Q12778 (FOXO1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Forkhead box protein O1

Alternative name(s):
Forkhead box protein O1A
Forkhead in rhabdomyosarcoma

Gene names

Name:	FOXO1
Synonyms:	FKHR, FOXO1A

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	655 AA.
Sequence status	Complete.
Protein existence	Evidence 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.8 Ref.12 Ref.13 Ref.14 Ref.18 Ref.19 Ref.22
Subunit structure	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-256 leading to its nuclear import By similarity. 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. Ref.10 Ref.13 Ref.14 Ref.15 Ref.16 Ref.18
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-256 by PKB/AKT1 leads, via stimulation of Thr-24 phosphorylation, to binding of 14-3-3 proteins and nuclear export to the cytoplasm where it is degraded by the ubiquitin-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. Retained in the nucleus on methylation. Ref.9 Ref.10 Ref.12 Ref.14 Ref.19 Ref.22
Tissue specificity	Ubiquitous. Ref.2
Induction	Expression is regulated by KRIT1. Levels of expression also regulated by FOXC1 which binds to a conserved element in the FOXO1 promoter. Ref.20
Post-translational modification	Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 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-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, 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-329 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta-cells under oxidative stress leading to nuclear retention By similarity. Phosphorylation of Ser-249 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-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.14 Ref.18 Ref.19 Ref.22 Ref.24 Ubiquitinated by SRT2. Ubiquitination leads to proteasomal degradation. Ref.15 Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress By similarity. 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-256. 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.
Involvement in disease	Rhabdomyosarcoma 2 (RMS2) [MIM:268220]: A form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchimal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. Note: The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.
Sequence similarities	Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
Biological process	Apoptosis Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Chromosomal rearrangement
Disease	Proto-oncogene
Ligand	DNA-binding
Molecular function	Activator
PTM	Acetylation Methylation Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW blood vessel development Inferred from Biological aspect of Ancestor. Source: RefGenome cellular glucose homeostasis Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB cellular response to cold Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB cellular response to nitric oxide Inferred from sequence or structural similarity. Source: UniProtKB cellular response to starvation Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB embryo development Inferred from Biological aspect of Ancestor. Source: RefGenome endocrine pancreas development Traceable author statement. Source: Reactome epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fat cell differentiation Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome innate immune response Traceable author statement. Source: Reactome insulin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from direct assay PubMed 10871843. Source: UniProtKB negative regulation of fat cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of stress-activated MAPK cascade Inferred from direct assay PubMed 19696738. Source: BHF-UCL negative regulation of transcription, DNA-dependent Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB neurotrophin TRK receptor signaling pathway Traceable author statement. Source: Reactome pattern specification process Inferred from Biological aspect of Ancestor. Source: RefGenome phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome positive regulation of gluconeogenesis Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 10871843Ref.12. Source: UniProtKB protein acetylation Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB regulation of cell proliferation Inferred from Biological aspect of Ancestor. Source: RefGenome regulation of energy homeostasis Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB regulation of sequence-specific DNA binding transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome response to DNA damage stimulus Inferred from sequence or structural similarity. Source: UniProtKB temperature homeostasis Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB tissue development Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular_component	cytosol Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB mitochondrion Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB transcription factor complex Inferred from Biological aspect of Ancestor. Source: RefGenome
Molecular_function	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 electronic annotation. Source: Compara RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome chromatin binding Inferred from sequence or structural similarity PubMed 22510882. Source: UniProtKB double-stranded DNA binding Inferred from Biological aspect of Ancestor. Source: RefGenome protein kinase binding Inferred from Biological aspect of Ancestor. Source: RefGenome protein phosphatase 2A binding Inferred from sequence or structural similarity. Source: UniProtKB sequence-specific DNA binding Inferred from direct assay Ref.12. Source: UniProtKB transcription factor binding Inferred from Biological aspect of Ancestor. Source: RefGenome
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDK1	P06493	5	EBI-1108782,EBI-444308
CREBBP	Q92793	2	EBI-1108782,EBI-81215
ESR1	P03372	2	EBI-1108782,EBI-78473
FHL2	Q14192	8	EBI-1108782,EBI-701903
SIRT1	Q96EB6	3	EBI-1108782,EBI-1802965
Sirt1	Q923E4	2	EBI-1108782,EBI-1802585	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 655

655

Forkhead box protein O1

PRO_0000091872

Regions

DNA binding

159 – 235

77

Fork-head Ref.8 Ref.24

Region

211 – 218

8

DNA-binding

Region

234 – 237

4

DNA-binding

Region

283 – 563

281

Sufficient for interaction with NLK By similarity

Region

363 – 459

97

Required for interaction with RUNX2 By similarity

Motif

251 – 253

3

Nuclear localization signal

Motif

462 – 466

5

Required for interaction with SIRT1 By similarity

Compositional bias

91 – 102

12

Poly-Ala

Compositional bias

120 – 130

11

Poly-Pro

Compositional bias

152 – 155

4

Poly-Ser

Sites

Site

158

1

DNA-binding

Site

165

1

DNA-binding

Site

225

1

DNA-binding

Amino acid modifications

Modified residue

24

1

Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1 Ref.7 Ref.10 Ref.11

Modified residue

212

1

Phosphoserine; by STK4/MST1 Ref.19 Ref.22 Ref.24

Modified residue

245

1

N6-acetyllysine By similarity

Modified residue

248

1

N6-acetyllysine By similarity

Modified residue

249

1

Phosphoserine; by CDK1 Ref.18

Modified residue

251

1

Omega-N-methylarginine; by PRMT1 By similarity

Modified residue

253

1

Omega-N-methylarginine; by PRMT1 By similarity

Modified residue

256

1

Phosphoserine; by PKB/AKT1 and SGK1 Ref.7 Ref.8 Ref.10 Ref.11

Modified residue

265

1

N6-acetyllysine By similarity

Modified residue

287

1

Phosphoserine Ref.17 Ref.21 Ref.23

Modified residue

319

1

Phosphoserine; by PKB/AKT1 Ref.7 Ref.10 Ref.11

Modified residue

322

1

Phosphoserine; by CK1 and SGK1 Ref.11

Modified residue

325

1

Phosphoserine; by CK1 Ref.11

Modified residue

329

1

Phosphoserine; by DYRK1A Ref.9 Ref.11

Modified residue

467

1

Phosphothreonine By similarity

Modified residue

468

1

Phosphoserine By similarity

Experimental info

Mutagenesis

24

1

T → A: Abolishes PKB/AKT1-mediated phosphorylation but does not prevent phosphorylation of Ser-256 or Ser-319. Also inhibits binding of 14-3-3 proteins. Nuclear in unstimulated cells, and little export to cytoplasm on IGF1 stimulation. Inhibits the PKB/AKT1-mediated activity towards other substrates but does not block the IGF1-activated 'T-308' of phosphorylation of PKB/AKT1; when associated with A-256 and A-319. Targeted to the nucleus and enhances transactivation; when associated with A-319. Ref.10 Ref.12

Mutagenesis

212

1

S → A: Abolishes STK4/MST1-mediated phosphorylation. Ref.19

Mutagenesis

245

1

K → A: Disrupts DNA-binding; when associated with A-248.

Mutagenesis

248

1

K → A: Disrupts DNA-binding; when associated with A-245.

Mutagenesis

249

1

S → A: Impaired phosphorylation by CDK1. Ref.18 Ref.24

Mutagenesis

249

1

S → E: No effect on DNA-binding. Ref.18 Ref.24

Mutagenesis

251 – 253

3

RRR → SAS: No targeting to the nucleus and disruption of DNA-binding.

Mutagenesis

256

1

S → A: Completely abolishes PKB/AKT1-mediated phosphorylation at all three sites, and inhibits binding of 14-3-3 proteins. Inhibits the PKB/AKT1-mediated activity towards other substrates but does not block the IGF1-activated 'T-308' of phosphorylation of PKB/AKT1; when associated with or without A-24 and A-319. Nuclear in unstimulated cells, and little export to cytoplasm on IGF1 stimulation. Abolishes the ability of IGF1 to suppress transactivation. Prevents T-24 and S-319 phosphorylation. Enhances transactivation; when associated with A-24 and A-319. Ref.10 Ref.12 Ref.15

Mutagenesis

256

1

S → D: Reduces DNA binding, promotes nuclear exclusion and partially promotes T-24 and S-319 phosphorylation. Reduces DNA binding, does not promote nuclear exclusion but reduces transactivation; when associated with A-24 and A-319. Ref.10 Ref.12 Ref.15

Mutagenesis

319

1

S → A: Abolishes PKB/AKT1-mediated phosphorylation but does not prevent phosphorylation of Ser-24 or Ser-256. Inhibits the PKB/AKT1-mediated activity towards other substrates but does not block the IGF1-activated 'T-308' of phosphorylation of PKB/AKT1; when associated with A-24 and A-256. Targeted to the nucleus and enhances transactivation; when associated with A-24. Ref.10 Ref.12

Mutagenesis

329

1

S → A: Targeted to the nucleus and enhances transactivation. Ref.9

Sequence conflict

131

1

L → V in AAA03629. Ref.1

Sequence conflict

343

1

V → M in AAH70065. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

655

Helix Strand Turn

Details...

Beta strand

156 – 158

3

Helix

165 – 175

11

Beta strand

176 – 179

4

Helix

183 – 193

11

Helix

195 – 197

3

Helix

203 – 219

17

Beta strand

223 – 226

4

Turn

230 – 232

3

Beta strand

236 – 239

4

Sequences

	Sequence		Length	Mass (Da)
	Q12778 [UniParc]. Last modified October 17, 2006. Version 2. Checksum: 6DEF6C994BDFDBAB	FASTA	655	69,662
	10 20 30 40 50 60 MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGSAAA NPDAAAGLPS 70 80 90 100 110 120 ASAAAVSADF MSNLSLLEES EDFPQAPGSV AAAVAAAAAA AATGGLCGDF QGPEAGCLHP 130 140 150 160 170 180 APPQPPPPGP LSQHPPVPPA AAGPLAGQPR KSSSSRRNAW GNLSYADLIT KAIESSAEKR 190 200 210 220 230 240 LTLSQIYEWM VKSVPYFKDK GDSNSSAGWK NSIRHNLSLH SKFIRVQNEG TGKSSWWMLN 250 260 270 280 290 300 PEGGKSGKSP RRRAASMDNN SKFAKSRSRA AKKKASLQSG QEGAGDSPGS QFSKWPASPG 310 320 330 340 350 360 SHSNDDFDNW STFRPRTSSN ASTISGRLSP IMTEQDDLGE GDVHSMVYPP SAAKMASTLP 370 380 390 400 410 420 SLSEISNPEN MENLLDNLNL LSSPTSLTVS TQSSPGTMMQ QTPCYSFAPP NTSLNSPSPN 430 440 450 460 470 480 YQKYTYGQSS MSPLPQMPIQ TLQDNKSSYG GMSQYNCAPG LLKELLTSDS PPHNDIMTPV 490 500 510 520 530 540 DPGVAQPNSR VLGQNVMMGP NSVMSTYGSQ ASHNKMMNPS SHTHPGHAQQ TSAVNGRPLP 550 560 570 580 590 600 HTVSTMPHTS GMNRLTQVKT PVQVPLPHPM QMSALGGYSS VSSCNGYGRM GLLHQEKLPS 610 620 630 640 650 DLDGMFIERL DCDMESIIRN DLMDGDTLDF NFDNVLPNQS FPHSVKTTTH SWVSG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma." Galili N., Davis R.J., Fredericks W.J., Mukhopadhyay S., Rauscher F.J. III, Emanuel B.S., Rovera G., Barr F.G. Nat. Genet. 5:230-235(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH PAX3.
[2]	"Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily." Anderson M.J., Viars C.S., Czekay S., Cavenee W.K., Arden K.C. Genomics 47:187-199(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Rhabdomyosarcoma.
[3]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lymph and Placenta.
[6]	"Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma." Davis R.J., D'Cruz C.M., Lovell M.A., Biegel J.A., Barr F.G. Cancer Res. 54:2869-2872(1994) [PubMed] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH PAX7.
[7]	"Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B." Rena G., Guo S., Cichy S.C., Unterman T.G., Cohen P. J. Biol. Chem. 274:17179-17183(1999) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-24; SER-256 AND SER-319.
[8]	"Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence." Guo S., Rena G., Cichy S., He X., Cohen P., Unterman T. J. Biol. Chem. 274:17184-17192(1999) [PubMed] [Europe PMC] [Abstract] Cited for: DNA-BINDING, PHOSPHORYLATION AT SER-256, FUNCTION.
[9]	"The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site." Woods Y.L., Rena G., Morrice N., Barthel A., Becker W., Guo S., Unterman T.G., Cohen P. Biochem. J. 355:597-607(2001) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-329, MUTAGENESIS OF SER-329.
[10]	"Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting." Rena G., Prescott A.R., Guo S., Cohen P., Unterman T.G. Biochem. J. 354:605-612(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH YWHAG AND YWHAZ, PHOSPHORYLATION AT THR-24; SER-256 AND SER-319, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-24; SER-256 AND SER-319.
[11]	"Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion." Rena G., Woods Y.L., Prescott A.R., Peggie M., Unterman T.G., Williams M.R., Cohen P. EMBO J. 21:2263-2271(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-24; SER-256; SER-319; SER-322; SER-325 AND SER-329.
[12]	"Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding." Zhang X., Gan L., Pan H., Guo S., He X., Olson S.T., Mesecar A., Adam S., Unterman T.G. J. Biol. Chem. 277:45276-45284(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-24; SER-256 AND SER-319.
[13]	"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: INTERACTION WITH CREBBP AND SIRT1, ACETYLATION, DEACETYLATION, FUNCTION.
[14]	"The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription." Perrot V., Rechler M.M. Mol. Endocrinol. 19:2283-2298(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EP300, ACETYLATION, SUBCELLULAR LOCATION, PHOSPHORYLATION, FUNCTION.
[15]	"Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation." Huang H., Regan K.M., Wang F., Wang D., Smith D.I., van Deursen J.M., Tindall D.J. Proc. Natl. Acad. Sci. U.S.A. 102:1649-1654(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SKP2, UBIQUITINATION, MUTAGENESIS OF SER-256.
[16]	"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: INTERACTION WITH PRMT1.
[17]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[18]	"Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons." Yuan Z., Becker E.B.E., Merlo P., Yamada T., DiBacco S., Konishi Y., Schaefer E.M., Bonni A. Science 319:1665-1668(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-249 BY CDK1, INTERACTION WITH CDK1 AND 14-3-3 PROTEINS, MUTAGENESIS OF SER-249.
[19]	"Regulation of neuronal cell death by MST1-FOXO1 signaling." Yuan Z., Lehtinen M.K., Merlo P., Villen J., Gygi S., Bonni A. J. Biol. Chem. 284:11285-11292(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-212, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF SER-212.
[20]	"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: INDUCTION.
[21]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[22]	"Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner." Valis K., Prochazka L., Boura E., Chladova J., Obsil T., Rohlena J., Truksa J., Dong L.F., Ralph S.J., Neuzil J. Cancer Res. 71:946-954(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-212.
[23]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, MASS SPECTROMETRY.
[24]	"Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification." Brent M.M., Anand R., Marmorstein R. Structure 16:1407-1416(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 151-266, DNA-BINDING, PHOSPHORYLATION AT SER-212; SER-218; SER-234 AND SER-235, ACETYLATION, MASS SPECTROMETRY, MUTAGENESIS OF SER-249.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U02310 mRNA. Translation: AAA03629.1.
AF032885 mRNA. Translation: AAC39591.1.
BT007455 mRNA. Translation: AAP36123.1.
AL355132, AL133318 Genomic DNA. Translation: CAH70978.1.
AL133318, AL355132 Genomic DNA. Translation: CAI16970.1.
BC021981 mRNA. Translation: AAH21981.1.
BC070065 mRNA. Translation: AAH70065.3.

IPI

IPI00289866.

PIR

S40521.

RefSeq

NP_002006.2. NM_002015.3.

UniGene

Hs.370666.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3CO6	X-ray	2.10	C	151-249	[»]
3CO7	X-ray	2.91	C/F	151-266	[»]
3COA	X-ray	2.20	C/F	151-266	[»]

ProteinModelPortal

Q12778.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-35654N.

IntAct

Q12778. 8 interactions.

STRING

9606.ENSP00000368880.

PTM databases

PhosphoSite

Q12778.

Polymorphism databases

DMDM

116241368.

Proteomic databases

PaxDb

Q12778.

PRIDE

Q12778.

Protocols and materials databases

DNASU

2308.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000379561; ENSP00000368880; ENSG00000150907.

GeneID

2308.

KEGG

hsa:2308.

UCSC

uc001uxl.4. human.

Organism-specific databases

CTD

2308.

GeneCards

GC13M041129.

HGNC

HGNC:3819. FOXO1.

HPA

CAB022326.
HPA001252.

MIM

136533. gene.
268220. phenotype.

neXtProt

NX_Q12778.

Orphanet

99756. Alveolar rhabdomyosarcoma.

PharmGKB

PA28237.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5025.

HOGENOM

HOG000251635.

HOVERGEN

HBG057789.

InParanoid

Q12778.

KO

K07201.

OMA

GVKTTTH.

OrthoDB

EOG49S66C.

PhylomeDB

Q12778.

Enzyme and pathway databases

Pathway_Interaction_DB

angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
foxopathway. FoxO family signaling.
il6_7pathway. IL6-mediated signaling events.
ar_tf_pathway. Regulation of Androgen receptor activity.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
hdac_classiii_pathway. Signaling events mediated by HDAC Class III.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

SignaLink

Q12778.

Gene expression databases

Bgee

Q12778.

CleanEx

HS_FOXO1.

Genevestigator

Q12778.

GermOnline

ENSG00000150907. Homo sapiens.

Family and domain databases

Gene3D

1.10.10.10. 1 hit.

InterPro

IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]

Pfam

PF00250. Fork_head. 1 hit.
[Graphical view]

PRINTS

PR00053. FORKHEAD.

SMART

SM00339. FH. 1 hit.
[Graphical view]

PROSITE

PS00657. FORK_HEAD_1. False negative.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q12778.

ChEMBL

CHEMBL5294.

ChiTaRS

FOXO1. human.

EvolutionaryTrace

Q12778.

GenomeRNAi

2308.

NextBio

9375.

SOURCE

Search...

Entry information

Entry name

FOXO1_HUMAN

Accession

Primary (citable) accession number: Q12778
Secondary accession number(s): O43523, Q5VYC7, Q6NSK6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	October 17, 2006
Last modified:	May 29, 2013
This is version 140 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.