FOXO3_MOUSE
ID FOXO3_MOUSE Reviewed; 672 AA.
AC Q9WVH4; D3Z6Y6; Q05CZ4;
DT 25-JAN-2012, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Forkhead box protein O3 {ECO:0000305};
GN Name=Foxo3 {ECO:0000312|MGI:MGI:1890081};
GN Synonyms=Fkhr2 {ECO:0000303|PubMed:11353388},
GN Foxo3a {ECO:0000303|PubMed:11353388};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11353388; DOI=10.1007/s003350020002;
RA Biggs W.H. III, Cavenee W.K., Arden K.C.;
RT "Identification and characterization of members of the FKHR (FOX O)
RT subclass of winged-helix transcription factors in the mouse.";
RL Mamm. Genome 12:416-425(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Cerebellum;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-255.
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 ACETYLATION, DEACETYLATION BY SIRT2, AND INTERACTION WITH SIRT2.
RX PubMed=17521387; DOI=10.1111/j.1474-9726.2007.00304.x;
RA Wang F., Nguyen M., Qin F.X., Tong Q.;
RT "SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric
RT restriction.";
RL Aging Cell 6:505-514(2007).
RN [7]
RP FUNCTION.
RX PubMed=18054316; DOI=10.1016/j.cmet.2007.11.004;
RA Zhao J., Brault J.J., Schild A., Cao P., Sandri M., Schiaffino S.,
RA Lecker S.H., Goldberg A.L.;
RT "FoxO3 coordinately activates protein degradation by the
RT autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.";
RL Cell Metab. 6:472-483(2007).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
RX PubMed=18054315; DOI=10.1016/j.cmet.2007.11.001;
RA Mammucari C., Milan G., Romanello V., Masiero E., Rudolf R.,
RA Del Piccolo P., Burden S.J., Di Lisi R., Sandri C., Zhao J., Goldberg A.L.,
RA Schiaffino S., Sandri M.;
RT "FoxO3 controls autophagy in skeletal muscle in vivo.";
RL Cell Metab. 6:458-471(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Pancreas, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [10]
RP TISSUE SPECIFICITY.
RX PubMed=22510882; DOI=10.1038/emboj.2012.97;
RA Nakae J., Cao Y., Hakuno F., Takemori H., Kawano Y., Sekioka R., Abe T.,
RA Kiyonari H., Tanaka T., Sakai J., Takahashi S., Itoh H.;
RT "Novel repressor regulates insulin sensitivity through interaction with
RT Foxo1.";
RL EMBO J. 31:2275-2295(2012).
RN [11]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH SIRT3 AND POLRMT, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
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 [12]
RP FUNCTION, INTERACTION WITH CALCINEURIN A; CAMK2A AND CAMK2B,
RP PHOSPHORYLATION AT SER-298, MUTAGENESIS OF SER-298, AND IDENTIFICATION BY
RP 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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-241, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [14]
RP FUNCTION.
RX PubMed=25402684; DOI=10.1038/ncb3062;
RA Bowman C.J., Ayer D.E., Dynlacht B.D.;
RT "Foxk proteins repress the initiation of starvation-induced atrophy and
RT autophagy programs.";
RL Nat. Cell Biol. 16:1202-1214(2014).
RN [15]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PROTEOLYTIC CLEAVAGE.
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 [16]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=32103177; DOI=10.1038/s41586-020-2050-1;
RA van Gastel N., Stegen S., Eelen G., Schoors S., Carlier A., Daniels V.W.,
RA Baryawno N., Przybylski D., Depypere M., Stiers P.J., Lambrechts D.,
RA Van Looveren R., Torrekens S., Sharda A., Agostinis P., Lambrechts D.,
RA Maes F., Swinnen J.V., Geris L., Van Oosterwyck H., Thienpont B.,
RA Carmeliet P., Scadden D.T., Carmeliet G.;
RT "Lipid availability determines fate of skeletal progenitor cells via
RT SOX9.";
RL Nature 579:111-117(2020).
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:18054316, PubMed:18054315,
CC PubMed:23805378). Acts as a positive regulator of autophagy in skeletal
CC muscle: in starved cells, enters the nucleus following
CC dephosphorylation and binds the promoters of autophagy genes, such as
CC GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression,
CC resulting in proteolysis of skeletal muscle proteins (PubMed:18054316,
CC PubMed:18054315, PubMed:25402684). Triggers apoptosis in the absence of
CC survival factors, including neuronal cell death upon oxidative stress
CC (By similarity). 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 (By similarity). In response to metabolic stress, translocates into the
CC mitochondria where it promotes mtDNA transcription (PubMed:23283301).
CC Also acts as a key regulator of chondrogenic commitment of skeletal
CC progenitor cells in response to lipid availability: when lipids levels
CC are low, translocates to the nucleus and promotes expression of SOX9,
CC which induces chondrogenic commitment and suppresses fatty acid
CC oxidation (PubMed:32103177). Also acts as a key regulator of regulatory
CC T-cells (Treg) differentiation by activating expression of FOXP3 (By
CC similarity). {ECO:0000250|UniProtKB:O43524,
CC ECO:0000269|PubMed:18054315, ECO:0000269|PubMed:18054316,
CC ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:23805378,
CC ECO:0000269|PubMed:25402684, ECO:0000269|PubMed:32103177}.
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 (By similarity).
CC Interacts with SIRT2; the interaction occurs independently of SIRT2
CC deacetylase activity (PubMed:17521387). Interacts with YWHAB/14-3-3-
CC beta and YWHAZ/14-3-3-zeta, which are required for cytosolic
CC sequestration. Upon oxidative stress, interacts with STK4/MST1, which
CC disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear
CC translocation. Interacts with PIM1. Interacts with DDIT3/CHOP.
CC Interacts (deacetylated form) with SKP2. Interacts with CHUK and IKBKB
CC (By similarity). Interacts with CAMK2A, CAMK2B and calcineurin A
CC (PubMed:23805378). Interacts with NUPR1; this interaction represses
CC FOXO3 transactivation (By similarity). {ECO:0000250|UniProtKB:O43524,
CC ECO:0000269|PubMed:17521387, ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:23805378}.
CC -!- INTERACTION:
CC Q9WVH4; P0DJI6: Fcor; NbExp=2; IntAct=EBI-6127038, EBI-6126630;
CC Q9WVH4; Q8WTS6: SETD7; Xeno; NbExp=5; IntAct=EBI-6127038, EBI-1268586;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:18054315,
CC ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:32103177}. Nucleus
CC {ECO:0000269|PubMed:18054315, ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:32103177}. Mitochondrion matrix
CC {ECO:0000269|PubMed:23283301, ECO:0000269|PubMed:29445193}.
CC Mitochondrion outer membrane {ECO:0000269|PubMed:29445193}; Peripheral
CC membrane protein {ECO:0000269|PubMed:29445193}; Cytoplasmic side
CC {ECO:0000269|PubMed:29445193}. Note=Retention in the cytoplasm
CC contributes to its inactivation (By similarity). Translocates to the
CC nucleus upon oxidative stress and in the absence of survival factors
CC (By similarity). Translocates from the cytosol to the nucleus following
CC dephosphorylation in response to autophagy-inducing stimuli
CC (PubMed:18054315). 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 (PubMed:32103177). {ECO:0000250|UniProtKB:O43524,
CC ECO:0000269|PubMed:18054315, ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:29445193, ECO:0000269|PubMed:32103177}.
CC -!- TISSUE SPECIFICITY: Expressed in white and brown adipose tissues (at
CC protein level) (PubMed:22510882). Expressed in liver, kidney, lung and
CC colon (at protein level) (PubMed:29445193). Expressed in skeletal
CC muscles (at protein level) (PubMed:23283301).
CC {ECO:0000269|PubMed:22510882, ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:29445193}.
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 (By similarity). Deacetylation by SIRT2
CC stimulates FOXO3-mediated transcriptional activity in response to
CC oxidative stress (PubMed:17521387). Deacetylated by SIRT3 (By
CC similarity). Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA
CC transcriptional activity in response to metabolic stress (By
CC similarity). {ECO:0000250|UniProtKB:O43524,
CC ECO:0000269|PubMed:17521387}.
CC -!- PTM: In the presence of survival factors such as IGF-1, phosphorylated
CC on Thr-32 and Ser-252 by AKT1/PKB (Probable). This phosphorylated form
CC then interacts with 14-3-3 proteins and is retained in the cytoplasm
CC (Probable). Survival factor withdrawal induces dephosphorylation and
CC promotes translocation to the nucleus where the dephosphorylated
CC protein induces transcription of target genes and triggers apoptosis
CC (By similarity). Although AKT1/PKB doesn't appear to phosphorylate Ser-
CC 314 directly, it may activate other kinases that trigger
CC phosphorylation at this residue (By similarity). Phosphorylated by
CC STK4/MST1 on Ser-208 upon oxidative stress, which leads to dissociation
CC from YWHAB/14-3-3-beta and nuclear translocation (By similarity).
CC Phosphorylated by PIM1 (By similarity). Phosphorylation by AMPK leads
CC to the activation of transcriptional activity without affecting
CC subcellular localization (By similarity). Phosphorylated by AMPK on
CC Ser-30 in response to metabolic stress which mediates FOXO3
CC mitochondrial translocation (By similarity). Phosphorylation by
CC MAPKAPK5 promotes nuclear localization and DNA-binding, leading to
CC induction of miR-34b and miR-34c expression, 2 post-transcriptional
CC regulators of MYC that bind to the 3'UTR of MYC transcript and prevent
CC its translation (By similarity). Phosphorylated by CHUK/IKKA and
CC IKBKB/IKKB (By similarity). TNF-induced inactivation of FOXO3 requires
CC its phosphorylation at Ser-643 by IKBKB/IKKB which promotes FOXO3
CC retention in the cytoplasm, polyubiquitination and ubiquitin-mediated
CC proteasomal degradation (By similarity). May be dephosphorylated by
CC calcineurin A on Ser-298 which abolishes FOXO3 transcriptional activity
CC (PubMed:23805378). Phosphorylation at Ser-252 promotes its degradation
CC by the proteasome (By similarity). Dephosphorylation at Ser-252 by
CC protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction
CC with PPP2CA is enhanced by AMBRA1 (By similarity).
CC {ECO:0000250|UniProtKB:O43524, ECO:0000269|PubMed:23805378,
CC ECO:0000305|PubMed:18054315}.
CC -!- PTM: Heavily methylated by SET9 which decreases stability, while
CC moderately increasing transcriptional activity. The main methylation
CC site is Lys-270. Methylation doesn't affect subcellular location.
CC {ECO:0000250|UniProtKB:O43524}.
CC -!- PTM: Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2,
CC leading to proteasomal degradation. {ECO:0000250|UniProtKB:O43524}.
CC -!- PTM: The N-terminus is cleaved following import into the mitochondrion.
CC {ECO:0000269|PubMed:29445193}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH19532.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
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DR EMBL; AF114259; AAD42107.1; -; mRNA.
DR EMBL; AK047413; BAC33049.1; -; mRNA.
DR EMBL; AC116179; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC140402; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466540; EDL04998.1; -; Genomic_DNA.
DR EMBL; BC019532; AAH19532.1; ALT_SEQ; mRNA.
DR CCDS; CCDS23810.1; -.
DR RefSeq; NP_062714.1; NM_019740.2.
DR RefSeq; XP_006512869.1; XM_006512806.1.
DR AlphaFoldDB; Q9WVH4; -.
DR BMRB; Q9WVH4; -.
DR SMR; Q9WVH4; -.
DR BioGRID; 208010; 36.
DR ComplexPortal; CPX-1144; FOXO3-MYC complex.
DR ComplexPortal; CPX-1148; Foxo3-Ywhaz complex.
DR IntAct; Q9WVH4; 3.
DR MINT; Q9WVH4; -.
DR STRING; 10090.ENSMUSP00000050683; -.
DR iPTMnet; Q9WVH4; -.
DR PhosphoSitePlus; Q9WVH4; -.
DR EPD; Q9WVH4; -.
DR jPOST; Q9WVH4; -.
DR MaxQB; Q9WVH4; -.
DR PaxDb; Q9WVH4; -.
DR PeptideAtlas; Q9WVH4; -.
DR PRIDE; Q9WVH4; -.
DR ProteomicsDB; 267404; -.
DR DNASU; 56484; -.
DR Ensembl; ENSMUST00000056974; ENSMUSP00000050683; ENSMUSG00000048756.
DR Ensembl; ENSMUST00000105502; ENSMUSP00000101141; ENSMUSG00000048756.
DR Ensembl; ENSMUST00000175881; ENSMUSP00000135380; ENSMUSG00000048756.
DR GeneID; 56484; -.
DR KEGG; mmu:56484; -.
DR UCSC; uc007eyl.1; mouse.
DR CTD; 2309; -.
DR MGI; MGI:1890081; Foxo3.
DR VEuPathDB; HostDB:ENSMUSG00000048756; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000159826; -.
DR HOGENOM; CLU_023456_1_0_1; -.
DR InParanoid; Q9WVH4; -.
DR OMA; EWMVRSI; -.
DR OrthoDB; 1160384at2759; -.
DR PhylomeDB; Q9WVH4; -.
DR TreeFam; TF315583; -.
DR Reactome; R-MMU-1181150; Signaling by NODAL.
DR Reactome; R-MMU-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-MMU-5687128; MAPK6/MAPK4 signaling.
DR Reactome; R-MMU-9607240; FLT3 Signaling.
DR Reactome; R-MMU-9614399; Regulation of localization of FOXO transcription factors.
DR Reactome; R-MMU-9617629; Regulation of FOXO transcriptional activity by acetylation.
DR Reactome; R-MMU-9617828; FOXO-mediated transcription of cell cycle genes.
DR Reactome; R-MMU-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR BioGRID-ORCS; 56484; 4 hits in 75 CRISPR screens.
DR ChiTaRS; Foxo3; mouse.
DR PRO; PR:Q9WVH4; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q9WVH4; protein.
DR Bgee; ENSMUSG00000048756; Expressed in secondary oocyte and 274 other tissues.
DR ExpressionAtlas; Q9WVH4; baseline and differential.
DR Genevisible; Q9WVH4; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005759; C:mitochondrial matrix; ISO:MGI.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0008013; F:beta-catenin binding; ISO:MGI.
DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:UniProtKB.
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; IBA:GO_Central.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IGI:MGI.
DR GO; GO:0034246; F:mitochondrial transcription factor activity; IMP:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:BHF-UCL.
DR GO; GO:0001221; F:transcription coregulator binding; ISO:MGI.
DR GO; GO:0007568; P:aging; ISO:MGI.
DR GO; GO:0001547; P:antral ovarian follicle growth; IMP:MGI.
DR GO; GO:0048854; P:brain morphogenesis; IGI:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IGI:MGI.
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; ISO:MGI.
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; IDA:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IDA:MGI.
DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; IGI:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IMP:MGI.
DR GO; GO:0001544; P:initiation of primordial ovarian follicle growth; IMP:MGI.
DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IGI:MGI.
DR GO; GO:0030336; P:negative regulation of cell migration; ISO:MGI.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:ComplexPortal.
DR GO; GO:0097150; P:neuronal stem cell population maintenance; IGI:MGI.
DR GO; GO:0001556; P:oocyte maturation; IMP:MGI.
DR GO; GO:0001542; P:ovulation from ovarian follicle; IMP:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProtKB.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; ISO:MGI.
DR GO; GO:0045648; P:positive regulation of erythrocyte differentiation; ISO:MGI.
DR GO; GO:1901300; P:positive regulation of hydrogen peroxide-mediated programmed cell death; ISO:MGI.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IMP:BHF-UCL.
DR GO; GO:0014737; P:positive regulation of muscle atrophy; IDA:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; ISO:MGI.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:2000177; P:regulation of neural precursor cell proliferation; IGI:MGI.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IGI:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0006417; P:regulation of translation; ISS:UniProtKB.
DR GO; GO:0071548; P:response to dexamethasone; IEA:Ensembl.
DR GO; GO:0070542; P:response to fatty acid; IDA:UniProtKB.
DR GO; GO:0042594; P:response to starvation; IDA: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; ISS:UniProtKB.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
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 Acetylation; Activator; Apoptosis; Cytoplasm; DNA-binding; Membrane;
KW Methylation; Mitochondrion; Mitochondrion outer membrane; Nucleus;
KW Phosphoprotein; Proto-oncogene; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..672
FT /note="Forkhead box protein O3"
FT /id="PRO_0000415334"
FT DNA_BIND 156..250
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..85
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 80..108
FT /note="Required for mitochondrial import"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT REGION 110..152
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 230..301
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 299..672
FT /note="Mediates interaction with CHUK/IKKA and IKBKB/IKKB"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT REGION 399..441
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 535..583
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 241..258
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT COMPBIAS 55..69
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 279..301
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 412..441
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 30
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 32
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 46
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 148
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 178
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 208
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 214
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 229
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 241
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 252
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 261
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 270
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 279
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 283
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 289
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 293
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 298
FT /note="Phosphoserine; by CaMK2A"
FT /evidence="ECO:0000269|PubMed:23805378"
FT MOD_RES 310
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 314
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 398
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 412
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 418
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 420
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 550
FT /note="Phosphoserine; by MAPKAPK5"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 554
FT /note="Phosphoserine; by AMPK and MAPKAPK5"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 587
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 625
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MOD_RES 643
FT /note="Phosphoserine; by IKKB"
FT /evidence="ECO:0000250|UniProtKB:O43524"
FT MUTAGEN 298
FT /note="S->A: Abolishes phosphorylation by CAMK2A. Loss of
FT transcriptional activity."
FT /evidence="ECO:0000269|PubMed:23805378"
SQ SEQUENCE 672 AA; 71064 MW; EC218D9BA0C1DAC5 CRC64;
MAEAPASPVP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE TAADSMIPEE
DDDEDDEDGG GRASSAMVIG GGVSSTLGSG LLLEDSAMLL APGGQDLGSG PASAAGALSG
GTPTQLQPQQ PLPQPQPGAA GGSGQPRKCS SRRNAWGNLS YADLITRAIE SSPDKRLTLS
QIYEWMVRCV PYFKDKGDSN SSAGWKNSIR HNLSLHSRFM RVQNEGTGKS SWWIINPDGG
KSGKAPRRRA VSMDNSNKYT KSRGRAAKKK AALQAAPESA DDSPSQLSKW PGSPTSRSSD
ELDAWTDFRS RTNSNASTVS GRLSPILAST ELDDVQDDDG PLSPMLYSSS ASLSPSVSKP
CTVELPRLTD MAGTMNLNDG LAENLMDDLL DNIALPPSQP SPPGGLMQRG SSFPYTAKSS
GLGSPTGSFN STVFGPSSLN SLRQSPMQTI QENRPATFSS VSHYGNQTLQ DLLASDSLSH
SDVMMTQSDP LMSQASTAVS AQNARRNVML RNDPMMSFAA QPTQGSLVNQ NLLHHQHQTQ
GALGGSRALS NSVSNMGLSD SSSLGSAKHQ QQSPASQSMQ TLSDSLSGSS LYSASANLPV
MGHDKFPSDL DLDMFNGSLE CDMESIIRSE LMDADGLDFN FDSLISTQNV VGLNVGNFTG
AKQASSQSWV PG
