FOXO4_HUMAN
ID FOXO4_HUMAN Reviewed; 505 AA.
AC P98177; B7WPJ7; O43821; Q13720; Q3KPF1; Q8TDK9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 25-JUL-2006, sequence version 5.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Forkhead box protein O4;
DE AltName: Full=Fork head domain transcription factor AFX1;
GN Name=FOXO4; Synonyms=AFX, AFX1, MLLT7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=9341872; DOI=10.1007/s004390050553;
RA Peters U., Haberhausen G., Kostrzewa M., Nolte D., Mueller U.;
RT "AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as
RT candidate genes of X-linked dystonia parkinsonism.";
RL Hum. Genet. 100:569-572(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9010221; DOI=10.1038/sj.onc.1200814;
RA Borkhardt A., Repp R., Haas O.A., Leis T., Harbott J., Kreuder J.,
RA Hammermann J., Henn T., Lampert F.;
RT "Cloning and characterization of AFX, the gene that fuses to MLL in acute
RT leukemias with a t(X;11)(q13;q23).";
RL Oncogene 14:195-202(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZETA).
RX PubMed=11779849; DOI=10.1074/jbc.m106091200;
RA Yang Z., Whelan J., Babb R., Bowen B.R.;
RT "An mRNA splice variant of the AFX gene with altered transcriptional
RT activity.";
RL J. Biol. Chem. 277:8068-8075(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP CHROMOSOMAL TRANSLOCATION.
RC TISSUE=Bone marrow;
RX PubMed=7529552; DOI=10.1002/gcc.2870110203;
RA Parry P., Wei Y., Evans G.;
RT "Cloning and characterization of the t(X;11) breakpoint from a leukemic
RT cell line identify a new member of the forkhead gene family.";
RL Genes Chromosomes Cancer 11:79-84(1994).
RN [8]
RP FUNCTION, PHOSPHORYLATION AT SER-197 AND SER-262, AND MUTAGENESIS OF
RP SER-197 AND SER-262.
RX PubMed=10217147; DOI=10.1038/19328;
RA Kops G.J.P.L., de Ruiter N.D., De Vries-Smits A.M.M., Powell D.R.,
RA Bos J.L., Burgering B.M.T.;
RT "Direct control of the forkhead transcription factor AFX by protein kinase
RT B.";
RL Nature 398:630-634(1999).
RN [9]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-197 AND SER-262, AND
RP MUTAGENESIS OF THR-32; SER-197 AND SER-262.
RX PubMed=10518537; DOI=10.1073/pnas.96.21.11836;
RA Takaishi H., Konishi H., Matsuzaki H., Ono Y., Shirai Y., Saito N.,
RA Kitamura T., Ogawa W., Kasuga M., Kikkawa U., Nishizuka Y.;
RT "Regulation of nuclear translocation of forkhead transcription factor AFX
RT by protein kinase B.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:11836-11841(1999).
RN [10]
RP FUNCTION.
RX PubMed=10783894; DOI=10.1038/35008115;
RA Medema R.H., Kops G.J.P.L., Bos J.L., Burgering B.M.T.;
RT "AFX-like forkhead transcription factors mediate cell-cycle regulation by
RT Ras and PKB through p27kip1.";
RL Nature 404:782-787(2000).
RN [11]
RP FUNCTION.
RX PubMed=12761217; DOI=10.1074/jbc.m302042200;
RA Tang T.T.-L., Lasky L.A.;
RT "The forkhead transcription factor FOXO4 induces the down-regulation of
RT hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent
RT mechanism.";
RL J. Biol. Chem. 278:30125-30135(2003).
RN [12]
RP FUNCTION, INTERACTION WITH CREBBP AND SIRT1, AND ACETYLATION.
RX PubMed=15126506; DOI=10.1074/jbc.m401138200;
RA van der Horst A., Tertoolen L.G.J., de Vries-Smits L.M.M., Frye R.A.,
RA Medema R.H., Burgering B.M.T.;
RT "FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity
RT protein hSir2(SIRT1).";
RL J. Biol. Chem. 279:28873-28879(2004).
RN [13]
RP INTERACTION WITH YWHAZ, AND SUBCELLULAR LOCATION.
RX PubMed=16114898; DOI=10.1021/bi050618r;
RA Obsilova V., Vecer J., Herman P., Pabianova A., Sulc M., Teisinger J.,
RA Boura E., Obsil T.;
RT "14-3-3 protein interacts with nuclear localization sequence of forkhead
RT transcription factor FoxO4.";
RL Biochemistry 44:11608-11617(2005).
RN [14]
RP FUNCTION, AND INTERACTION WITH MYOCD AND SRF.
RX PubMed=16054032; DOI=10.1016/j.devcel.2005.05.017;
RA Liu Z.-P., Wang Z., Yanagisawa H., Olson E.N.;
RT "Phenotypic modulation of smooth muscle cells through interaction of Foxo4
RT and myocardin.";
RL Dev. Cell 9:261-270(2005).
RN [15]
RP PHOSPHORYLATION AT THR-32; SER-197 AND SER-262, AND MUTAGENESIS OF THR-32;
RP SER-197 AND SER-262.
RX PubMed=16272144; DOI=10.1093/jb/mvi146;
RA Matsuzaki H., Ichino A., Hayashi T., Yamamoto T., Kikkawa U.;
RT "Regulation of intracellular localization and transcriptional activity of
RT FOXO4 by protein kinase B through phosphorylation at the motif sites
RT conserved among the FOXO family.";
RL J. Biochem. 138:485-491(2005).
RN [16]
RP PHARMACEUTICAL USE.
RX PubMed=15688030; DOI=10.1038/sj.onc.1208352;
RA Yang H., Zhao R., Yang H.-Y., Lee M.-H.;
RT "Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1
RT stability, and suppresses HER2-mediated tumorigenicity.";
RL Oncogene 24:1924-1935(2005).
RN [17]
RP FUNCTION, INTERACTION WITH USP7, UBIQUITINATION, DEUBIQUITINATION BY USP7,
RP AND SUBCELLULAR LOCATION.
RX PubMed=16964248; DOI=10.1038/ncb1469;
RA van der Horst A., de Vries-Smits A.M., Brenkman A.B., van Triest M.H.,
RA van den Broek N., Colland F., Maurice M.M., Burgering B.M.;
RT "FOXO4 transcriptional activity is regulated by monoubiquitination and
RT USP7/HAUSP.";
RL Nat. Cell Biol. 8:1064-1073(2006).
RN [18]
RP FUNCTION, AND INTERACTION WITH NLK; CTNNB1 AND CREBBP.
RX PubMed=20874444; DOI=10.1089/ars.2010.3243;
RA Szypowska A.A., de Ruiter H., Meijer L.A.T., Smits L.M.M.,
RA Burgering B.M.T.;
RT "Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-
RT like kinase.";
RL Antioxid. Redox Signal. 14:563-578(2011).
RN [19]
RP FUNCTION, AND MUTAGENESIS OF THR-32; SER-197 AND SER-262.
RX PubMed=22972301; DOI=10.1038/nature11468;
RA Vilchez D., Boyer L., Morantte I., Lutz M., Merkwirth C., Joyce D.,
RA Spencer B., Page L., Masliah E., Berggren W.T., Gage F.H., Dillin A.;
RT "Increased proteasome activity in human embryonic stem cells is regulated
RT by PSMD11.";
RL Nature 489:304-308(2012).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [21]
RP STRUCTURE BY NMR OF 86-211.
RX PubMed=10921784; DOI=10.1023/a:1008358816478;
RA Weigelt J., Climent I., Dahlman-Wright K., Wikstrom M.;
RT "1H, 13C and 15N resonance assignments of the DNA binding domain of the
RT human forkhead transcription factor AFX.";
RL J. Biomol. NMR 17:181-182(2000).
RN [22]
RP STRUCTURE BY NMR OF 86-211.
RX PubMed=11352721; DOI=10.1021/bi001663w;
RA Weigelt J., Climent I., Dahlman-Wright K., Wikstrom M.;
RT "Solution structure of the DNA binding domain of the human forkhead
RT transcription factor AFX (FOXO4).";
RL Biochemistry 40:5861-5869(2001).
CC -!- FUNCTION: Transcription factor involved in the regulation of the
CC insulin signaling pathway. Binds to insulin-response elements (IREs)
CC and can activate transcription of IGFBP1. Down-regulates expression of
CC HIF1A and suppresses hypoxia-induced transcriptional activation of
CC HIF1A-modulated genes. Also involved in negative regulation of the cell
CC cycle. Involved in increased proteasome activity in embryonic stem
CC cells (ESCs) by activating expression of PSMD11 in ESCs, leading to
CC enhanced assembly of the 26S proteasome, followed by higher proteasome
CC activity. {ECO:0000269|PubMed:10217147, ECO:0000269|PubMed:10783894,
CC ECO:0000269|PubMed:12761217, ECO:0000269|PubMed:15126506,
CC ECO:0000269|PubMed:16054032, ECO:0000269|PubMed:16964248,
CC ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:22972301}.
CC -!- SUBUNIT: Interacts with CREBBP/CBP, CTNNB1, MYOCD, SIRT1, SRF and
CC YWHAZ. Acetylated by CREBBP/CBP and deacetylated by SIRT1. Binding of
CC YWHAZ inhibits DNA-binding. Interacts with USP7; the interaction is
CC enhanced in presence of hydrogen peroxide and occurs independently of
CC TP53. Interacts with NLK, and this inhibits monoubiquitination and
CC transcriptional activity. Interacts with FOXK1; the interaction
CC inhibits MEF2C transactivation activity (By similarity).
CC {ECO:0000250|UniProtKB:Q9WVH3, ECO:0000269|PubMed:15126506,
CC ECO:0000269|PubMed:16054032, ECO:0000269|PubMed:16114898,
CC ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:20874444}.
CC -!- INTERACTION:
CC P98177; P98177: FOXO4; NbExp=2; IntAct=EBI-4481939, EBI-4481939;
CC P98177; Q04864: REL; NbExp=3; IntAct=EBI-4481939, EBI-307352;
CC P98177; P31947: SFN; NbExp=3; IntAct=EBI-4481939, EBI-476295;
CC P98177; Q96EB6: SIRT1; NbExp=3; IntAct=EBI-4481939, EBI-1802965;
CC P98177; Q13485: SMAD4; NbExp=2; IntAct=EBI-4481939, EBI-347263;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=When phosphorylated,
CC translocated from nucleus to cytoplasm. Dephosphorylation triggers
CC nuclear translocation. Monoubiquitination increases nuclear
CC localization. When deubiquitinated, translocated from nucleus to
CC cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=FOXO4a;
CC IsoId=P98177-1; Sequence=Displayed;
CC Name=Zeta; Synonyms=AFXzeta, FOXO4b;
CC IsoId=P98177-2; Sequence=VSP_001552;
CC -!- TISSUE SPECIFICITY: Heart, brain, placenta, lung, liver, skeletal
CC muscle, kidney and pancreas. Isoform zeta is most abundant in the
CC liver, kidney, and pancreas.
CC -!- PTM: Acetylation by CREBBP/CBP, which is induced by peroxidase stress,
CC inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-
CC dependent and stimulates transcriptional activity.
CC {ECO:0000269|PubMed:15126506}.
CC -!- PTM: Phosphorylation by PKB/AKT1 inhibits transcriptional activity and
CC is responsible for cytoplasmic localization. May be phosphorylated at
CC multiple sites by NLK. {ECO:0000269|PubMed:10217147,
CC ECO:0000269|PubMed:10518537, ECO:0000269|PubMed:16272144}.
CC -!- PTM: Monoubiquitinated; monoubiquitination is induced by oxidative
CC stress and reduced by deacetylase inhibitors; results in its
CC relocalization to the nucleus and its increased transcriptional
CC activity. Deubiquitinated by USP7; deubiquitination is induced by
CC oxidative stress; enhances its interaction with USP7 and consequently,
CC deubiquitination; increases its translocation to the cytoplasm and
CC inhibits its transcriptional activity. Hydrogene-peroxide-induced
CC ubiquitination and USP7-mediated deubiquitination have no major effect
CC on its protein stability. {ECO:0000269|PubMed:16964248}.
CC -!- DISEASE: Note=A chromosomal aberration involving FOXO4 is found in
CC acute leukemias. Translocation t(X;11)(q13;q23) with KMT2A/MLL1. The
CC result is a rogue activator protein.
CC -!- PHARMACEUTICAL: A constitutively active FOXO4 mutant where
CC phosphorylation sites Thr-32, Ser-197 and Ser-262 have been mutated to
CC alanine may have therapeutic potential in ERBB2/HER2-overexpressing
CC cancers as it inhibits ERBB2-mediated cell survival, transformation and
CC tumorigenicity.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/AFX1ID57.html";
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DR EMBL; Y11284; CAA72156.1; -; Genomic_DNA.
DR EMBL; Y11285; CAA72156.1; JOINED; Genomic_DNA.
DR EMBL; Y11286; CAA72156.1; JOINED; Genomic_DNA.
DR EMBL; X93996; CAA63819.1; -; mRNA.
DR EMBL; AF384029; AAL85197.1; -; mRNA.
DR EMBL; AL590764; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471132; EAX05321.1; -; Genomic_DNA.
DR EMBL; BC106761; AAI06762.1; -; mRNA.
DR EMBL; U10072; AAA82171.1; ALT_SEQ; mRNA.
DR CCDS; CCDS43969.1; -. [P98177-1]
DR CCDS; CCDS55440.1; -. [P98177-2]
DR PIR; I38654; I38654.
DR RefSeq; NP_001164402.1; NM_001170931.1. [P98177-2]
DR RefSeq; NP_005929.2; NM_005938.3. [P98177-1]
DR PDB; 1E17; NMR; -; A=86-211.
DR PDB; 3L2C; X-ray; 1.87 A; A=86-187.
DR PDBsum; 1E17; -.
DR PDBsum; 3L2C; -.
DR AlphaFoldDB; P98177; -.
DR BMRB; P98177; -.
DR SMR; P98177; -.
DR BioGRID; 110449; 27.
DR CORUM; P98177; -.
DR IntAct; P98177; 16.
DR MINT; P98177; -.
DR STRING; 9606.ENSP00000363377; -.
DR GlyGen; P98177; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P98177; -.
DR PhosphoSitePlus; P98177; -.
DR BioMuta; FOXO4; -.
DR DMDM; 110825720; -.
DR EPD; P98177; -.
DR jPOST; P98177; -.
DR MassIVE; P98177; -.
DR MaxQB; P98177; -.
DR PaxDb; P98177; -.
DR PeptideAtlas; P98177; -.
DR PRIDE; P98177; -.
DR ProteomicsDB; 57814; -. [P98177-1]
DR ProteomicsDB; 57815; -. [P98177-2]
DR Antibodypedia; 6096; 1051 antibodies from 46 providers.
DR DNASU; 4303; -.
DR Ensembl; ENST00000341558.3; ENSP00000342209.3; ENSG00000184481.17. [P98177-2]
DR Ensembl; ENST00000374259.8; ENSP00000363377.3; ENSG00000184481.17. [P98177-1]
DR GeneID; 4303; -.
DR KEGG; hsa:4303; -.
DR MANE-Select; ENST00000374259.8; ENSP00000363377.3; NM_005938.4; NP_005929.2.
DR UCSC; uc004dys.3; human. [P98177-1]
DR CTD; 4303; -.
DR DisGeNET; 4303; -.
DR GeneCards; FOXO4; -.
DR HGNC; HGNC:7139; FOXO4.
DR HPA; ENSG00000184481; Tissue enhanced (placenta).
DR MIM; 300033; gene.
DR neXtProt; NX_P98177; -.
DR OpenTargets; ENSG00000184481; -.
DR PharmGKB; PA162388882; -.
DR VEuPathDB; HostDB:ENSG00000184481; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000159334; -.
DR HOGENOM; CLU_023456_1_1_1; -.
DR InParanoid; P98177; -.
DR OMA; GKWGVNS; -.
DR OrthoDB; 1160384at2759; -.
DR PhylomeDB; P98177; -.
DR TreeFam; TF315583; -.
DR PathwayCommons; P98177; -.
DR Reactome; R-HSA-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-9614399; Regulation of localization of FOXO transcription factors.
DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes.
DR Reactome; R-HSA-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR Reactome; R-HSA-9617629; Regulation of FOXO transcriptional activity by acetylation.
DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes.
DR SignaLink; P98177; -.
DR SIGNOR; P98177; -.
DR BioGRID-ORCS; 4303; 17 hits in 735 CRISPR screens.
DR ChiTaRS; FOXO4; human.
DR EvolutionaryTrace; P98177; -.
DR GeneWiki; FOXO4; -.
DR GenomeRNAi; 4303; -.
DR Pharos; P98177; Tbio.
DR PRO; PR:P98177; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; P98177; protein.
DR Bgee; ENSG00000184481; Expressed in adrenal tissue and 205 other tissues.
DR Genevisible; P98177; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:1990841; F:promoter-specific chromatin binding; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; IEA:Ensembl.
DR GO; GO:0007517; P:muscle organ development; IEA:UniProtKB-KW.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0070317; P:negative regulation of G0 to G1 transition; IDA:UniProtKB.
DR GO; GO:0051151; P:negative regulation of smooth muscle cell differentiation; IDA:UniProtKB.
DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:1990785; P:response to water-immersion restraint stress; IEA:Ensembl.
DR GO; GO:0048863; P:stem cell differentiation; IMP:UniProtKB.
DR CDD; cd00059; FH; 1.
DR DisProt; DP01788; -.
DR Gene3D; 1.10.10.10; -; 1.
DR IDEAL; IID00460; -.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR032067; FOXO-TAD.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR Pfam; PF00250; Forkhead; 1.
DR Pfam; PF16676; FOXO-TAD; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative splicing; Cell cycle;
KW Chromosomal rearrangement; Cytoplasm; Developmental protein;
KW Differentiation; DNA-binding; Myogenesis; Nucleus; Pharmaceutical;
KW Phosphoprotein; Proto-oncogene; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..505
FT /note="Forkhead box protein O4"
FT /id="PRO_0000091875"
FT DNA_BIND 100..188
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..100
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 176..246
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 32
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:16272144"
FT MOD_RES 197
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:10217147,
FT ECO:0000269|PubMed:10518537, ECO:0000269|PubMed:16272144"
FT MOD_RES 262
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:10217147,
FT ECO:0000269|PubMed:10518537, ECO:0000269|PubMed:16272144"
FT VAR_SEQ 58..112
FT /note="Missing (in isoform Zeta)"
FT /evidence="ECO:0000303|PubMed:11779849"
FT /id="VSP_001552"
FT MUTAGEN 32
FT /note="T->A: Abolishes phosphorylation. Protein is located
FT mainly in nucleus and shows increased transcriptional
FT activity. Increased transcriptional and proteasome
FT activities in embryonic stem cells; when associated with A-
FT 197 and A-262."
FT /evidence="ECO:0000269|PubMed:10518537,
FT ECO:0000269|PubMed:16272144, ECO:0000269|PubMed:22972301"
FT MUTAGEN 197
FT /note="S->A: Abolishes phosphorylation. Protein is located
FT mainly in nucleus and shows increased transcriptional
FT activity. Increased transcriptional and proteasome
FT activities in embryonic stem cells; when associated with A-
FT 32 and A-262."
FT /evidence="ECO:0000269|PubMed:10217147,
FT ECO:0000269|PubMed:10518537, ECO:0000269|PubMed:16272144,
FT ECO:0000269|PubMed:22972301"
FT MUTAGEN 262
FT /note="S->A: Abolishes phosphorylation. No effect on
FT cellular location or transcriptional activity. Increased
FT transcriptional and proteasome activities in embryonic stem
FT cells; when associated with A-32 and A-197."
FT /evidence="ECO:0000269|PubMed:10217147,
FT ECO:0000269|PubMed:10518537, ECO:0000269|PubMed:16272144,
FT ECO:0000269|PubMed:22972301"
FT CONFLICT 1..11
FT /note="MDPGNENSATE -> MRIQPQK (in Ref. 2; CAA63819)"
FT /evidence="ECO:0000305"
FT CONFLICT 25..34
FT /note="QSRPRSCTWP -> RAVPLLHLA (in Ref. 1; CAA72156)"
FT /evidence="ECO:0000305"
FT CONFLICT 74
FT /note="P -> S (in Ref. 2; CAA63819)"
FT /evidence="ECO:0000305"
FT CONFLICT 79
FT /note="G -> A (in Ref. 1; CAA72156)"
FT /evidence="ECO:0000305"
FT CONFLICT 109
FT /note="L -> F (in Ref. 2; CAA63819)"
FT /evidence="ECO:0000305"
FT CONFLICT 422
FT /note="P -> R (in Ref. 2; CAA63819 and 3; AAL85197)"
FT /evidence="ECO:0000305"
FT HELIX 106..116
FT /evidence="ECO:0007829|PDB:3L2C"
FT STRAND 117..119
FT /evidence="ECO:0007829|PDB:1E17"
FT HELIX 124..134
FT /evidence="ECO:0007829|PDB:3L2C"
FT HELIX 136..138
FT /evidence="ECO:0007829|PDB:3L2C"
FT HELIX 139..142
FT /evidence="ECO:0007829|PDB:1E17"
FT HELIX 149..160
FT /evidence="ECO:0007829|PDB:3L2C"
FT STRAND 164..167
FT /evidence="ECO:0007829|PDB:3L2C"
FT TURN 170..172
FT /evidence="ECO:0007829|PDB:1E17"
FT STRAND 173..175
FT /evidence="ECO:0007829|PDB:1E17"
FT STRAND 177..180
FT /evidence="ECO:0007829|PDB:3L2C"
SQ SEQUENCE 505 AA; 53684 MW; 0C71C8E2167CEE68 CRC64;
MDPGNENSAT EAAAIIDLDP DFEPQSRPRS CTWPLPRPEI ANQPSEPPEV EPDLGEKVHT
EGRSEPILLP SRLPEPAGGP QPGILGAVTG PRKGGSRRNA WGNQSYAELI SQAIESAPEK
RLTLAQIYEW MVRTVPYFKD KGDSNSSAGW KNSIRHNLSL HSKFIKVHNE ATGKSSWWML
NPEGGKSGKA PRRRAASMDS SSKLLRGRSK APKKKPSVLP APPEGATPTS PVGHFAKWSG
SPCSRNREEA DMWTTFRPRS SSNASSVSTR LSPLRPESEV LAEEIPASVS SYAGGVPPTL
NEGLELLDGL NLTSSHSLLS RSGLSGFSLQ HPGVTGPLHT YSSSLFSPAE GPLSAGEGCF
SSSQALEALL TSDTPPPPAD VLMTQVDPIL SQAPTLLLLG GLPSSSKLAT GVGLCPKPLE
APGPSSLVPT LSMIAPPPVM ASAPIPKALG TPVLTPPTEA ASQDRMPQDL DLDMYMENLE
CDMDNIISDL MDEGEGLDFN FEPDP
