Forkhead box protein O1 - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot Q12778 (FOXO1_HUMAN)

Last modified November 25, 2008. Version 86. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	655 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Transcription factor.
Subunit structure	Interacts with LRPPRC By similarity.
Subcellular location	Cytoplasm. Nucleus. Note= Shuttles between cytoplasm and nucleus.
Tissue specificity	Ubiquitous.
Post-translational modification	Phosphorylated by AKT1; insulin-induced By similarity. IGF1 rapidly induces phosphorylation of Ser-256, Thr-24, and Ser-319. 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 CK1, leading to nuclear exclusion and loss of function. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Phosphorylated upon DNA damage, probably by ATM or ATR.
Involvement in disease	Chromosomal aberrations involving FOXO1 are a cause of rhabdomyosarcoma 2 (RMS2) [MIM:268220]; also known as alveolar rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3; translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.
Sequence similarities	Contains 1 fork-head DNA-binding domain.

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Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Chromosomal rearrangement
Disease	Proto-oncogene
Ligand	DNA-binding
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	anti-apoptosis Inferred from direct assay. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Ref.9 Inferred from direct assay. Source: UniProtKB
Cellular component	cytoplasm Ref.7 Ref.9 Inferred from direct assay. Source: UniProtKB nucleus Ref.7 Ref.9 Inferred from direct assay. Source: UniProtKB
Molecular function	protein binding Inferred from physical interaction. Source: IntAct sequence-specific DNA binding Ref.9 Inferred from direct assay. Source: UniProtKB transcription activator activity Ref.9 Inferred from direct assay. Source: UniProtKB transcription factor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
AR	P10275	1	EBI-1108782,EBI-608057
CDC2	P06493	4	EBI-1108782,EBI-444308
ESR1	P03372	1	EBI-1108782,EBI-78473

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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

Fork-head

Compositional bias

91 – 102

Poly-Ala

Compositional bias

120 – 130

Poly-Pro

Compositional bias

152 – 155

Poly-Ser

Amino acid modifications

Modified residue

Phosphothreonine; by PKB/AKT1

Modified residue

256

Phosphoserine; by PKB/AKT1

Modified residue

287

Phosphoserine

Modified residue

319

Phosphoserine; by PKB/AKT1

Modified residue

322

Phosphoserine; by CK1

Modified residue

325

Phosphoserine; by CK1

Modified residue

329

Phosphoserine; by DYRK1A

Modified residue

467

Phosphothreonine By similarity

Modified residue

468

Phosphoserine By similarity

Modified residue

505

Phosphoserine

Modified residue

509

Phosphoserine

Experimental info

Mutagenesis

T → A: Nuclear targeting and enhanced transactivation; when associated with A-319

Mutagenesis

245

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

Mutagenesis

248

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

Mutagenesis

251 – 253

RRR → SAS: Disrupts DNA binding

Mutagenesis

256

S → A: Nuclear targeting. 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

Mutagenesis

256

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

Mutagenesis

319

S → A: Nuclear targeting and enhanced transactivation; when associated with A-24

Mutagenesis

329

S → A: Nuclear targeting and enhanced transactivation

Sequence conflict

131

L → V in AAA03629. Ref.1

Sequence conflict

343

V → M in AAH70065. Ref.5

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Sequences

Sequence

Length

Mass (Da)

Tools

Q12778-1 [UniParc].

Last modified October 17, 2006. Version 2.
Checksum: 6DEF6C994BDFDBAB
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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

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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: 8275086] [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: 9479491] [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. Ross M.T. Nature 428:522-528(2004) [PubMed: 15057823] [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lymph and Placenta.
[6]	"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: 10358075] [Abstract] Cited for: PHOSPHORYLATION AT THR-24; SER-256 AND SER-319.
[7]	"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: 11311120] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-329, MUTAGENESIS OF SER-329.
[8]	"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: 11980723] [Abstract] Cited for: PHOSPHORYLATION AT THR-24; SER-256; SER-319; SER-322; SER-325 AND SER-329.
[9]	"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: 12228231] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-24; SER-256 AND SER-319.
[10]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-505 AND SER-509, MASS SPECTROMETRY.
[11]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, MASS SPECTROMETRY.
+	Additional computationally mapped references.

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Cross-references

Sequence databases

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.

PIR

S40521.

RefSeq

NP_002006.2.

UniGene

Hs.370666

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3CO6	X-ray	2.10	C	150-249	[»]
3CO7	X-ray	2.91	C/F	150-266	[»]
3COA	X-ray	2.20	C/F	150-266	[»]

SMR

Q12778. Positions 155-244.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q12778.

PTM databases

PhosphoSite

Q12778.

Genome annotation databases

Ensembl

ENSG00000150907. Homo sapiens. [Contig view]

GeneID

2308.

KEGG

hsa:2308.

Organism-specific databases

HGNC

HGNC:3819. FOXO1.

HPA

HPA001252.

MIM

136533. gene.
268220. phenotype.

Orphanet

780. Rhabdomyosarcoma.
99756. Rhabdomyosarcoma, alveolar.

PharmGKB

PA28237.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

Q12778.

HOVERGEN

Q12778.

Gene expression databases

ArrayExpress

Q12778.

CleanEx

HS_FOXO1.

GermOnline

ENSG00000150907. Homo sapiens.

Family and domain databases

InterPro

IPR001766. TF_Fork_head.
IPR011991. Wing_hlx_DNA_bd.
[Graphical view]

Gene3D

G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 1 hit.

PANTHER

PTHR11829. Fork_box_protein. 1 hit.

Pfam

PF00250. Fork_head. 1 hit.
[Graphical view]

PRINTS

PR00053. FORKHEAD.

ProDom

PD000425. TF_Fork_head. 1 hit.
[Graphical view] [Entries sharing at least one domain]

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 Resources

NextBio

9375.

SOURCE

Search...

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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:	November 25, 2008
This is version 86 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

Human chromosome 13

Human chromosome 13: entries, gene names and cross-references to MIM

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents