Reviewed, UniProtKB/Swiss-Prot O43524 (FOXO3_HUMAN)

Names and origin

Protein names

Recommended name:
    Forkhead box protein O3
Alternative name(s):
    Forkhead in rhabdomyosarcoma-like 1
    AF6q21 protein

Gene names

Name:	FOXO3
Synonyms:	FKHRL1, FOXO3A

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	673 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Ref.5 Ref.7
Subunit structure	Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration. Upon oxidative stress, interacts with STK4, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation. Ref.7
Subcellular location	Cytoplasm › cytosol. Nucleus. Note: Translocates to the nucleus upon oxidative stress and in the absence of survival factors. Ref.5 Ref.7
Tissue specificity	Ubiquitous. Ref.1
Post-translational modification	In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB. This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm. Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis. Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue. Phosphorylated by STK4 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation. Ref.5 Ref.7 Ref.6 Ref.8 Ref.9
Involvement in disease	A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX.
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	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	apoptosis Ref.5 Inferred from direct assay. Source: UniProtKB positive regulation of erythrocyte differentiation Inferred from direct assay. Source: MGI positive regulation of transcription from RNA polymerase II promoter Ref.5 Inferred from direct assay. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Ref.5 Ref.7 Inferred from direct assay. Source: UniProtKB
Molecular function	protein kinase binding Ref.7 Inferred from physical interaction. Source: UniProtKB sequence-specific DNA binding Ref.5 Inferred from direct assay. Source: UniProtKB transcription activator activity Ref.5 Inferred from direct assay. Source: UniProtKB transcription factor activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FOXM1	Q08050	1	EBI-1644164,EBI-866480
SIRT3	Q9NTG7	1	EBI-1644164,EBI-724621

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 673

673

Forkhead box protein O3

PRO_0000091874

Regions

DNA binding

157 – 251

95

Fork-head

Motif

242 – 259

18

Nuclear localization signal Ref.11

Amino acid modifications

Modified residue

32

1

Phosphothreonine; by PKB/AKT1 Ref.5

Modified residue

209

1

Phosphoserine; by STK4 Ref.7

Modified residue

253

1

Phosphoserine; by PKB/AKT1 Ref.5

Modified residue

280

1

Phosphoserine Ref.9

Modified residue

284

1

Phosphoserine Ref.9

Modified residue

315

1

Phosphoserine; by SGK Ref.5 Ref.6

Modified residue

421

1

Phosphoserine Ref.8

Modified residue

427

1

Phosphothreonine Ref.8

Experimental info

Mutagenesis

32

1

T → A: Abolishes YWHAZ-binding; when associated with A-253. Exclusively nuclear, induces transcription and promotes apoptosis; when associated with A-253 and A-315. Ref.5

Mutagenesis

209

1

S → A: Impairs nuclear translocation upon oxidative stress. Ref.7

Mutagenesis

242

1

K → A: Slightly decreases DNA affinity. Ref.11

Mutagenesis

245

1

K → A: Decreases DNA affinity. Ref.11

Mutagenesis

253

1

S → A: Abolishes YWHAZ-binding; when associated with A-32. Exclusively nuclear, induces transcription and promotes apoptosis; when associated with A-32 and A-315. Ref.5

Mutagenesis

315

1

S → A: No effect on YWHAZ-binding. Promotes nuclear translocation. Exclusively nuclear, induces transcription and promotes apoptosis; when associated with A-32 and A-253. Ref.5

Sequence conflict

156 – 163

8

AWGNLSYA → WGKPVYS in CAA04860. Ref.4

Sequence conflict

238 – 246

9

PDGGKSGKA → LMGEERKT in CAA04860. Ref.4

Sequence conflict

253

1

S → T in CAA04860. Ref.4

Sequence conflict

271

1

Missing in CAA04860. Ref.4

Sequence conflict

292 – 330

39

PGSPT…PIMAS → AWQPHVNAAVMSWMRGRTSV HAPILTPAQSVAACRPSWQV in CAA04860. Ref.4

Sequence conflict

345 – 361

17

PMLYS…SVSKP → AHALQHVSQPVTFSKQA in CAA04860. Ref.4

Sequence conflict

367

1

P → R in CAA04860. Ref.4

Sequence conflict

371

1

D → E in CAA04860. Ref.4

Sequence conflict

382 – 383

2

LT → AD in CAA04860. Ref.4

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

673

Helix Strand Turn

Details...

Helix

162 – 169

8

Beta strand

172 – 176

5

Helix

180 – 189

10

Beta strand

198 – 200

3

Helix

206 – 216

11

Beta strand

217 – 223

7

Beta strand

226 – 229

4

Beta strand

233 – 236

4

Sequences

	Sequence		Length	Mass (Da)
	O43524-1 [UniParc]. Last modified June 1, 1998. Version 1. Checksum: E5B4E830665A9982	FASTA	673	71,277
	10 20 30 40 50 60 MAEAPASPAP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE TAADSMIPEE 70 80 90 100 110 120 EDDEDDEDGG GRAGSAMAIG GGGGSGTLGS GLLLEDSARV LAPGGQDPGS GPATAAGGLS 130 140 150 160 170 180 GGTQALLQPQ QPLPPPQPGA AGGSGQPRKC SSRRNAWGNL SYADLITRAI ESSPDKRLTL 190 200 210 220 230 240 SQIYEWMVRC VPYFKDKGDS NSSAGWKNSI RHNLSLHSRF MRVQNEGTGK SSWWIINPDG 250 260 270 280 290 300 GKSGKAPRRR AVSMDNSNKY TKSRGRAAKK KAALQTAPES ADDSPSQLSK WPGSPTSRSS 310 320 330 340 350 360 DELDAWTDFR SRTNSNASTV SGRLSPIMAS TELDEVQDDD APLSPMLYSS SASLSPSVSK 370 380 390 400 410 420 PCTVELPRLT DMAGTMNLND GLTENLMDDL LDNITLPPSQ PSPTGGLMQR SSSFPYTTKG 430 440 450 460 470 480 SGLGSPTSSF NSTVFGPSSL NSLRQSPMQT IQENKPATFS SMSHYGNQTL QDLLTSDSLS 490 500 510 520 530 540 HSDVMMTQSD PLMSQASTAV SAQNSRRNVM LRNDPMMSFA AQPNQGSLVN QNLLHHQHQT 550 560 570 580 590 600 QGALGGSRAL SNSVSNMGLS ESSSLGSAKH QQQSPVSQSM QTLSDSLSGS SLYSTSANLP 610 620 630 640 650 660 VMGHEKFPSD LDLDMFNGSL ECDMESIIRS ELMDADGLDF NFDSLISTQN VVGLNVGNFT 670 GAKQASSQSW VPG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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.
[2]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"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: Muscle and Placenta.
[4]	"AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily." Hillion J., Le Coniat M., Jonveaux P., Berger R., Bernard O.A. Blood 90:3714-3719(1997) [PubMed: 9345057] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-383, INVOLVEMENT IN SECONDARY ACUTE LEUKEMIAS.
[5]	"Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor." Brunet A., Bonni A., Zigmond M.J., Lin M.Z., Juo P., Hu L.S., Anderson M.J., Arden K.C., Blenis J., Greenberg M.E. Cell 96:857-868(1999) [PubMed: 10102273] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-32; SER-253 AND SER-315, MUTAGENESIS OF THR-32; SER-253 AND SER-315.
[6]	"Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)." Brunet A., Park J., Tran H., Hu L.S., Hemmings B.A., Greenberg M.E. Mol. Cell. Biol. 21:952-965(2001) [PubMed: 11154281] [Abstract] Cited for: PHOSPHORYLATION AT SER-315.
[7]	"A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span." Lehtinen M.K., Yuan Z., Boag P.R., Yang Y., Villen J., Becker E.B.E., DiBacco S., de la Iglesia N., Gygi S.P., Blackwell T.K., Bonni A. Cell 125:987-1001(2006) [PubMed: 16751106] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-209, INTERACTION WITH STK4 AND YWHAB, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-209.
[8]	"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis." Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421 AND THR-427, MASS SPECTROMETRY.
[9]	"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-280 AND SER-284, MASS SPECTROMETRY.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification." Tsai K.-L., Sun Y.-J., Huang C.-Y., Yang J.-Y., Hung M.-C., Hsiao C.-D. Nucleic Acids Res. 35:6984-6994(2007) [PubMed: 17940099] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 158-253 IN COMPLEX WITH DNA, MUTAGENESIS OF LYS-242 AND LYS-245, NUCLEAR LOCALIZATION SIGNAL.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF032886 mRNA. Translation: AAC39592.1.
AL391646, AL365509 Genomic DNA. Translation: CAI16405.1.
AL365509, AL391646 Genomic DNA. Translation: CAI16295.1.
BC020227 mRNA. Translation: AAH20227.1.
BC021224 mRNA. Translation: AAH21224.1.
BC068552 mRNA. Translation: AAH68552.1.
AJ001589 mRNA. Translation: CAA04860.1.
AJ001590 Genomic DNA. Translation: CAA04861.1.

IPI

IPI00012856.

RefSeq

NP_001446.1.
NP_963853.1.

UniGene

Hs.220950

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2K86	NMR	-	A	151-251	[»]
2UZK	X-ray	2.70	A/C	158-253	[»]

SMR

O43524. Positions 152-241.

ModBase

Search...

Protein-protein interaction databases

IntAct

O43524. 10 interactions.

PTM databases

PhosphoSite

O43524.

Proteomic databases

PRIDE

O43524.

Genome annotation databases

Ensembl

ENSG00000118689. Homo sapiens. [Contig view]

GeneID

2309.

KEGG

hsa:2309.

Organism-specific databases

GeneCards

GC06P108988.

H-InvDB

HIX0006119.

HGNC

HGNC:3821. FOXO3.

HPA

CAB004074.

MIM

602681. gene.

PharmGKB

PA28239.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O43524.

HOVERGEN

O43524.

OMA

O43524. RSDPMMS.

Enzyme and pathway databases

Pathway_Interaction_DB

pi3kcipathway. Class I PI3K signaling events.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
foxopathway. FoxO family signaling.
il2_pi3kpathway. IL2 signaling events mediated by PI3K.
insulin_pathway. Insulin Pathway.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
hdac_classiii_pathway. Signaling events mediated by HDAC Class III.
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
pi3kplctrkpathway. Trk receptor signaling mediated by PI3K and PLC-gamma.

Reactome

REACT_11061. Signalling by NGF.

Gene expression databases

ArrayExpress

O43524.

Bgee

O43524.

CleanEx

HS_FOXO3.

GermOnline

ENSG00000118689. Homo sapiens.

Family and domain databases

InterPro

IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
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

9379.

SOURCE

Search...

Entry information

Entry name

FOXO3_HUMAN

Accession

Primary (citable) accession number: O43524
Secondary accession number(s): O15171, Q5T2I7, Q9BZ04

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	June 1, 1998
Last modified:	June 16, 2009
This is version 98 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)