Ref.21
Mutagenesis2481R → K: Some decrease in levels of methylation. Greatly decreased methylation levels; when associated with K-250. Ref.12
Mutagenesis2491R → K: No change in methylation levels.
Mutagenesis2501R → K: Some decrease in levels of methylation. Greatly decreased methylation levels; when associated with K-248. Ref.12
Mutagenesis2531S → A: 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. Ref.1 Ref.8 Ref.10 Ref.14
Mutagenesis2591K → Q: 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. Ref.14 Ref.21
Mutagenesis2591K → R: 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. Ref.14 Ref.21
Mutagenesis2621K → Q: Mimics acetylation. Decreased DNA-binding by about half and enhanced phosphorylation by PKB/AKT1; 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. Ref.7 Ref.8 Ref.14 Ref.21
Mutagenesis2621K → R: Significant reduction in acetylation and transcriptional activity increased by about 2.0 fold. Completely abolishes acetylation 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. Ref.7 Ref.8 Ref.14 Ref.21
Mutagenesis2711K → Q: 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. Ref.14 Ref.21
Mutagenesis2711K → R: 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. Ref.14 Ref.21
Mutagenesis2841S → A: Decreases phosphorylation by NLK; when associated with A-295; A-326; A-380; A-391; A-399; A-413 and A-415. Ref.13
Mutagenesis2911K → Q: 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. Ref.14 Ref.21
Mutagenesis2911K → R: 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. Ref.14 Ref.21
Mutagenesis2951S → A: Decreases phosphorylation by NLK; when associated with A-284; A-326; A-380; A-391; A-399; A-413 and A-415. Ref.13
Mutagenesis3111R → K: Little change in levels of methylation; when associated with K-29; K-147; K-154 and K-313. Ref.12
Mutagenesis3131R → K: Little change in levels of methylation; when associated with K-29; K-147; K-154 and K-311. Ref.12
Mutagenesis3161S → A: 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. Ref.1 Ref.10
Mutagenesis3261S → A: Decreases phosphorylation by NLK; when associated with A-284; A-295; A-380; A-391; A-399; A-413 and A-415. Ref.13
Mutagenesis3801S → A: Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-391; A-399; A-413 and A-415. Ref.13
Mutagenesis3911S → A: Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-399; A-413 and A-415. Ref.13
Mutagenesis3991T → A: Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-391; A-413 and A-415. Ref.13
Mutagenesis4131S → A: Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-391; A-399 and A-415. Ref.13
Mutagenesis4151S → A: Decreases phosphorylation by NLK; when associated with A-284; A-295; A-326; A-380; A-391; A-399 and A-413. Ref.13
Mutagenesis4621L → A: 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. Ref.10
Mutagenesis4631L → A: 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. Ref.10
Sequence conflict6191L → P in AAD40636. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q9R1E0 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 3FF58636EA85205F

FASTA65269,518
        10         20         30         40         50         60 
MAEAPQVVET DPDFEPLPRQ RSCTWPLPRP EFNQSNSTTS SPAPSGGAAA NPDAAASLAS 

        70         80         90        100        110        120 
ASAVSTDFMS NLSLLEESED FARAPGCVAV AAAAAASRGL CGDFQGPEAG CVHPAPPQPP 

       130        140        150        160        170        180 
PTGPLSQPPP VPPSAAAAAG PLAGQPRKTS SSRRNAWGNL SYADLITKAI ESSAEKRLTL 

       190        200        210        220        230        240 
SQIYEWMVKS VPYFKDKGDS NSSAGWKNSI RHNLSLHSKF IRVQNEGTGK SSWWMLNPEG 

       250        260        270        280        290        300 
GKSGKSPRRR AASMDNNSKF AKSRGRAAKK KASLQSGQEG PGDSPGSQFS KWPASPGSHS 

       310        320        330        340        350        360 
NDDFDNWSTF RPRTSSNAST ISGRLSPIMT EQDDLGDGDV HSLVYPPSAA KMASTLPSLS 

       370        380        390        400        410        420 
EISNPENMEN LLDNLNLLSS PTSLTVSTQS SPGSMMQQTP CYSFAPPNTS LNSPSPNYSK 

       430        440        450        460        470        480 
YTYGQSSMSP LPQMPMQTLQ DSKSSYGGLN QYNCAPGLLK ELLTSDSPPH NDIMSPVDPG 

       490        500        510        520        530        540 
VAQPNSRVLG QNVMMGPNSV MPAYGSQASH NKMMNPSSHT HPGHAQQTAS VNGRTLPHVV 

       550        560        570        580        590        600 
NTMPHTSAMN RLTPVKTPLQ VPLSHPMQMS ALGSYSSVSS CNGYGRMGVL HQEKLPSDLD 

       610        620        630        640        650 
GMFIERLDCD MESIIRNDLM DGDTLDFNFD NVLPNQSFPH SVKTTTHSWV SG 

« Hide

References

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[1]"Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway."
Nakae J., Park B.C., Accili D.
J. Biol. Chem. 274:15982-15985(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PHOSPHORYLATION AT THR-24; SER-253 AND SER-316, MUTAGENESIS OF THR-24; SER-253 AND SER-316.
Tissue: Liver.
[2]"The forkhead FKHR is involved in thymocyte proliferation."
Leenders H., Benoist C., Mathis D.
Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J and NOD.
Tissue: Thymus and Vagina.
[4]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction."
Puigserver P., Rhee J., Donovan J., Walkey C.J., Yoon J.C., Oriente F., Kitamura Y., Altomonte J., Dong H., Accili D., Spiegelman B.M.
Nature 423:550-555(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPARGC1A, FUNCTION, PHOSPHORYLATION.
[6]"Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice."
Furuyama T., Kitayama K., Shimoda Y., Ogawa M., Sone K., Yoshida-Araki K., Hisatsune H., Nishikawa S., Nakayama K., Nakayama K., Ikeda K., Motoyama N., Mori N.
J. Biol. Chem. 279:34741-34749(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[7]"Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity."
Daitoku H., Hatta M., Matsuzaki H., Aratani S., Ohshima T., Miyagishi M., Nakajima T., Fukamizu A.
Proc. Natl. Acad. Sci. U.S.A. 101:10042-10047(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION AT LYS-242; LYS-245 AND LYS-262, INTERACTION WITH SIRT1, DEACETYLATION, FUNCTION, MUTAGENESIS OF LYS-242; LYS-245 AND LYS-262.
[8]"Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation."
Matsuzaki H., Daitoku H., Hatta M., Aoyama H., Yoshimochi K., Fukamizu A.
Proc. Natl. Acad. Sci. U.S.A. 102:11278-11283(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION AT LYS-242; LYS-245 AND LYS-262, PHOSPHORYLATION AT SER-253, DNA-BINDING, MUTAGENESIS OF LYS-242; LYS-245; SER-253 AND LYS-262.
[9]"Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex."
Cooper M.P., Qu L., Rohas L.M., Lin J., Yang W., Erdjument-Bromage H., Tempst P., Spiegelman B.M.
Genes Dev. 20:2996-3009(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LRPPRC.
[10]"The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity."
Nakae J., Cao Y., Daitoku H., Fukamizu A., Ogawa W., Yano Y., Hayashi Y.
J. Clin. Invest. 116:2473-2483(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SIRT1, PHOSPHORYLATION, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF THR-24; SER-253; SER-316; LEU-462 AND LEU-463.
[11]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[12]"Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt."
Yamagata K., Daitoku H., Takahashi Y., Namiki K., Hisatake K., Kako K., Mukai H., Kasuya Y., Fukamizu A.
Mol. Cell 32:221-231(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, SUBCELLULAR LOCATION, METHYLATION AT ARG-248 AND ARG-250, MUTAGENESIS OF ARG-29; ARG-147; ARG-154; ARG-248; ARG-250; ARG-311 AND ARG-313.
[13]"Regulation of FOXO1 by TAK1-Nemo-like kinase pathway."
Kim S., Kim Y., Lee J., Chung J.
J. Biol. Chem. 285:8122-8129(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NLK, SUBCELLULAR LOCATION, PHOSPHORYLATION BY NLK, MUTAGENESIS OF SER-284; SER-295; SER-326; SER-380; SER-391; THR-399; SER-413 AND SER-415.
[14]"Uncoupling of acetylation from phosphorylation regulates FoxO1 function independent of its subcellular localization."
Qiang L., Banks A.S., Accili D.
J. Biol. Chem. 285:27396-27401(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-24 AND SER-253, ACETYLATION, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF THR-24; LYS-219; LYS-242; LYS-245; SER-253; LYS-259; LYS-262; LYS-271 AND LYS-291.
[15]"Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates adipocyte differentiation via forkhead box O1."
Di Pietro N., Panel V., Hayes S., Bagattin A., Meruvu S., Pandolfi A., Hugendubler L., Fejes-Toth G., Naray-Fejes-Toth A., Mueller E.
Mol. Endocrinol. 24:370-380(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-24; SER-253 AND SER-319 BY SGK1, SUBCELLULAR LOCATION.
[16]"KRIT1 regulates the homeostasis of intracellular reactive oxygen species."
Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P., Retta S.F.
PLoS ONE 5:E11786-E11786(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION, INTERACTION WITH SIRT1, INDUCTION.
[17]"FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide."
Hughes K.J., Meares G.P., Hansen P.A., Corbett J.A.
J. Biol. Chem. 286:8338-8348(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, ACETYLATION, RESPONSE TO NITRIC OXIDE.
[18]"Nucleo-cytosolic shuttling of FoxO1 directly regulates mouse Ins2 but not Ins1 gene expression in pancreatic beta cells (MIN6)."
Meur G., Qian Q., da Silva Xavier G., Pullen T.J., Tsuboi T., McKinnon C., Fletcher L., Tavare J.M., Hughes S., Johnson P., Rutter G.A.
J. Biol. Chem. 286:13647-13656(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, FUNCTION, DNA-BINDING.
[19]"Foxo1 mediates insulin-like growth factor 1 (IGF1)/insulin regulation of osteocalcin expression by antagonizing Runx2 in osteoblasts."
Yang S., Xu H., Yu S., Cao H., Fan J., Ge C., Fransceschi R.T., Dong H.H., Xiao G.
J. Biol. Chem. 286:19149-19158(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RUNX2, FUNCTION.
[20]"The B55alpha-containing PP2A holoenzyme dephosphorylates FOXO1 in islet beta-cells under oxidative stress."
Yan L., Guo S., Brault M., Harmon J., Robertson R.P., Hamid R., Stein R., Yang E.
Biochem. J. 444:239-247(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERISTICS OF AN ANIMAL MODEL OF DIABETES MELLITUS TYPE 2, FUNCTION, DEPHOSPHORYLATION AT THR-24 AND SER-253, INTERACTION WITH PPP2R1A.
[21]"Novel repressor regulates insulin sensitivity through interaction with Foxo1."
Nakae J., Cao Y., Hakuno F., Takemori H., Kawano Y., Sekioka R., Abe T., Kiyonari H., Tanaka T., Sakai J., Takahashi S., Itoh H.
EMBO J. 31:2275-2295(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS A TRANSCRIPTIONAL ACTIVATOR, INTERACTION WITH FCOR AND SIRT1, TISSUE SPECIFICITY, MUTAGENESIS OF LYS-242; LYS-245; LYS-259; LYS-262; LYS-271 AND LYS-291.
[22]"FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis."
Kode A., Mosialou I., Silva B.C., Joshi S., Ferron M., Rached M.T., Kousteni S.
J. Biol. Chem. 287:8757-8768(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, INTERACTION WITH ATF4, FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF126056 mRNA. Translation: AAD40636.1.
AJ252157 mRNA. Translation: CAB86873.1.
AK137629 mRNA. Translation: BAE23437.1.
AK154041 mRNA. Translation: BAE32333.1.
CH466530 Genomic DNA. Translation: EDL35224.1.
CCDSCCDS17343.1.
RefSeqNP_062713.2. NM_019739.3.
UniGeneMm.29891.

3D structure databases

ProteinModelPortalQ9R1E0.
SMRQ9R1E0. Positions 151-266.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid207997. 4 interactions.
IntActQ9R1E0. 13 interactions.
MINTMINT-5112421.
STRING10090.ENSMUSP00000055308.

PTM databases

PhosphoSiteQ9R1E0.

Proteomic databases

MaxQBQ9R1E0.
PaxDbQ9R1E0.
PRIDEQ9R1E0.

Protocols and materials databases

DNASU56458.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000053764; ENSMUSP00000055308; ENSMUSG00000044167.
GeneID56458.
KEGGmmu:56458.
UCSCuc008pei.2. mouse.

Organism-specific databases

CTD2308.
MGIMGI:1890077. Foxo1.

Phylogenomic databases

eggNOGCOG5025.
GeneTreeENSGT00390000000589.
HOGENOMHOG000251635.
HOVERGENHBG057789.
InParanoidQ9JJW4.
KOK07201.
OMAGVKTTTH.
OrthoDBEOG7SJD45.
TreeFamTF315583.

Enzyme and pathway databases

ReactomeREACT_13641. Regulation of Beta-Cell Development.

Gene expression databases

ArrayExpressQ9R1E0.
BgeeQ9R1E0.
CleanExMM_FOXO1.
GenevestigatorQ9R1E0.

Family and domain databases

Gene3D1.10.10.10. 1 hit.
InterProIPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamPF00250. Fork_head. 1 hit.
[Graphical view]
PRINTSPR00053. FORKHEAD.
SMARTSM00339. FH. 1 hit.
[Graphical view]
PROSITEPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio312698.
PROQ9R1E0.
SOURCESearch...

Entry information

Entry nameFOXO1_MOUSE
AccessionPrimary (citable) accession number: Q9R1E0
Secondary accession number(s): Q9JJW4
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 129 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot