P98177 (FOXO4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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) [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	505 AA.
Sequence status	Complete.
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. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity. Ref.8 Ref.10 Ref.11 Ref.12 Ref.14 Ref.17 Ref.19 Ref.20
Subunit structure	Interacts with CREBBP/CBP, CTNNB1, MYOCD, SIRT1, SRF and YWHAZ. Acetylated by CREBBP/CBP and deacetylated by SIRT1. Binding of YWHAZ inhibits DNA-binding. Interacts with USP7; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of TP53. Interacts with NLK, and this inhibits monoubiquitination and transcriptional activity. Ref.12 Ref.13 Ref.14 Ref.17 Ref.19
Subcellular location	Cytoplasm. Nucleus. Note: When phosphorylated, translocated from nucleus to cytoplasm. Dephosphorylation triggers nuclear translocation. Monoubiquitination increases nuclear localization. When deubiquitinated, translocated from nucleus to cytoplasm. Ref.9 Ref.13 Ref.17
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 CREBBP/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. May be phosphorylated at multiple sites by NLK. Ref.8 Ref.9 Ref.15 Ref.18 Monoubiquitinated; monoubiquitination is induced by oxidative stress and reduced by deacetylase inhibitors; results in its relocalization to the nucleus and its increased transcriptional activity. Deubiquitinated by USP7; deubiquitination is induced by oxidative stress; enhances its interaction with USP7 and consequently, deubiquitination; increases its translocation to the cytoplasm and inhibits its transcriptional activity. Hydrogene-peroxide-induced ubiquitination and USP7-mediated deubiquitination have no major effect on its protein stability.
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-197 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 Ubl conjugation
Technical term	3D-structure Complete proteome Pharmaceutical Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Inferred from direct assay Ref.10. Source: UniProtKB cell cycle arrest Inferred from direct assay Ref.10. Source: UniProtKB embryo development Inferred from Biological aspect of Ancestor. Source: RefGenome epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome insulin receptor signaling pathway Inferred from direct assay Ref.8. Source: UniProtKB mitotic G2 DNA damage checkpoint Inferred from Biological aspect of Ancestor. Source: RefGenome muscle organ development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of angiogenesis Inferred from direct assay Ref.11. Source: UniProtKB negative regulation of cell proliferation Inferred from direct assay Ref.10. Source: UniProtKB negative regulation of smooth muscle cell differentiation Inferred from direct assay Ref.14. Source: UniProtKB nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome organ development Inferred from Biological aspect of Ancestor. Source: RefGenome pattern specification process Inferred from Biological aspect of Ancestor. Source: RefGenome phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome positive regulation of transcription from RNA polymerase II promoter Inferred from Biological aspect of Ancestor. Source: RefGenome regulation of sequence-specific DNA binding transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome stem cell differentiation Inferred from mutant phenotype Ref.20. Source: UniProtKB tissue development Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular_component	cytosol Inferred from direct assay Ref.15. 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 distal enhancer sequence-specific DNA binding transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome double-stranded DNA binding Inferred from Biological aspect of Ancestor. Source: RefGenome protein kinase binding Inferred from Biological aspect of Ancestor. Source: RefGenome sequence-specific DNA binding Inferred from mutant phenotype Ref.20. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
SIRT1	Q96EB6	3	EBI-4481939,EBI-1802965

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.15

Modified residue

197

1

Phosphoserine; by PKB/AKT1 Ref.8 Ref.9 Ref.15 Ref.18

Modified residue

200

1

Phosphoserine Ref.18

Modified residue

262

1

Phosphoserine; by PKB/AKT1 Ref.8 Ref.9 Ref.15

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 nucleus and shows increased transcriptional activity. Increased transcriptional and proteasome activities in embryonic stem cells; when associated with A-197 and A-262. Ref.9 Ref.15 Ref.20

Mutagenesis

197

1

S → A: Abolishes phosphorylation. Protein is located mainly in nucleus and shows increased transcriptional activity. Increased transcriptional and proteasome activities in embryonic stem cells; when associated with A-32 and A-262. Ref.8 Ref.9 Ref.15 Ref.20

Mutagenesis

262

1

S → A: Abolishes phosphorylation. No effect on cellular location or transcriptional activity. Increased transcriptional and proteasome activities in embryonic stem cells; when associated with A-32 and A-197. Ref.8 Ref.9 Ref.15 Ref.20

Sequence conflict

1 – 11

11

MDPGNENSATE → MRIQPQK in CAA63819. 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 in CAA63819. Ref.2

Sequence conflict

422

1

P → R in AAL85197. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

505

Helix Strand Turn

Details...

Helix

106 – 116

11

Beta strand

117 – 119

3

Helix

124 – 134

11

Helix

136 – 138

3

Helix

139 – 142

4

Helix

149 – 160

12

Beta strand

164 – 167

4

Turn

170 – 172

3

Beta strand

173 – 175

3

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) [UniParc]. 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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZETA).
[4]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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] (ISOFORM 1).
[7]	"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] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION. Tissue: Bone marrow.
[8]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-197 AND SER-262, MUTAGENESIS OF SER-197 AND SER-262.
[9]	"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] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-197 AND SER-262, MUTAGENESIS OF THR-32; SER-197 AND SER-262.
[10]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH CREBBP AND SIRT1, ACETYLATION.
[13]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH YWHAZ, SUBCELLULAR LOCATION.
[14]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MYOCD AND SRF.
[15]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-32; SER-197 AND SER-262, MUTAGENESIS OF THR-32; SER-197 AND SER-262.
[16]	"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] [Europe PMC] [Abstract] Cited for: PHARMACEUTICAL USE.
[17]	"FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP." van der Horst A., de Vries-Smits A.M., Brenkman A.B., van Triest M.H., van den Broek N., Colland F., Maurice M.M., Burgering B.M. Nat. Cell Biol. 8:1064-1073(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH USP7, UBIQUITINATION, DEUBIQUITINATION BY USP7, SUBCELLULAR LOCATION.
[18]	Carrascal M., Abian J. Submitted (JAN-2008) to UniProtKB Cited for: PHOSPHORYLATION AT SER-197 AND SER-200, MASS SPECTROMETRY.
[19]	"Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase." Szypowska A.A., de Ruiter H., Meijer L.A.T., Smits L.M.M., Burgering B.M.T. Antioxid. Redox Signal. 14:563-578(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH NLK; CTNNB1 AND CREBBP.
[20]	"Increased proteasome activity in human embryonic stem cells is regulated by PSMD11." Vilchez D., Boyer L., Morantte I., Lutz M., Merkwirth C., Joyce D., Spencer B., Page L., Masliah E., Berggren W.T., Gage F.H., Dillin A. Nature 489:304-308(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF THR-32; SER-197 AND SER-262.
[21]	"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] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 86-211.
[22]	"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] [Europe PMC] [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

EMBL
GenBank
DDBJ

Y11284, Y11285, Y11286 Genomic DNA. Translation: CAA72156.1.
X93996 mRNA. Translation: CAA63819.1.
AF384029 mRNA. Translation: AAL85197.1.
AL590764 Genomic DNA. No translation available.
CH471132 Genomic DNA. Translation: EAX05321.1.
BC106761 mRNA. Translation: AAI06762.1.
U10072 mRNA. Translation: AAA82171.1. Sequence problems.

IPI

IPI00024316.
IPI00220121.

PIR

I38654.

RefSeq

NP_001164402.1. NM_001170931.1.
NP_005929.2. NM_005938.3.

UniGene

Hs.584654.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E17	NMR	-	A	86-211	[»]
3L2C	X-ray	1.87	A	86-187	[»]

ProteinModelPortal

P98177.

ModBase

Search...

Protein-protein interaction databases

IntAct

P98177. 2 interactions.

STRING

9606.ENSP00000363377.

PTM databases

PhosphoSite

P98177.

Polymorphism databases

DMDM

110825720.

Proteomic databases

PaxDb

P98177.

PRIDE

P98177.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000341558; ENSP00000342209; ENSG00000184481.
ENST00000374259; ENSP00000363377; ENSG00000184481.

GeneID

4303.

KEGG

hsa:4303.

UCSC

uc004dys.2. human.
uc004dyt.2. human.

Organism-specific databases

CTD

4303.

GeneCards

GC0XP070316.

HGNC

HGNC:7139. FOXO4.

HPA

CAB037151.

MIM

300033. gene.

neXtProt

NX_P98177.

PharmGKB

PA162388882.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5025.

HOGENOM

HOG000251635.

HOVERGEN

HBG057789.

KO

K12358.

OMA

FSLQHPG.

OrthoDB

EOG441QBC.

PhylomeDB

P98177.

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_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

Gene expression databases

Bgee

P98177.

CleanEx

HS_FOXO4.

Genevestigator

P98177.

GermOnline

ENSG00000184481. 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

EvolutionaryTrace

P98177.

GenomeRNAi

4303.

NextBio

16943.

SOURCE

Search...

Entry information

Entry name

FOXO4_HUMAN

Accession

Primary (citable) accession number: P98177
Secondary accession number(s): B7WPJ7 , O43821, Q13720, Q3KPF1, Q8TDK9

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	July 25, 2006
Last modified:	May 1, 2013
This is version 136 of the entry and version 5 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.