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Protein

Forkhead box protein O1

Gene

FOXO1

Organism
Ictidomys tridecemlineatus (Thirteen-lined ground squirrel) (Spermophilus tridecemlineatus)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 synergistically 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. Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei156 – 1561DNA-bindingBy similarity
Sitei163 – 1631DNA-bindingBy similarity
Sitei223 – 2231DNA-bindingBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi157 – 23377Fork-headPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Apoptosis, Autophagy, Differentiation, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein O1
Alternative name(s):
Forkhead box protein O1A
Forkhead in rhabdomyosarcoma
Gene namesi
Name:FOXO1
Synonyms:FOXO1A
OrganismiIctidomys tridecemlineatus (Thirteen-lined ground squirrel) (Spermophilus tridecemlineatus)
Taxonomic identifieri43179 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiSciuridaeXerinaeMarmotiniIctidomys
Proteomesi
  • UP000005215 Componenti: Unassembled WGS sequence

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus PROSITE-ProRule annotationBy similarity

  • Note: Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells. In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus. Insulin-induced phosphorylation at Ser-254 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-247 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. Retained in the nucleus on methylation (By similarity).By similarity

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • mitochondrion Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 653653Forkhead box protein O1PRO_0000250522Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei24 – 241Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1By similarity
Modified residuei210 – 2101Phosphoserine; by STK4/MST1By similarity
Modified residuei216 – 2161PhosphoserineBy similarity
Modified residuei232 – 2321PhosphoserineBy similarity
Modified residuei233 – 2331PhosphoserineBy similarity
Modified residuei243 – 2431N6-acetyllysineBy similarity
Modified residuei246 – 2461N6-acetyllysineBy similarity
Modified residuei247 – 2471Phosphoserine; by CDK1By similarity
Modified residuei249 – 2491Omega-N-methylarginine; by PRMT1By similarity
Modified residuei251 – 2511Omega-N-methylarginine; by PRMT1By similarity
Modified residuei254 – 2541Phosphoserine; by PKB/AKT1 and SGK1By similarity
Modified residuei260 – 2601N6-acetyllysineBy similarity
Modified residuei263 – 2631N6-acetyllysineBy similarity
Modified residuei272 – 2721N6-acetyllysineBy similarity
Modified residuei285 – 2851PhosphoserineBy similarity
Modified residuei296 – 2961PhosphoserineBy similarity
Modified residuei317 – 3171Phosphoserine; by PKB/AKT1 or PKB/AKT2By similarity
Modified residuei320 – 3201Phosphoserine; by CK1 and SGK1By similarity
Modified residuei323 – 3231PhosphoserineBy similarity
Modified residuei327 – 3271Phosphoserine; by DYRK1ABy similarity
Modified residuei331 – 3311PhosphothreonineBy similarity

Post-translational modificationi

Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-254 and Ser-320 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-254 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-317, permitting phosphorylation of Ser-320 and Ser-323, 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-327 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-254 by PP2A in beta-cells under oxidative stress leading to nuclear retention. Phosphorylation of Ser-247 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-210, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export (By similarity).By similarity
Ubiquitinated by SRT2. Ubiquitination leads to proteasomal degradation (By similarity).By similarity
Methylation inhibits AKT1-mediated phosphorylation at Ser-254 and is increased by oxidative stress.By similarity
Acetylation at Lys-260 and Lys-272 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death. 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-254. 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 (By similarity).By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein, Ubl conjugation

Interactioni

Subunit structurei

Interacts with LRPPRC. 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-254 leading to its nuclear import. 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. Binds to CDK1. 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. The interaction requires the presence of KRIT1. 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 PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. 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. Interacts with XBP1; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway. Interacts with WDFY2. Forms a complex with WDFY2 and AKT1.By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi43179.ENSSTOP00000008695.

Structurei

3D structure databases

ProteinModelPortaliQ810W5.
SMRiQ810W5. Positions 159-254.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni209 – 2168DNA-bindingBy similarity
Regioni232 – 2354DNA-bindingBy similarity
Regioni281 – 561281Sufficient for interaction with NLKBy similarityAdd
BLAST
Regioni361 – 45797Required for interaction with RUNX2By similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi249 – 2513Nuclear localization signalBy similarity
Motifi460 – 4645Required for interaction with SIRT1By similarity

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi91 – 10111Poly-AlaAdd
BLAST

Sequence similaritiesi

Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG2294. Eukaryota.
COG5025. LUCA.
HOVERGENiHBG057789.
InParanoidiQ810W5.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR032067. FOXO-TAD.
IPR032068. FOXO_KIX-bd.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF16676. FOXO-TAD. 1 hit.
PF16675. FOXO_KIX_bdg. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q810W5-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGGATA
60 70 80 90 100
NPDASAGLPP ASAAAVSADF MSNLSLLEES EDFPQAPGSV AAAVAAAAAA
110 120 130 140 150
ATGGLCGDFQ GLEAGCLHPA PPQPPPPGPL SQHPPVPPAA GPLAGQPRKS
160 170 180 190 200
SSSRRNAWGN LSYADLITKA IESSAEKRLT LSQIYEWMVK SVPYFKDKGD
210 220 230 240 250
SNSSAGWKNS IRHNLSLHSK FIRVQNEGTG KSSWWMLNPE GGKSGKSPRR
260 270 280 290 300
RAASMDNNSK FAKSRGQAAK KKASLQSGQE GAGDSPGSQF SKWPASPGSH
310 320 330 340 350
SNDDFDNWST FRPRTSSNAS TISGRFSPIM TEQDDLGDGD VHSLVYPPSA
360 370 380 390 400
SKMASTLPSL SEISNPENME NLLDNLNLLS SPTSLTVSTQ SSPGSMMQQT
410 420 430 440 450
PCYSFAPPST SLNSPSPNYQ KYTYGQSSMS PLSQMPMQTL QDNKSSYGGL
460 470 480 490 500
NQFNCAQGLL KELLTSDSPP HNDIMSSVDP GVAQPNSRVL GQNVMLGPNS
510 520 530 540 550
VMPAYGNQAS HNKMMNPSSH THPGHAQQTS VVNGRALPHT VNTMPHTSGM
560 570 580 590 600
NRLTPVKTPL QVPLLHHMQM SALGGYSSVS SCSGYGRMGV LHQEKLPSDL
610 620 630 640 650
DGMFIERLDC DMESIIRNDL MDGDALDFNF DNVLPNQSFP HGVKTTTHSW

VSG
Length:653
Mass (Da):69,444
Last modified:June 1, 2003 - v1
Checksum:i31B6A6785F4F7E59
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY255525 mRNA. Translation: AAO72710.1.
RefSeqiNP_001269185.1. NM_001282256.1.

Genome annotation databases

GeneIDi101967490.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY255525 mRNA. Translation: AAO72710.1.
RefSeqiNP_001269185.1. NM_001282256.1.

3D structure databases

ProteinModelPortaliQ810W5.
SMRiQ810W5. Positions 159-254.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi43179.ENSSTOP00000008695.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi101967490.

Organism-specific databases

CTDi2308.

Phylogenomic databases

eggNOGiKOG2294. Eukaryota.
COG5025. LUCA.
HOVERGENiHBG057789.
InParanoidiQ810W5.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR032067. FOXO-TAD.
IPR032068. FOXO_KIX-bd.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF16676. FOXO-TAD. 1 hit.
PF16675. FOXO_KIX_bdg. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFOXO1_ICTTR
AccessioniPrimary (citable) accession number: Q810W5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 3, 2006
Last sequence update: June 1, 2003
Last modified: March 16, 2016
This is version 87 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.