FOXO3_HUMAN
ID FOXO3_HUMAN Reviewed; 673 AA.
AC O43524; B4DVZ6; E1P5E6; O15171; Q5T2I7; Q9BZ04;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 227.
DE RecName: Full=Forkhead box protein O3 {ECO:0000305};
DE AltName: Full=AF6q21 protein {ECO:0000303|PubMed:9345057};
DE AltName: Full=Forkhead in rhabdomyosarcoma-like 1 {ECO:0000303|PubMed:9479491};
GN Name=FOXO3 {ECO:0000312|HGNC:HGNC:3821};
GN Synonyms=FKHRL1 {ECO:0000303|PubMed:9479491},
GN FOXO3A {ECO:0000303|PubMed:11154281};
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 [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Rhabdomyosarcoma;
RX PubMed=9479491; DOI=10.1006/geno.1997.5122;
RA Anderson M.J., Viars C.S., Czekay S., Cavenee W.K., Arden K.C.;
RT "Cloning and characterization of three human forkhead genes that comprise
RT an FKHR-like gene subfamily.";
RL Genomics 47:187-199(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Stomach;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle, and Placenta;
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 [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-383 (ISOFORM 1), AND
RP INVOLVEMENT IN SECONDARY ACUTE LEUKEMIAS.
RX PubMed=9345057;
RA Hillion J., Le Coniat M., Jonveaux P., Berger R., Bernard O.A.;
RT "AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a
RT forkhead transcriptional factor subfamily.";
RL Blood 90:3714-3719(1997).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-32; SER-253 AND
RP SER-315, AND MUTAGENESIS OF THR-32; SER-253 AND SER-315.
RX PubMed=10102273; DOI=10.1016/s0092-8674(00)80595-4;
RA Brunet A., Bonni A., Zigmond M.J., Lin M.Z., Juo P., Hu L.S.,
RA Anderson M.J., Arden K.C., Blenis J., Greenberg M.E.;
RT "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead
RT transcription factor.";
RL Cell 96:857-868(1999).
RN [8]
RP PHOSPHORYLATION AT SER-315.
RX PubMed=11154281; DOI=10.1128/mcb.21.3.952-965.2001;
RA Brunet A., Park J., Tran H., Hu L.S., Hemmings B.A., Greenberg M.E.;
RT "Protein kinase SGK mediates survival signals by phosphorylating the
RT forkhead transcription factor FKHRL1 (FOXO3a).";
RL Mol. Cell. Biol. 21:952-965(2001).
RN [9]
RP INTERACTION WITH CHUK AND IKBKB, REGION, SUBCELLULAR LOCATION,
RP PHOSPHORYLATION AT SER-644, AND MUTAGENESIS OF SER-644.
RX PubMed=15084260; DOI=10.1016/s0092-8674(04)00302-2;
RA Hu M.C., Lee D.F., Xia W., Golfman L.S., Ou-Yang F., Yang J.Y., Zou Y.,
RA Bao S., Hanada N., Saso H., Kobayashi R., Hung M.C.;
RT "IkappaB kinase promotes tumorigenesis through inhibition of forkhead
RT FOXO3a.";
RL Cell 117:225-237(2004).
RN [10]
RP FUNCTION, PHOSPHORYLATION AT SER-209, INTERACTION WITH STK4/MST1 AND YWHAB,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-209.
RX PubMed=16751106; DOI=10.1016/j.cell.2006.03.046;
RA Lehtinen M.K., Yuan Z., Boag P.R., Yang Y., Villen J., Becker E.B.E.,
RA DiBacco S., de la Iglesia N., Gygi S.P., Blackwell T.K., Bonni A.;
RT "A conserved MST-FOXO signaling pathway mediates oxidative-stress responses
RT and extends life span.";
RL Cell 125:987-1001(2006).
RN [11]
RP PHOSPHORYLATION AT THR-179; SER-399; SER-413; SER-555; SER-588 AND SER-626,
RP MUTAGENESIS OF THR-179; SER-399; SER-413; SER-555; SER-588 AND SER-626, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17711846; DOI=10.1074/jbc.m705325200;
RA Greer E.L., Oskoui P.R., Banko M.R., Maniar J.M., Gygi M.P., Gygi S.P.,
RA Brunet A.;
RT "The energy sensor AMP-activated protein kinase directly regulates the
RT mammalian FOXO3 transcription factor.";
RL J. Biol. Chem. 282:30107-30119(2007).
RN [12]
RP INTERACTION WITH PIM1, AND PHOSPHORYLATION.
RX PubMed=18593906; DOI=10.1158/0008-5472.can-08-0634;
RA Morishita D., Katayama R., Sekimizu K., Tsuruo T., Fujita N.;
RT "Pim kinases promote cell cycle progression by phosphorylating and down-
RT regulating p27Kip1 at the transcriptional and posttranscriptional levels.";
RL Cancer Res. 68:5076-5085(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-280 AND SER-284, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-280, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [17]
RP INTERACTION WITH NUPR1.
RX PubMed=20181828; DOI=10.1091/mbc.e09-09-0818;
RA Kong D.K., Georgescu S.P., Cano C., Aronovitz M.J., Iovanna J.L.,
RA Patten R.D., Kyriakis J.M., Goruppi S.;
RT "Deficiency of the transcriptional regulator p8 results in increased
RT autophagy and apoptosis, and causes impaired heart function.";
RL Mol. Biol. Cell 21:1335-1349(2010).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP FUNCTION, SUBCELLULAR LOCATION, DNA-BINDING, AND PHOSPHORYLATION AT
RP SER-215; SER-253; SER-551 AND SER-555.
RX PubMed=21329882; DOI=10.1016/j.molcel.2011.01.023;
RA Kress T.R., Cannell I.G., Brenkman A.B., Samans B., Gaestel M., Roepman P.,
RA Burgering B.M., Bushell M., Rosenwald A., Eilers M.;
RT "The MK5/PRAK kinase and Myc form a negative feedback loop that is
RT disrupted during colorectal tumorigenesis.";
RL Mol. Cell 41:445-457(2011).
RN [20]
RP METHYLATION AT LYS-46; LYS-149; LYS-230; LYS-262; LYS-271; LYS-290 AND
RP LYS-419, AND MUTAGENESIS OF LYS-269; LYS-270 AND LYS-271.
RX PubMed=22820736; DOI=10.18632/aging.100471;
RA Calnan D.R., Webb A.E., White J.L., Stowe T.R., Goswami T., Shi X.,
RA Espejo A., Bedford M.T., Gozani O., Gygi S.P., Brunet A.;
RT "Methylation by Set9 modulates FoxO3 stability and transcriptional
RT activity.";
RL Aging (Albany NY) 4:462-479(2012).
RN [21]
RP INTERACTION WITH IKBKB, AND SUBCELLULAR LOCATION.
RX PubMed=22313691; DOI=10.1016/j.cellsig.2012.01.012;
RA Tezil T., Bodur C., Kutuk O., Basaga H.;
RT "IKK-beta mediates chemoresistance by sequestering FOXO3; a critical factor
RT for cell survival and death.";
RL Cell. Signal. 24:1361-1368(2012).
RN [22]
RP ACETYLATION, DEACETYLATION BY SIRT2, INTERACTION WITH SKP2, UBIQUITINATION
RP BY SKP2, AND MUTAGENESIS OF LYS-242; LYS-259; LYS-290 AND LYS-569.
RX PubMed=21841822; DOI=10.1038/onc.2011.347;
RA Wang F., Chan C.H., Chen K., Guan X., Lin H.K., Tong Q.;
RT "Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3
RT ubiquitination and degradation.";
RL Oncogene 31:1546-1557(2012).
RN [23]
RP INTERACTION WITH DDIT3, AND SUBCELLULAR LOCATION.
RX PubMed=22761832; DOI=10.1371/journal.pone.0039586;
RA Ghosh A.P., Klocke B.J., Ballestas M.E., Roth K.A.;
RT "CHOP potentially co-operates with FOXO3a in neuronal cells to regulate
RT PUMA and BIM expression in response to ER stress.";
RL PLoS ONE 7:E39586-E39586(2012).
RN [24]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH SIRT3 AND POLRMT, SUBCELLULAR
RP LOCATION, AND ACETYLATION.
RX PubMed=23283301; DOI=10.1007/s00018-012-1244-6;
RA Peserico A., Chiacchiera F., Grossi V., Matrone A., Latorre D.,
RA Simonatto M., Fusella A., Ryall J.G., Finley L.W., Haigis M.C., Villani G.,
RA Puri P.L., Sartorelli V., Simone C.;
RT "A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing
RT glucose levels.";
RL Cell. Mol. Life Sci. 70:2015-2029(2013).
RN [25]
RP PHOSPHORYLATION AT SER-299, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23805378; DOI=10.7554/elife.00518;
RA Tao L., Xie Q., Ding Y.H., Li S.T., Peng S., Zhang Y.P., Tan D., Yuan Z.,
RA Dong M.Q.;
RT "CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans
RT through the FOXO transcription factor DAF-16.";
RL Elife 2:E00518-E00518(2013).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-280; SER-284; SER-299;
RP SER-311; SER-413 AND SER-551, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
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 [27]
RP IDENTIFICATION IN A COMPLEX WITH SIRT3; TFAM AND POLRMT, SUBCELLULAR
RP LOCATION, PROTEOLYTIC CLEAVAGE, PHOSPHORYLATION AT SER-30, NUCLEAR
RP LOCALIZATION SIGNAL, AND MUTAGENESIS OF 2-ALA--SER-30; 2-ALA--ARG-148;
RP SER-12; SER-30; 80-GLY--PRO-108 AND 241-LYS--LYS-271.
RX PubMed=29445193; DOI=10.1038/s41419-018-0336-0;
RA Celestini V., Tezil T., Russo L., Fasano C., Sanese P., Forte G.,
RA Peserico A., Lepore Signorile M., Longo G., De Rasmo D., Signorile A.,
RA Gadaleta R.M., Scialpi N., Terao M., Garattini E., Cocco T., Villani G.,
RA Moschetta A., Grossi V., Simone C.;
RT "Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells
RT undergoing metabolic stress and chemotherapy.";
RL Cell Death Dis. 9:231-231(2018).
RN [28]
RP FUNCTION, PHOSPHORYLATION AT SER-253 AND SER-294, AND DEPHOSPHORYLATION.
RX PubMed=30513302; DOI=10.1016/j.devcel.2018.11.010;
RA Becher J., Simula L., Volpe E., Procaccini C., La Rocca C., D'Acunzo P.,
RA Cianfanelli V., Strappazzon F., Caruana I., Nazio F., Weber G.,
RA Gigantino V., Botti G., Ciccosanti F., Borsellino G., Campello S.,
RA Mandolesi G., De Bardi M., Fimia G.M., D'Amelio M., Ruffini F., Furlan R.,
RA Centonze D., Martino G., Braghetta P., Chrisam M., Bonaldo P., Matarese G.,
RA Locatelli F., Battistini L., Cecconi F.;
RT "AMBRA1 controls regulatory T-cell differentiation and homeostasis upstream
RT of the FOXO3-FOXP3 axis.";
RL Dev. Cell 47:592-607(2018).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 158-253 IN COMPLEX WITH DNA,
RP MUTAGENESIS OF LYS-242 AND LYS-245, AND NUCLEAR LOCALIZATION SIGNAL.
RX PubMed=17940099; DOI=10.1093/nar/gkm703;
RA Tsai K.-L., Sun Y.-J., Huang C.-Y., Yang J.-Y., Hung M.-C., Hsiao C.-D.;
RT "Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects
RT of post-translational modification.";
RL Nucleic Acids Res. 35:6984-6994(2007).
CC -!- FUNCTION: Transcriptional activator that recognizes and binds to the
CC DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes,
CC such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106,
CC PubMed:21329882, PubMed:30513302). Acts as a positive regulator of
CC autophagy in skeletal muscle: in starved cells, enters the nucleus
CC following dephosphorylation and binds the promoters of autophagy genes,
CC such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their
CC expression, resulting in proteolysis of skeletal muscle proteins (By
CC similarity). Triggers apoptosis in the absence of survival factors,
CC including neuronal cell death upon oxidative stress (PubMed:10102273,
CC PubMed:16751106). Participates in post-transcriptional regulation of
CC MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-
CC 34b and miR-34c expression, 2 post-transcriptional regulators of MYC
CC that bind to the 3'UTR of MYC transcript and prevent its translation
CC (PubMed:21329882). In response to metabolic stress, translocates into
CC the mitochondria where it promotes mtDNA transcription
CC (PubMed:23283301). In response to metabolic stress, translocates into
CC the mitochondria where it promotes mtDNA transcription. Also acts as a
CC key regulator of chondrogenic commitment of skeletal progenitor cells
CC in response to lipid availability: when lipids levels are low,
CC translocates to the nucleus and promotes expression of SOX9, which
CC induces chondrogenic commitment and suppresses fatty acid oxidation (By
CC similarity). Also acts as a key regulator of regulatory T-cells (Treg)
CC differentiation by activating expression of FOXP3 (PubMed:30513302).
CC {ECO:0000250|UniProtKB:Q9WVH4, ECO:0000269|PubMed:10102273,
CC ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:21329882,
CC ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:30513302}.
CC -!- SUBUNIT: Upon metabolic stress, forms a complex composed of FOXO3,
CC SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited
CC to mtDNA in a SIRT3-dependent manner (PubMed:23283301). Also forms a
CC complex composed of FOXO3, SIRT3, TFAM and POLRMT (PubMed:29445193).
CC Interacts with SIRT2; the interaction occurs independently of SIRT2
CC deacetylase activity (By similarity). Interacts with YWHAB/14-3-3-beta
CC and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration
CC (PubMed:16751106). Upon oxidative stress, interacts with STK4/MST1,
CC which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear
CC translocation (PubMed:16751106). Interacts with PIM1 (PubMed:18593906).
CC Interacts with DDIT3/CHOP (PubMed:22761832). Interacts (deacetylated
CC form) with SKP2 (PubMed:21841822). Interacts with CHUK and IKBKB
CC (PubMed:15084260, PubMed:22313691). Interacts with CAMK2A, CAMK2B and
CC calcineurin A (By similarity). Interacts with NUPR1; this interaction
CC represses FOXO3 transactivation (PubMed:20181828).
CC {ECO:0000250|UniProtKB:Q9WVH4, ECO:0000269|PubMed:15084260,
CC ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:18593906,
CC ECO:0000269|PubMed:20181828, ECO:0000269|PubMed:21841822,
CC ECO:0000269|PubMed:22313691, ECO:0000269|PubMed:22761832,
CC ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193}.
CC -!- INTERACTION:
CC O43524; P31749: AKT1; NbExp=3; IntAct=EBI-1644164, EBI-296087;
CC O43524; Q92974: ARHGEF2; NbExp=2; IntAct=EBI-1644164, EBI-302405;
CC O43524; P30260: CDC27; NbExp=2; IntAct=EBI-1644164, EBI-994813;
CC O43524; Q92793: CREBBP; NbExp=3; IntAct=EBI-1644164, EBI-81215;
CC O43524; P03372: ESR1; NbExp=7; IntAct=EBI-1644164, EBI-78473;
CC O43524; Q92731: ESR2; NbExp=4; IntAct=EBI-1644164, EBI-78505;
CC O43524; P85037: FOXK1; NbExp=2; IntAct=EBI-1644164, EBI-2509974;
CC O43524; Q08050: FOXM1; NbExp=2; IntAct=EBI-1644164, EBI-866480;
CC O43524; P51610: HCFC1; NbExp=2; IntAct=EBI-1644164, EBI-396176;
CC O43524; P01106: MYC; NbExp=3; IntAct=EBI-1644164, EBI-447544;
CC O43524; P11309-1: PIM1; NbExp=2; IntAct=EBI-1644164, EBI-1018629;
CC O43524; Q96T60: PNKP; NbExp=2; IntAct=EBI-1644164, EBI-1045072;
CC O43524; P06400: RB1; NbExp=2; IntAct=EBI-1644164, EBI-491274;
CC O43524; P28749: RBL1; NbExp=3; IntAct=EBI-1644164, EBI-971402;
CC O43524; Q96EB6: SIRT1; NbExp=5; IntAct=EBI-1644164, EBI-1802965;
CC O43524; P84022: SMAD3; NbExp=5; IntAct=EBI-1644164, EBI-347161;
CC O43524; Q13485: SMAD4; NbExp=9; IntAct=EBI-1644164, EBI-347263;
CC O43524; O75529: TAF5L; NbExp=2; IntAct=EBI-1644164, EBI-1785876;
CC O43524; P63104: YWHAZ; NbExp=3; IntAct=EBI-1644164, EBI-347088;
CC O43524; Q60987: Foxg1; Xeno; NbExp=5; IntAct=EBI-1644164, EBI-11166131;
CC O43524; P63101: Ywhaz; Xeno; NbExp=2; IntAct=EBI-1644164, EBI-354751;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10102273,
CC ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106,
CC ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:21329882,
CC ECO:0000269|PubMed:22313691, ECO:0000269|PubMed:22761832,
CC ECO:0000269|PubMed:23283301}. Nucleus {ECO:0000269|PubMed:10102273,
CC ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106,
CC ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:21329882,
CC ECO:0000269|PubMed:22313691, ECO:0000269|PubMed:22761832,
CC ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193}.
CC Mitochondrion matrix {ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:29445193}. Mitochondrion outer membrane
CC {ECO:0000269|PubMed:29445193}; Peripheral membrane protein
CC {ECO:0000269|PubMed:29445193}; Cytoplasmic side
CC {ECO:0000269|PubMed:29445193}. Note=Retention in the cytoplasm
CC contributes to its inactivation (PubMed:10102273, PubMed:15084260,
CC PubMed:16751106). Translocates to the nucleus upon oxidative stress and
CC in the absence of survival factors (PubMed:10102273, PubMed:16751106).
CC Translocates from the cytosol to the nucleus following
CC dephosphorylation in response to autophagy-inducing stimuli (By
CC similarity). Translocates in a AMPK-dependent manner into the
CC mitochondrion in response to metabolic stress (PubMed:23283301,
CC PubMed:29445193). Serum deprivation increases localization to the
CC nucleus, leading to activate expression of SOX9 and subsequent
CC chondrogenesis (By similarity). {ECO:0000250|UniProtKB:Q9WVH4,
CC ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:15084260,
CC ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:29445193}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O43524-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O43524-2; Sequence=VSP_056225;
CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:9479491}.
CC -!- PTM: In the presence of survival factors such as IGF-1, phosphorylated
CC on Thr-32 and Ser-253 by AKT1/PKB (PubMed:10102273). This
CC phosphorylated form then interacts with 14-3-3 proteins and is retained
CC in the cytoplasm (PubMed:10102273). Survival factor withdrawal induces
CC dephosphorylation and promotes translocation to the nucleus where the
CC dephosphorylated protein induces transcription of target genes and
CC triggers apoptosis (PubMed:10102273). Although AKT1/PKB doesn't appear
CC to phosphorylate Ser-315 directly, it may activate other kinases that
CC trigger phosphorylation at this residue (PubMed:10102273,
CC PubMed:11154281). Phosphorylated by STK4/MST1 on Ser-209 upon oxidative
CC stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear
CC translocation (PubMed:16751106). Phosphorylated by PIM1
CC (PubMed:18593906). Phosphorylation by AMPK leads to the activation of
CC transcriptional activity without affecting subcellular localization
CC (PubMed:17711846). In response to metabolic stress, phosphorylated by
CC AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation
CC (PubMed:29445193). Phosphorylation by MAPKAPK5 promotes nuclear
CC localization and DNA-binding, leading to induction of miR-34b and miR-
CC 34c expression, 2 post-transcriptional regulators of MYC that bind to
CC the 3'UTR of MYC transcript and prevent its translation
CC (PubMed:21329882). Phosphorylated by CHUK/IKKA and IKBKB/IKKB
CC (PubMed:15084260). TNF-induced inactivation of FOXO3 requires its
CC phosphorylation at Ser-644 by IKBKB/IKKB which promotes FOXO3 retention
CC in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal
CC degradation (PubMed:15084260). May be dephosphorylated by calcineurin A
CC on Ser-299 which abolishes FOXO3 transcriptional activity (By
CC similarity). In cancer cells, ERK mediated-phosphorylation of Ser-12 is
CC required for mitochondrial translocation of FOXO3 in response to
CC metabolic stress or chemotherapeutic agents (PubMed:29445193).
CC Phosphorylation at Ser-253 promotes its degradation by the proteasome
CC (PubMed:30513302). Dephosphorylation at Ser-253 by protein phosphatase
CC 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is
CC enhanced by AMBRA1 (PubMed:30513302). {ECO:0000250|UniProtKB:Q9WVH4,
CC ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:11154281,
CC ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:16751106,
CC ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18593906,
CC ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:29445193,
CC ECO:0000269|PubMed:30513302}.
CC -!- PTM: Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3
CC with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and
CC proteasomal degradation (PubMed:21841822). Deacetylation by SIRT2
CC stimulates FOXO3-mediated transcriptional activity in response to
CC oxidative stress (By similarity). Deacetylated by SIRT3
CC (PubMed:23283301). Deacetylation by SIRT3 stimulates FOXO3-mediated
CC mtDNA transcriptional activity in response to metabolic stress
CC (PubMed:23283301). {ECO:0000250|UniProtKB:Q9WVH4,
CC ECO:0000269|PubMed:21841822, ECO:0000269|PubMed:23283301}.
CC -!- PTM: Heavily methylated by SET9 which decreases stability, while
CC moderately increasing transcriptional activity. The main methylation
CC site is Lys-271. Methylation doesn't affect subcellular location.
CC {ECO:0000269|PubMed:22820736}.
CC -!- PTM: Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2,
CC leading to proteasomal degradation. {ECO:0000269|PubMed:21841822}.
CC -!- PTM: The N-terminus is cleaved following import into the mitochondrion.
CC {ECO:0000269|PubMed:29445193}.
CC -!- DISEASE: Note=A chromosomal aberration involving FOXO3 is found in
CC secondary acute leukemias. Translocation t(6;11)(q21;q23) with
CC KMT2A/MLL1.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/AF6q21ID125.html";
CC ---------------------------------------------------------------------------
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DR EMBL; AF032886; AAC39592.1; -; mRNA.
DR EMBL; AK301304; BAG62858.1; -; mRNA.
DR EMBL; AL096818; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL391646; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL365509; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW48373.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW48374.1; -; Genomic_DNA.
DR EMBL; BC020227; AAH20227.1; -; mRNA.
DR EMBL; BC021224; AAH21224.1; -; mRNA.
DR EMBL; BC068552; AAH68552.1; -; mRNA.
DR EMBL; AJ001589; CAA04860.1; -; mRNA.
DR EMBL; AJ001590; CAA04861.1; -; Genomic_DNA.
DR CCDS; CCDS5068.1; -. [O43524-1]
DR RefSeq; NP_001446.1; NM_001455.3. [O43524-1]
DR RefSeq; NP_963853.1; NM_201559.2. [O43524-1]
DR RefSeq; XP_005266925.1; XM_005266868.3. [O43524-2]
DR RefSeq; XP_011533930.1; XM_011535628.2. [O43524-2]
DR RefSeq; XP_011533931.1; XM_011535629.2. [O43524-2]
DR RefSeq; XP_016866075.1; XM_017010586.1. [O43524-2]
DR PDB; 2K86; NMR; -; A=151-251.
DR PDB; 2LQH; NMR; -; B=461-483.
DR PDB; 2LQI; NMR; -; B=461-483.
DR PDB; 2UZK; X-ray; 2.70 A; A/C=158-253.
DR PDB; 6MNL; NMR; -; A=237-252.
DR PDBsum; 2K86; -.
DR PDBsum; 2LQH; -.
DR PDBsum; 2LQI; -.
DR PDBsum; 2UZK; -.
DR PDBsum; 6MNL; -.
DR AlphaFoldDB; O43524; -.
DR BMRB; O43524; -.
DR SMR; O43524; -.
DR BioGRID; 108598; 78.
DR ComplexPortal; CPX-1123; FOXO3-MYC complex.
DR ComplexPortal; CPX-1147; FOXO3-YWHAZ complex.
DR CORUM; O43524; -.
DR DIP; DIP-29723N; -.
DR IntAct; O43524; 52.
DR MINT; O43524; -.
DR STRING; 9606.ENSP00000385824; -.
DR BindingDB; O43524; -.
DR ChEMBL; CHEMBL5778; -.
DR GlyConnect; 1253; 1 N-Linked glycan (1 site).
DR GlyGen; O43524; 9 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (8 sites).
DR iPTMnet; O43524; -.
DR PhosphoSitePlus; O43524; -.
DR BioMuta; FOXO3; -.
DR EPD; O43524; -.
DR jPOST; O43524; -.
DR MassIVE; O43524; -.
DR MaxQB; O43524; -.
DR PaxDb; O43524; -.
DR PeptideAtlas; O43524; -.
DR PRIDE; O43524; -.
DR ProteomicsDB; 49029; -. [O43524-1]
DR ProteomicsDB; 5304; -.
DR Antibodypedia; 3419; 1234 antibodies from 49 providers.
DR CPTC; O43524; 3 antibodies.
DR DNASU; 2309; -.
DR Ensembl; ENST00000343882.10; ENSP00000339527.6; ENSG00000118689.15. [O43524-1]
DR Ensembl; ENST00000406360.2; ENSP00000385824.1; ENSG00000118689.15. [O43524-1]
DR Ensembl; ENST00000540898.1; ENSP00000446316.1; ENSG00000118689.15. [O43524-2]
DR GeneID; 2309; -.
DR KEGG; hsa:2309; -.
DR MANE-Select; ENST00000406360.2; ENSP00000385824.1; NM_001455.4; NP_001446.1.
DR UCSC; uc003psk.3; human. [O43524-1]
DR CTD; 2309; -.
DR DisGeNET; 2309; -.
DR GeneCards; FOXO3; -.
DR HGNC; HGNC:3821; FOXO3.
DR HPA; ENSG00000118689; Low tissue specificity.
DR MIM; 602681; gene.
DR neXtProt; NX_O43524; -.
DR OpenTargets; ENSG00000118689; -.
DR PharmGKB; PA28239; -.
DR VEuPathDB; HostDB:ENSG00000118689; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000159826; -.
DR HOGENOM; CLU_023456_1_0_1; -.
DR InParanoid; O43524; -.
DR OMA; EWMVRSI; -.
DR OrthoDB; 1160384at2759; -.
DR PhylomeDB; O43524; -.
DR TreeFam; TF315583; -.
DR PathwayCommons; O43524; -.
DR Reactome; R-HSA-1181150; Signaling by NODAL.
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-5687128; MAPK6/MAPK4 signaling.
DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR Reactome; R-HSA-8952158; RUNX3 regulates BCL2L11 (BIM) transcription.
DR Reactome; R-HSA-9607240; FLT3 Signaling.
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 Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR SignaLink; O43524; -.
DR SIGNOR; O43524; -.
DR BioGRID-ORCS; 2309; 19 hits in 1069 CRISPR screens.
DR ChiTaRS; FOXO3; human.
DR EvolutionaryTrace; O43524; -.
DR GeneWiki; FOXO3; -.
DR GenomeRNAi; 2309; -.
DR Pharos; O43524; Tbio.
DR PRO; PR:O43524; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; O43524; protein.
DR Bgee; ENSG00000118689; Expressed in secondary oocyte and 211 other tissues.
DR Genevisible; O43524; 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:FlyBase.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0090571; C:RNA polymerase II transcription repressor complex; IPI:ComplexPortal.
DR GO; GO:0008013; F:beta-catenin binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:BHF-UCL.
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:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0034246; F:mitochondrial transcription factor activity; IMP:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:BHF-UCL.
DR GO; GO:0001221; F:transcription coregulator binding; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0001547; P:antral ovarian follicle growth; IEA:Ensembl.
DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IEA:Ensembl.
DR GO; GO:0071386; P:cellular response to corticosterone stimulus; IEA:Ensembl.
DR GO; GO:0042149; P:cellular response to glucose starvation; IDA:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IEA:Ensembl.
DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; IEA:Ensembl.
DR GO; GO:0001544; P:initiation of primordial ovarian follicle growth; IEA:Ensembl.
DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0030336; P:negative regulation of cell migration; IMP:BHF-UCL.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0097150; P:neuronal stem cell population maintenance; IEA:Ensembl.
DR GO; GO:0001556; P:oocyte maturation; IEA:Ensembl.
DR GO; GO:0001542; P:ovulation from ovarian follicle; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:BHF-UCL.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0045648; P:positive regulation of erythrocyte differentiation; IDA:MGI.
DR GO; GO:1901300; P:positive regulation of hydrogen peroxide-mediated programmed cell death; IEA:Ensembl.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; ISS:BHF-UCL.
DR GO; GO:0014737; P:positive regulation of muscle atrophy; ISS:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; IEA:Ensembl.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IDA:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:2000177; P:regulation of neural precursor cell proliferation; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0006417; P:regulation of translation; IDA:UniProtKB.
DR GO; GO:0071548; P:response to dexamethasone; IEA:Ensembl.
DR GO; GO:0070542; P:response to fatty acid; ISS:UniProtKB.
DR GO; GO:0042594; P:response to starvation; ISS:UniProtKB.
DR GO; GO:1990785; P:response to water-immersion restraint stress; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR IDEAL; IID00433; -.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR032067; FOXO-TAD.
DR InterPro; IPR032068; FOXO_KIX-bd.
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 Pfam; PF16675; FOXO_KIX_bdg; 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; Apoptosis;
KW Chromosomal rearrangement; Cytoplasm; DNA-binding; Membrane; Methylation;
KW Mitochondrion; Mitochondrion outer membrane; Nucleus; Phosphoprotein;
KW Proto-oncogene; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..673
FT /note="Forkhead box protein O3"
FT /id="PRO_0000091874"
FT DNA_BIND 157..251
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..153
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 80..108
FT /note="Required for mitochondrial import"
FT /evidence="ECO:0000269|PubMed:23283301"
FT REGION 231..302
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 300..673
FT /note="Mediates interaction with CHUK/IKKA and IKBKB/IKKB"
FT /evidence="ECO:0000269|PubMed:15084260"
FT REGION 536..587
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 242..259
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:17940099,
FT ECO:0000269|PubMed:29445193"
FT COMPBIAS 55..69
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 279..302
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 30
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:29445193"
FT MOD_RES 32
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:10102273"
FT MOD_RES 46
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 149
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 179
FT /note="Phosphothreonine; by AMPK"
FT /evidence="ECO:0000269|PubMed:17711846"
FT MOD_RES 209
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000269|PubMed:16751106"
FT MOD_RES 215
FT /note="Phosphoserine; by MAPKAPK5"
FT /evidence="ECO:0000269|PubMed:21329882"
FT MOD_RES 230
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 242
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9WVH4"
FT MOD_RES 253
FT /note="Phosphoserine; by PKB/AKT1 and MAPKAPK5"
FT /evidence="ECO:0000269|PubMed:10102273,
FT ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:30513302"
FT MOD_RES 262
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 271
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 280
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 284
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 290
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 294
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:30513302"
FT MOD_RES 299
FT /note="Phosphoserine; by CaMK2A"
FT /evidence="ECO:0000269|PubMed:23805378,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 311
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 315
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000269|PubMed:10102273,
FT ECO:0000269|PubMed:11154281"
FT MOD_RES 399
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:17711846"
FT MOD_RES 413
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:17711846,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 419
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:22820736"
FT MOD_RES 421
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18220336"
FT MOD_RES 551
FT /note="Phosphoserine; by MAPKAPK5"
FT /evidence="ECO:0000269|PubMed:21329882,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 555
FT /note="Phosphoserine; by AMPK and MAPKAPK5"
FT /evidence="ECO:0000269|PubMed:17711846,
FT ECO:0000269|PubMed:21329882"
FT MOD_RES 588
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:17711846"
FT MOD_RES 626
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:17711846"
FT MOD_RES 644
FT /note="Phosphoserine; by IKKB"
FT /evidence="ECO:0000269|PubMed:15084260"
FT VAR_SEQ 1..220
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056225"
FT MUTAGEN 2..148
FT /note="Missing: Loss of localization to the mitochondrion
FT outer membrane and loss of translocation into the
FT mitochondrion following metabolic stress."
FT /evidence="ECO:0000269|PubMed:29445193"
FT MUTAGEN 2..30
FT /note="Missing: Loss of translocation into the
FT mitochondrion following metabolic stress."
FT /evidence="ECO:0000269|PubMed:29445193"
FT MUTAGEN 12
FT /note="S->A: In normal cells, no defect in mitochondrion
FT import following metabolic stress. In cancer cells,
FT defective mitochondrion import following metabolic stress
FT and abolition of ERK-mediated phosphorylation."
FT /evidence="ECO:0000269|PubMed:29445193"
FT MUTAGEN 30
FT /note="S->A: Abolishes phosphorylation. Loss of
FT localization to the mitochondrion outer membrane and loss
FT of translocation into the mitochondrion following metabolic
FT stress."
FT /evidence="ECO:0000269|PubMed:29445193"
FT MUTAGEN 32
FT /note="T->A: Abolishes YWHAZ-binding; when associated with
FT A-253. Exclusively nuclear, induces transcription and
FT promotes apoptosis; when associated with A-253 and A-315."
FT /evidence="ECO:0000269|PubMed:10102273"
FT MUTAGEN 80..108
FT /note="Missing: Loss of translocation into the
FT mitochondrion following metabolic stress."
FT /evidence="ECO:0000269|PubMed:29445193"
FT MUTAGEN 179
FT /note="T->A: Decreased phosphorylation by AMPK and impaired
FT ability to transactivate a reporter gene; when associated
FT with A-399; A-413; A-555; A-588 and A-626."
FT /evidence="ECO:0000269|PubMed:17711846"
FT MUTAGEN 209
FT /note="S->A: Impairs nuclear translocation upon oxidative
FT stress."
FT /evidence="ECO:0000269|PubMed:16751106"
FT MUTAGEN 242..271
FT /note="Missing: Loss of nuclear import."
FT /evidence="ECO:0000269|PubMed:29445193"
FT MUTAGEN 242
FT /note="K->A: Slightly decreases DNA affinity."
FT /evidence="ECO:0000269|PubMed:17940099,
FT ECO:0000269|PubMed:21841822"
FT MUTAGEN 242
FT /note="K->R: Reduces acetylation, increases interaction
FT with SKP2 and inhibits FOXO3 ubiquitination and
FT degradation; when associated with R-259; R-290 and R-569."
FT /evidence="ECO:0000269|PubMed:17940099,
FT ECO:0000269|PubMed:21841822"
FT MUTAGEN 245
FT /note="K->A: Decreases DNA affinity."
FT /evidence="ECO:0000269|PubMed:17940099"
FT MUTAGEN 253
FT /note="S->A: Abolishes YWHAZ-binding; when associated with
FT A-32. Exclusively nuclear, induces transcription and
FT promotes apoptosis; when associated with A-32 and A-315."
FT /evidence="ECO:0000269|PubMed:10102273"
FT MUTAGEN 259
FT /note="K->R: Reduces acetylation, increases interaction
FT with SKP2 and inhibits FOXO3 ubiquitination and
FT degradation; when associated with R-242; R-290 and R-569."
FT /evidence="ECO:0000269|PubMed:21841822"
FT MUTAGEN 269
FT /note="K->R: Methylation levels similar to wild-type; when
FT associated with ARG-270."
FT /evidence="ECO:0000269|PubMed:22820736"
FT MUTAGEN 270
FT /note="K->R: Methylation levels similar to wild-type; when
FT associated with ARG-269."
FT /evidence="ECO:0000269|PubMed:22820736"
FT MUTAGEN 271
FT /note="K->R: Methylation levels strongly reduced."
FT /evidence="ECO:0000269|PubMed:22820736"
FT MUTAGEN 290
FT /note="K->R: Reduces acetylation, increases interaction
FT with SKP2 and inhibits FOXO3 ubiquitination and
FT degradation; when associated with R-242; R-259 and R-569."
FT /evidence="ECO:0000269|PubMed:21841822"
FT MUTAGEN 315
FT /note="S->A: No effect on YWHAZ-binding. Promotes nuclear
FT translocation. Exclusively nuclear, induces transcription
FT and promotes apoptosis; when associated with A-32 and A-
FT 253."
FT /evidence="ECO:0000269|PubMed:10102273"
FT MUTAGEN 399
FT /note="S->A: Decreased phosphorylation by AMPK and impaired
FT ability to transactivate a reporter gene; when associated
FT with A-179; A-413; A-555; A-588 and A-626."
FT /evidence="ECO:0000269|PubMed:17711846"
FT MUTAGEN 413
FT /note="S->A: Decreased phosphorylation by AMPK and impaired
FT ability to transactivate a reporter gene; when associated
FT with A-179; A-399; A-555; A-588 and A-626."
FT /evidence="ECO:0000269|PubMed:17711846"
FT MUTAGEN 555
FT /note="S->A: Decreased phosphorylation by AMPK and impaired
FT ability to transactivate a reporter gene; when associated
FT with A-179; A-399; A-413; A-588 and A-626."
FT /evidence="ECO:0000269|PubMed:17711846"
FT MUTAGEN 569
FT /note="K->R: Reduces acetylation, increases interaction
FT with SKP2 and inhibits FOXO3 ubiquitination and
FT degradation; when associated with R-242; R-259 and R-290."
FT /evidence="ECO:0000269|PubMed:21841822"
FT MUTAGEN 588
FT /note="S->A: Decreased phosphorylation by AMPK and impaired
FT ability to transactivate a reporter gene; when associated
FT with A-179; A-399; A-413; A-555 and A-626."
FT /evidence="ECO:0000269|PubMed:17711846"
FT MUTAGEN 626
FT /note="S->A: Decreased phosphorylation by AMPK and impaired
FT ability to transactivate a reporter gene; when associated
FT with A-179; A-399; A-413; A-555 and A-588."
FT /evidence="ECO:0000269|PubMed:17711846"
FT MUTAGEN 644
FT /note="S->A: Loss of phosphorylation by IKKB."
FT /evidence="ECO:0000269|PubMed:15084260"
FT CONFLICT 156..163
FT /note="AWGNLSYA -> WGKPVYS (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 238..246
FT /note="PDGGKSGKA -> LMGEERKT (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 253
FT /note="S -> T (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 271
FT /note="Missing (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 292..330
FT /note="PGSPTSRSSDELDAWTDFRSRTNSNASTVSGRLSPIMAS -> AWQPHVNAA
FT VMSWMRGRTSVHAPILTPAQSVAACRPSWQV (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 345..361
FT /note="PMLYSSSASLSPSVSKP -> AHALQHVSQPVTFSKQA (in Ref. 6;
FT CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 367
FT /note="P -> R (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 371
FT /note="D -> E (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT CONFLICT 382..383
FT /note="LT -> AD (in Ref. 6; CAA04860)"
FT /evidence="ECO:0000305"
FT TURN 156..158
FT /evidence="ECO:0007829|PDB:2K86"
FT HELIX 162..169
FT /evidence="ECO:0007829|PDB:2UZK"
FT STRAND 172..176
FT /evidence="ECO:0007829|PDB:2UZK"
FT HELIX 180..189
FT /evidence="ECO:0007829|PDB:2UZK"
FT STRAND 198..200
FT /evidence="ECO:0007829|PDB:2UZK"
FT HELIX 206..216
FT /evidence="ECO:0007829|PDB:2UZK"
FT STRAND 217..229
FT /evidence="ECO:0007829|PDB:2UZK"
FT STRAND 233..236
FT /evidence="ECO:0007829|PDB:2UZK"
FT STRAND 238..240
FT /evidence="ECO:0007829|PDB:2K86"
FT STRAND 463..465
FT /evidence="ECO:0007829|PDB:2LQH"
FT HELIX 468..477
FT /evidence="ECO:0007829|PDB:2LQH"
FT TURN 478..480
FT /evidence="ECO:0007829|PDB:2LQH"
SQ SEQUENCE 673 AA; 71277 MW; E5B4E830665A9982 CRC64;
MAEAPASPAP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE TAADSMIPEE
EDDEDDEDGG GRAGSAMAIG GGGGSGTLGS GLLLEDSARV LAPGGQDPGS GPATAAGGLS
GGTQALLQPQ QPLPPPQPGA AGGSGQPRKC SSRRNAWGNL SYADLITRAI ESSPDKRLTL
SQIYEWMVRC VPYFKDKGDS NSSAGWKNSI RHNLSLHSRF MRVQNEGTGK SSWWIINPDG
GKSGKAPRRR AVSMDNSNKY TKSRGRAAKK KAALQTAPES ADDSPSQLSK WPGSPTSRSS
DELDAWTDFR SRTNSNASTV SGRLSPIMAS TELDEVQDDD APLSPMLYSS SASLSPSVSK
PCTVELPRLT DMAGTMNLND GLTENLMDDL LDNITLPPSQ PSPTGGLMQR SSSFPYTTKG
SGLGSPTSSF NSTVFGPSSL NSLRQSPMQT IQENKPATFS SMSHYGNQTL QDLLTSDSLS
HSDVMMTQSD PLMSQASTAV SAQNSRRNVM LRNDPMMSFA AQPNQGSLVN QNLLHHQHQT
QGALGGSRAL SNSVSNMGLS ESSSLGSAKH QQQSPVSQSM QTLSDSLSGS SLYSTSANLP
VMGHEKFPSD LDLDMFNGSL ECDMESIIRS ELMDADGLDF NFDSLISTQN VVGLNVGNFT
GAKQASSQSW VPG
