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 27-MAR-2024, entry version 236. 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}, FOXO3A GN {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; P31947: SFN; NbExp=3; IntAct=EBI-1644164, EBI-476295; 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; P62258: YWHAE; NbExp=4; IntAct=EBI-1644164, EBI-356498; CC O43524; P63104: YWHAZ; NbExp=4; 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="https://atlasgeneticsoncology.org/gene/125/AF6q21"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_011533930.1; XM_011535628.2. DR RefSeq; XP_011533931.1; XM_011535629.2. 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 PDB; 7V9B; X-ray; 1.85 A; B=248-258. DR PDBsum; 2K86; -. DR PDBsum; 2LQH; -. DR PDBsum; 2LQI; -. DR PDBsum; 2UZK; -. DR PDBsum; 6MNL; -. DR PDBsum; 7V9B; -. DR AlphaFoldDB; O43524; -. DR BMRB; O43524; -. DR SMR; O43524; -. DR BioGRID; 108598; 84. DR ComplexPortal; CPX-1123; FOXO3-MYC complex. DR ComplexPortal; CPX-1147; FOXO3-YWHAZ complex. DR CORUM; O43524; -. DR DIP; DIP-29723N; -. DR IntAct; O43524; 53. DR MINT; O43524; -. DR STRING; 9606.ENSP00000339527; -. DR BindingDB; O43524; -. DR ChEMBL; CHEMBL5778; -. DR GlyConnect; 1253; 1 N-Linked glycan (1 site). DR GlyCosmos; O43524; 9 sites, 2 glycans. DR GlyGen; O43524; 10 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (9 sites). DR iPTMnet; O43524; -. DR PhosphoSitePlus; O43524; -. DR BioMuta; FOXO3; -. DR CPTAC; CPTAC-5836; -. DR CPTAC; non-CPTAC-5392; -. DR CPTAC; non-CPTAC-5394; -. DR CPTAC; non-CPTAC-5739; -. DR CPTAC; non-CPTAC-5740; -. DR EPD; O43524; -. DR jPOST; O43524; -. DR MassIVE; O43524; -. DR MaxQB; O43524; -. DR PaxDb; 9606-ENSP00000385824; -. DR PeptideAtlas; O43524; -. DR ProteomicsDB; 49029; -. [O43524-1] DR ProteomicsDB; 5304; -. DR Pumba; O43524; -. DR Antibodypedia; 3419; 1470 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 AGR; HGNC:3821; -. 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; TGGMMQR; -. DR OrthoDB; 5385885at2759; -. 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; 20 hits in 1150 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 213 other cell types or tissues. 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: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:0045893; P:positive regulation of DNA-templated transcription; IDA: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: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; cd20061; FH_FOXO3; 1. DR Gene3D; 6.10.250.1690; -; 2. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 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 PANTHER; PTHR45767; FORKHEAD BOX PROTEIN O; 1. DR PANTHER; PTHR45767:SF4; FORKHEAD BOX PROTEIN O3; 1. 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; Winged helix' DNA-binding domain; 1. DR PROSITE; PS00658; FORK_HEAD_2; 1. DR PROSITE; PS50039; FORK_HEAD_3; 1. DR Genevisible; O43524; HS. 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 FT A-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 //