Reviewed, UniProtKB/Swiss-Prot P98177 (FOXO4_HUMAN)

Names and origin

Protein names

Recommended name:
    Forkhead box protein O4
Alternative name(s):
    Fork head domain transcription factor AFX1

Gene names

Name:	FOXO4
Synonyms:	AFX, AFX1, MLLT7

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

General annotation (Comments)

Function	Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Ref.6 Ref.8 Ref.9 Ref.10 Ref.12
Subunit structure	Interacts with CBP, MYOCD, SIRT1, SRF and YWHAZ. Acetylated by CBP and deacetylated by SIRT1. Binding of YWHAZ inhibits DNA-binding. Ref.10 Ref.12 Ref.11
Subcellular location	Cytoplasm. Nucleus. Note: When phosphorylated, translocated from nucleus to cytoplasm. Dephosphorylation triggers nuclear translocation. Ref.11 Ref.7
Tissue specificity	Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform zeta is most abundant in the liver, kidney, and pancreas.
Post-translational modification	Acetylation by CBP, which is induced by peroxidase stress, inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-dependent and stimulates transcriptional activity. Phosphorylation by PKB/AKT1 inhibits transcriptional activity and is responsible for cytoplasmic localization.
Involvement in disease	A chromosomal aberration involving FOXO4 is found in acute leukemias. Translocation t(X;11)(q13;q23) with MLL/HRX. The result is a rogue activator protein.
Pharmaceutical use	A constitutively active FOXO4 mutant where phosphorylation sites Thr-32, Ser-187 and Ser-262 have been mutated to alanine may have therapeutic potential in ERBB2/HER2-overexpressing cancers as it inhibits ERBB2-mediated cell survival, transformation and tumorigenicity.
Sequence similarities	Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
Biological process	Cell cycle Differentiation Myogenesis Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Chromosomal rearrangement
Disease	Proto-oncogene
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Pharmaceutical
Gene Ontology (GO)
Biological process	G1 phase of mitotic cell cycle Ref.8 Inferred from direct assay. Source: UniProtKB cell cycle arrest Ref.8 Inferred from direct assay. Source: UniProtKB cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW insulin receptor signaling pathway Ref.6 Inferred from direct assay. Source: UniProtKB muscle organ development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of angiogenesis Ref.9 Inferred from direct assay. Source: UniProtKB negative regulation of cell proliferation Ref.8 Inferred from direct assay. Source: UniProtKB negative regulation of smooth muscle cell differentiation Ref.12 Inferred from direct assay. Source: UniProtKB regulation of transcription, DNA-dependent Ref.10 Inferred from direct assay. Source: UniProtKB transcription from RNA polymerase II promoter Ref.8 Traceable author statement. Source: ProtInc
Cellular component	cytosol Ref.13 Inferred from direct assay. Source: UniProtKB nucleus Ref.13 Inferred from direct assay. Source: UniProtKB
Molecular function	enzyme binding Ref.10 Inferred from physical interaction. Source: UniProtKB transcription factor activity Ref.8 Inferred from direct assay. Source: UniProtKB transcription factor binding Ref.12 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P98177-1)

Also known as: FOXO4a;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Zeta (identifier: P98177-2)

Also known as: AFXzeta; FOXO4b;

The sequence of this isoform differs from the canonical sequence as follows:
     58-112: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 505

505

Forkhead box protein O4

PRO_0000091875

Regions

DNA binding

100 – 188

89

Fork-head

Amino acid modifications

Modified residue

32

1

Phosphothreonine; by PKB/AKT1 Ref.13

Modified residue

111

1

Phosphoserine Ref.15

Modified residue

197

1

Phosphoserine; by PKB/AKT1 Ref.6 Ref.7 Ref.13 Ref.16

Modified residue

200

1

Phosphoserine Ref.16

Modified residue

262

1

Phosphoserine; by PKB/AKT1 Ref.6 Ref.7 Ref.13

Natural variations

Alternative sequence

58 – 112

55

Missing in isoform Zeta.

VSP_001552

Experimental info

Mutagenesis

32

1

T → A: Abolishes phosphorylation. Protein is located mainly in cytoplasm and shows increased transcriptional activity. Ref.7 Ref.13

Mutagenesis

197

1

S → A: Abolishes phosphorylation. Protein is located mainly in cytoplasm and shows increased transcriptional activity. Ref.6 Ref.7 Ref.13

Mutagenesis

262

1

S → A: Abolishes phosphorylation. No effect on cellular location or transcriptional activity. Ref.6 Ref.7 Ref.13

Sequence conflict

1 – 11

11

MDPGNENSATE → MRIQPQK Ref.2

Sequence conflict

25 – 34

10

QSRPRSCTWP → RAVPLLHLA in CAA72156. Ref.1

Sequence conflict

74

1

P → S in CAA63819. Ref.2

Sequence conflict

79

1

G → A in CAA72156. Ref.1

Sequence conflict

109

1

L → F in CAA63819. Ref.2

Sequence conflict

422

1

P → R Ref.2

Sequence conflict

422

1

P → R Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

505

Helix Strand Turn

Details...

Helix

106 – 116

11

Helix

124 – 134

11

Helix

136 – 138

3

Helix

149 – 160

12

Beta strand

164 – 167

4

Beta strand

177 – 180

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (FOXO4a) [UniParc]. Last modified July 25, 2006. Version 5. Checksum: 0C71C8E2167CEE68	FASTA	505	53,684
	10 20 30 40 50 60 MDPGNENSAT EAAAIIDLDP DFEPQSRPRS CTWPLPRPEI ANQPSEPPEV EPDLGEKVHT 70 80 90 100 110 120 EGRSEPILLP SRLPEPAGGP QPGILGAVTG PRKGGSRRNA WGNQSYAELI SQAIESAPEK 130 140 150 160 170 180 RLTLAQIYEW MVRTVPYFKD KGDSNSSAGW KNSIRHNLSL HSKFIKVHNE ATGKSSWWML 190 200 210 220 230 240 NPEGGKSGKA PRRRAASMDS SSKLLRGRSK APKKKPSVLP APPEGATPTS PVGHFAKWSG 250 260 270 280 290 300 SPCSRNREEA DMWTTFRPRS SSNASSVSTR LSPLRPESEV LAEEIPASVS SYAGGVPPTL 310 320 330 340 350 360 NEGLELLDGL NLTSSHSLLS RSGLSGFSLQ HPGVTGPLHT YSSSLFSPAE GPLSAGEGCF 370 380 390 400 410 420 SSSQALEALL TSDTPPPPAD VLMTQVDPIL SQAPTLLLLG GLPSSSKLAT GVGLCPKPLE 430 440 450 460 470 480 APGPSSLVPT LSMIAPPPVM ASAPIPKALG TPVLTPPTEA ASQDRMPQDL DLDMYMENLE 490 500 CDMDNIISDL MDEGEGLDFN FEPDP
	Isoform Zeta (AFXzeta) (FOXO4b). Checksum: D44C18FAD9C2A747	FASTA	450	47,941
	10 20 30 40 50 60 MDPGNENSAT EAAAIIDLDP DFEPQSRPRS CTWPLPRPEI ANQPSEPPEV EPDLGEKAIE 70 80 90 100 110 120 SAPEKRLTLA QIYEWMVRTV PYFKDKGDSN SSAGWKNSIR HNLSLHSKFI KVHNEATGKS 130 140 150 160 170 180 SWWMLNPEGG KSGKAPRRRA ASMDSSSKLL RGRSKAPKKK PSVLPAPPEG ATPTSPVGHF 190 200 210 220 230 240 AKWSGSPCSR NREEADMWTT FRPRSSSNAS SVSTRLSPLR PESEVLAEEI PASVSSYAGG 250 260 270 280 290 300 VPPTLNEGLE LLDGLNLTSS HSLLSRSGLS GFSLQHPGVT GPLHTYSSSL FSPAEGPLSA 310 320 330 340 350 360 GEGCFSSSQA LEALLTSDTP PPPADVLMTQ VDPILSQAPT LLLLGGLPSS SKLATGVGLC 370 380 390 400 410 420 PKPLEAPGPS SLVPTLSMIA PPPVMASAPI PKALGTPVLT PPTEAASQDR MPQDLDLDMY 430 440 450 MENLECDMDN IISDLMDEGE GLDFNFEPDP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism." Peters U., Haberhausen G., Kostrzewa M., Nolte D., Mueller U. Hum. Genet. 100:569-572(1997) [PubMed: 9341872] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Blood.
[2]	"Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)." Borkhardt A., Repp R., Haas O.A., Leis T., Harbott J., Kreuder J., Hammermann J., Henn T., Lampert F. Oncogene 14:195-202(1997) [PubMed: 9010221] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"An mRNA splice variant of the AFX gene with altered transcriptional activity." Yang Z., Whelan J., Babb R., Bowen B.R. J. Biol. Chem. 277:8068-8075(2002) [PubMed: 11779849] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZETA).
[4]	"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] (ISOFORM 1).
[5]	"Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family." Parry P., Wei Y., Evans G. Genes Chromosomes Cancer 11:79-84(1994) [PubMed: 7529552] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION. Tissue: Bone marrow.
[6]	"Direct control of the forkhead transcription factor AFX by protein kinase B." Kops G.J.P.L., de Ruiter N.D., De Vries-Smits A.M.M., Powell D.R., Bos J.L., Burgering B.M.T. Nature 398:630-634(1999) [PubMed: 10217147] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-197 AND SER-262, MUTAGENESIS OF SER-197 AND SER-262.
[7]	"Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B." Takaishi H., Konishi H., Matsuzaki H., Ono Y., Shirai Y., Saito N., Kitamura T., Ogawa W., Kasuga M., Kikkawa U., Nishizuka Y. Proc. Natl. Acad. Sci. U.S.A. 96:11836-11841(1999) [PubMed: 10518537] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-197 AND SER-262, MUTAGENESIS OF THR-32; SER-197 AND SER-262.
[8]	"AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1." Medema R.H., Kops G.J.P.L., Bos J.L., Burgering B.M.T. Nature 404:782-787(2000) [PubMed: 10783894] [Abstract] Cited for: FUNCTION.
[9]	"The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism." Tang T.T.-L., Lasky L.A. J. Biol. Chem. 278:30125-30135(2003) [PubMed: 12761217] [Abstract] Cited for: FUNCTION.
[10]	"FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1)." van der Horst A., Tertoolen L.G.J., de Vries-Smits L.M.M., Frye R.A., Medema R.H., Burgering B.M.T. J. Biol. Chem. 279:28873-28879(2004) [PubMed: 15126506] [Abstract] Cited for: FUNCTION, INTERACTION WITH CBP AND SIRT1, ACETYLATION.
[11]	"14-3-3 protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4." Obsilova V., Vecer J., Herman P., Pabianova A., Sulc M., Teisinger J., Boura E., Obsil T. Biochemistry 44:11608-11617(2005) [PubMed: 16114898] [Abstract] Cited for: INTERACTION WITH YWHAZ, SUBCELLULAR LOCATION.
[12]	"Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin." Liu Z.-P., Wang Z., Yanagisawa H., Olson E.N. Dev. Cell 9:261-270(2005) [PubMed: 16054032] [Abstract] Cited for: FUNCTION, INTERACTION WITH MYOCD AND SRF.
[13]	"Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family." Matsuzaki H., Ichino A., Hayashi T., Yamamoto T., Kikkawa U. J. Biochem. 138:485-491(2005) [PubMed: 16272144] [Abstract] Cited for: PHOSPHORYLATION AT THR-32; SER-197 AND SER-262, MUTAGENESIS OF THR-32; SER-197 AND SER-262.
[14]	"Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity." Yang H., Zhao R., Yang H.-Y., Lee M.-H. Oncogene 24:1924-1935(2005) [PubMed: 15688030] [Abstract] Cited for: PHARMACEUTICAL USE.
[15]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-111, MASS SPECTROMETRY.
[16]	Carrascal M., Abian J. Submitted (JAN-2008) to UniProtKB Cited for: PHOSPHORYLATION AT SER-197 AND SER-200, MASS SPECTROMETRY.
[17]	"1H, 13C and 15N resonance assignments of the DNA binding domain of the human forkhead transcription factor AFX." Weigelt J., Climent I., Dahlman-Wright K., Wikstrom M. J. Biomol. NMR 17:181-182(2000) [PubMed: 10921784] [Abstract] Cited for: STRUCTURE BY NMR OF 86-211.
[18]	"Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4)." Weigelt J., Climent I., Dahlman-Wright K., Wikstrom M. Biochemistry 40:5861-5869(2001) [PubMed: 11352721] [Abstract] Cited for: STRUCTURE BY NMR OF 86-211.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

Y11284, Y11285, Y11286 Genomic DNA. Translation: CAA72156.1.
X93996 mRNA. Translation: CAA63819.1.
AF384029 mRNA. Translation: AAL85197.1.
BC106761 mRNA. Translation: AAI06762.1.
U10072 mRNA. Translation: AAA82171.1. Sequence problems.

IPI

IPI00024316.
IPI00220121.

PIR

I38654.

RefSeq

NP_005929.2.

UniGene

Hs.584654

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E17	NMR	-	A	86-211	[»]
3BPY	X-ray	1.87	A	97-181	[»]

ModBase

Search...

PTM databases

PhosphoSite

P98177.

Proteomic databases

PRIDE

P98177.

Genome annotation databases

Ensembl

ENSG00000184481. Homo sapiens. [Contig view]

GeneID

4303.

KEGG

hsa:4303.

Organism-specific databases

GeneCards

GC0XP070233.

HGNC

HGNC:7139. FOXO4.

MIM

300033. gene.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P98177.

HOVERGEN

P98177.

OMA

P98177. FSLQHPG.

Enzyme and pathway databases

Pathway_Interaction_DB

pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
foxopathway. FoxO family signaling.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
hdac_classiii_pathway. Signaling events mediated by HDAC Class III.

Reactome

REACT_11061. Signalling by NGF.

Gene expression databases

Bgee

P98177.

CleanEx

HS_FOXO4.

GermOnline

ENSG00000184481. 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

16943.

SOURCE

Search...

Entry information

Entry name

FOXO4_HUMAN

Accession

Primary (citable) accession number: P98177
Secondary accession number(s): O43821 , Q13720, Q3KPF1, Q8TDK9

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	July 25, 2006
Last modified:	June 16, 2009
This is version 93 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)