FOXO1_HUMAN
ID FOXO1_HUMAN Reviewed; 655 AA.
AC Q12778; O43523; Q5VYC7; Q6NSK6;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 222.
DE RecName: Full=Forkhead box protein O1 {ECO:0000305};
DE AltName: Full=Forkhead box protein O1A;
DE AltName: Full=Forkhead in rhabdomyosarcoma {ECO:0000303|PubMed:8275086};
GN Name=FOXO1 {ECO:0000303|PubMed:12228231, ECO:0000312|HGNC:HGNC:3819};
GN Synonyms=FKHR {ECO:0000303|PubMed:9479491}, FOXO1A;
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], AND CHROMOSOMAL TRANSLOCATION WITH PAX3.
RX PubMed=8275086; DOI=10.1038/ng1193-230;
RA Galili N., Davis R.J., Fredericks W.J., Mukhopadhyay S., Rauscher F.J. III,
RA Emanuel B.S., Rovera G., Barr F.G.;
RT "Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar
RT rhabdomyosarcoma.";
RL Nat. Genet. 5:230-235(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph, 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 CHROMOSOMAL TRANSLOCATION WITH PAX7.
RX PubMed=8187070;
RA Davis R.J., D'Cruz C.M., Lovell M.A., Biegel J.A., Barr F.G.;
RT "Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in
RT alveolar rhabdomyosarcoma.";
RL Cancer Res. 54:2869-2872(1994).
RN [7]
RP PHOSPHORYLATION AT THR-24; SER-256 AND SER-319.
RX PubMed=10358075; DOI=10.1074/jbc.274.24.17179;
RA Rena G., Guo S., Cichy S.C., Unterman T.G., Cohen P.;
RT "Phosphorylation of the transcription factor forkhead family member FKHR by
RT protein kinase B.";
RL J. Biol. Chem. 274:17179-17183(1999).
RN [8]
RP DNA-BINDING, PHOSPHORYLATION AT SER-256, AND FUNCTION.
RX PubMed=10358076; DOI=10.1074/jbc.274.24.17184;
RA Guo S., Rena G., Cichy S., He X., Cohen P., Unterman T.;
RT "Phosphorylation of serine 256 by protein kinase B disrupts transactivation
RT by FKHR and mediates effects of insulin on insulin-like growth factor-
RT binding protein-1 promoter activity through a conserved insulin response
RT sequence.";
RL J. Biol. Chem. 274:17184-17192(1999).
RN [9]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-329, AND MUTAGENESIS OF
RP SER-329.
RX PubMed=11311120; DOI=10.1042/bj3550597;
RA Woods Y.L., Rena G., Morrice N., Barthel A., Becker W., Guo S.,
RA Unterman T.G., Cohen P.;
RT "The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329
RT in vitro, a novel in vivo phosphorylation site.";
RL Biochem. J. 355:597-607(2001).
RN [10]
RP INTERACTION WITH YWHAG AND YWHAZ, PHOSPHORYLATION AT THR-24; SER-256 AND
RP SER-319, SUBCELLULAR LOCATION, AND MUTAGENESIS OF THR-24; SER-256 AND
RP SER-319.
RX PubMed=11237865; DOI=10.1042/0264-6021:3540605;
RA Rena G., Prescott A.R., Guo S., Cohen P., Unterman T.G.;
RT "Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in
RT regulating 14-3-3 binding, transactivation and nuclear targetting.";
RL Biochem. J. 354:605-612(2001).
RN [11]
RP PHOSPHORYLATION AT THR-24; SER-256; SER-319; SER-322; SER-325 AND SER-329.
RX PubMed=11980723; DOI=10.1093/emboj/21.9.2263;
RA Rena G., Woods Y.L., Prescott A.R., Peggie M., Unterman T.G.,
RA Williams M.R., Cohen P.;
RT "Two novel phosphorylation sites on FKHR that are critical for its nuclear
RT exclusion.";
RL EMBO J. 21:2263-2271(2002).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF THR-24; LYS-245;
RP LYS-248; 251-ARG--ARG-253; SER-256; LYS-262; LYS-265; LYS-274 AND SER-319.
RX PubMed=12228231; DOI=10.1074/jbc.m208063200;
RA Zhang X., Gan L., Pan H., Guo S., He X., Olson S.T., Mesecar A., Adam S.,
RA Unterman T.G.;
RT "Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1)
RT by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic
RT shuttling and DNA binding.";
RL J. Biol. Chem. 277:45276-45284(2002).
RN [13]
RP INTERACTION WITH CREBBP AND SIRT1, ACETYLATION, DEACETYLATION, AND
RP FUNCTION.
RX PubMed=15220471; DOI=10.1073/pnas.0400593101;
RA Daitoku H., Hatta M., Matsuzaki H., Aratani S., Ohshima T., Miyagishi M.,
RA Nakajima T., Fukamizu A.;
RT "Silent information regulator 2 potentiates Foxo1-mediated transcription
RT through its deacetylase activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:10042-10047(2004).
RN [14]
RP INTERACTION WITH EP300, ACETYLATION, SUBCELLULAR LOCATION, PHOSPHORYLATION,
RP AND FUNCTION.
RX PubMed=15890677; DOI=10.1210/me.2004-0292;
RA Perrot V., Rechler M.M.;
RT "The coactivator p300 directly acetylates the forkhead transcription factor
RT Foxo1 and stimulates Foxo1-induced transcription.";
RL Mol. Endocrinol. 19:2283-2298(2005).
RN [15]
RP INTERACTION WITH SKP2, UBIQUITINATION, AND MUTAGENESIS OF SER-256.
RX PubMed=15668399; DOI=10.1073/pnas.0406789102;
RA Huang H., Regan K.M., Wang F., Wang D., Smith D.I., van Deursen J.M.,
RA Tindall D.J.;
RT "Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated
RT degradation.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:1649-1654(2005).
RN [16]
RP FUNCTION.
RX PubMed=17024043; DOI=10.1038/nature05288;
RA Schilling M.M., Oeser J.K., Boustead J.N., Flemming B.P., O'Brien R.M.;
RT "Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection.";
RL Nature 443:E10-E11(2006).
RN [17]
RP INTERACTION WITH PRMT1.
RX PubMed=18951090; DOI=10.1016/j.molcel.2008.09.013;
RA Yamagata K., Daitoku H., Takahashi Y., Namiki K., Hisatake K., Kako K.,
RA Mukai H., Kasuya Y., Fukamizu A.;
RT "Arginine methylation of FOXO transcription factors inhibits their
RT phosphorylation by Akt.";
RL Mol. Cell 32:221-231(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, AND IDENTIFICATION BY
RP 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 [19]
RP FUNCTION, PHOSPHORYLATION AT SER-249 BY CDK1, INTERACTION WITH CDK1 AND
RP 14-3-3 PROTEINS, AND MUTAGENESIS OF SER-249.
RX PubMed=18356527; DOI=10.1126/science.1152337;
RA Yuan Z., Becker E.B.E., Merlo P., Yamada T., DiBacco S., Konishi Y.,
RA Schaefer E.M., Bonni A.;
RT "Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons.";
RL Science 319:1665-1668(2008).
RN [20]
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 [21]
RP PHOSPHORYLATION AT SER-212, SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS
RP OF SER-212.
RX PubMed=19221179; DOI=10.1074/jbc.m900461200;
RA Yuan Z., Lehtinen M.K., Merlo P., Villen J., Gygi S., Bonni A.;
RT "Regulation of neuronal cell death by MST1-FOXO1 signaling.";
RL J. Biol. Chem. 284:11285-11292(2009).
RN [22]
RP ACETYLATION AT LYS-262; LYS-265 AND LYS-274, DEACETYLATION BY SIRT2,
RP FUNCTION IN AUTOPHAGY, SUBCELLULAR LOCATION, AND INTERACTION WITH SIRT2 AND
RP ATG7.
RX PubMed=20543840; DOI=10.1038/ncb2069;
RA Zhao Y., Yang J., Liao W., Liu X., Zhang H., Wang S., Wang D., Feng J.,
RA Yu L., Zhu W.G.;
RT "Cytosolic FoxO1 is essential for the induction of autophagy and tumour
RT suppressor activity.";
RL Nat. Cell Biol. 12:665-675(2010).
RN [23]
RP INDUCTION.
RX PubMed=20668652; DOI=10.1371/journal.pone.0011786;
RA Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P.,
RA Retta S.F.;
RT "KRIT1 regulates the homeostasis of intracellular reactive oxygen
RT species.";
RL PLoS ONE 5:E11786-E11786(2010).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-212.
RX PubMed=21245099; DOI=10.1158/0008-5472.can-10-2203;
RA Valis K., Prochazka L., Boura E., Chladova J., Obsil T., Rohlena J.,
RA Truksa J., Dong L.F., Ralph S.J., Neuzil J.;
RT "Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a
RT FoxO1-dependent manner.";
RL Cancer Res. 71:946-954(2011).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [28]
RP ACETYLATION AT LYS-423, DEACETYLATION BY SIRT6, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF LYS-423; LYS-446; LYS-463 AND LYS-515.
RX PubMed=25009184; DOI=10.1073/pnas.1411026111;
RA Zhang P., Tu B., Wang H., Cao Z., Tang M., Zhang C., Gu B., Li Z., Wang L.,
RA Yang Y., Zhao Y., Wang H., Luo J., Deng C.X., Gao B., Roeder R.G.,
RA Zhu W.G.;
RT "Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by
RT promoting FoxO1 nuclear exclusion.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:10684-10689(2014).
RN [29]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-256,
RP DEPHOSPHORYLATION AT SER-256, AND INTERACTION WITH PPIA.
RX PubMed=31063815; DOI=10.1016/j.cellsig.2019.04.014;
RA Xie Y., Li X., Ge J.;
RT "Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis.";
RL Cell. Signal. 61:57-65(2019).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 151-266, DNA-BINDING,
RP PHOSPHORYLATION AT SER-212; SER-218; SER-234 AND SER-235, ACETYLATION,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF SER-249.
RX PubMed=18786403; DOI=10.1016/j.str.2008.06.013;
RA Brent M.M., Anand R., Marmorstein R.;
RT "Structural basis for DNA recognition by FoxO1 and its regulation by
RT posttranslational modification.";
RL Structure 16:1407-1416(2008).
CC -!- FUNCTION: Transcription factor that is the main target of insulin
CC signaling and regulates metabolic homeostasis in response to oxidative
CC stress (PubMed:10358076, PubMed:12228231, PubMed:15220471,
CC PubMed:15890677, PubMed:18356527, PubMed:19221179, PubMed:20543840,
CC PubMed:21245099). Binds to the insulin response element (IRE) with
CC consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family
CC binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'
CC (PubMed:10358076). Activity suppressed by insulin (PubMed:10358076).
CC Main regulator of redox balance and osteoblast numbers and controls
CC bone mass (By similarity). Orchestrates the endocrine function of the
CC skeleton in regulating glucose metabolism (By similarity). Also acts as
CC a 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). Acts synergistically with ATF4 to suppress
CC osteocalcin/BGLAP activity, increasing glucose levels and triggering
CC glucose intolerance and insulin insensitivity (By similarity). Also
CC suppresses the transcriptional activity of RUNX2, an upstream activator
CC of osteocalcin/BGLAP (By similarity). Acts as an inhibitor of glucose
CC sensing in pancreatic beta cells by acting as a transcription repressor
CC and suppressing expression of PDX1 (By similarity). In hepatocytes,
CC promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to
CC activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By
CC similarity). Also promotes gluconeogenesis by directly promoting
CC expression of PPARGC1A and G6PC1 (PubMed:17024043). Important regulator
CC of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1
CC (PubMed:18356527, PubMed:19221179). Promotes neural cell death
CC (PubMed:18356527). Mediates insulin action on adipose tissue (By
CC similarity). Regulates the expression of adipogenic genes such as PPARG
CC during preadipocyte differentiation and, adipocyte size and adipose
CC tissue-specific gene expression in response to excessive calorie intake
CC (By similarity). Regulates the transcriptional activity of GADD45A and
CC repair of nitric oxide-damaged DNA in beta-cells (By similarity).
CC Required for the autophagic cell death induction in response to
CC starvation or oxidative stress in a transcription-independent manner
CC (PubMed:20543840). Mediates the function of MLIP in cardiomyocytes
CC hypertrophy and cardiac remodeling (By similarity). Regulates
CC endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent
CC manner via transcription of CCL2 and BCL2L11 which are involved in EC
CC chemotaxis and apoptosis (PubMed:31063815).
CC {ECO:0000250|UniProtKB:A4L7N3, ECO:0000250|UniProtKB:G3V7R4,
CC ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:10358076,
CC ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:15220471,
CC ECO:0000269|PubMed:15890677, ECO:0000269|PubMed:17024043,
CC ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:19221179,
CC ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099,
CC ECO:0000269|PubMed:31063815}.
CC -!- SUBUNIT: Interacts with LRPPRC. Interacts with RUNX2; the interaction
CC inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-
CC dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the
CC interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-
CC 256 leading to its nuclear import. Interacts (acetylated form) with
CC PPARG. Interacts with XBP1 isoform 2; this interaction is direct and
CC leads to FOXO1 ubiquitination and degradation via the proteasome
CC pathway (By similarity). Interacts with NLK. Interacts with SIRT1; the
CC interaction results in the deacetylation of FOXO1 leading to activation
CC of FOXO1-mediated transcription of genes involved in DNA repair and
CC stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins,
CC YWHAG and YWHAZ; the interactions require insulin-stimulated
CC phosphorylation on Thr-24, promote nuclear exit and loss of
CC transcriptional activity. Interacts with SKP2; the interaction
CC ubiquitinates FOXO1 leading to its proteosomal degradation. The
CC interaction requires the presence of KRIT1. Interacts (via the C-
CC terminal half) with ATF4 (via its DNA-binding domain); the interaction
CC occurs in osteoblasts, regulates glucose homeostasis via suppression of
CC beta-cell proliferation and subsequent decrease in insulin production.
CC Interacts with PRMT1; the interaction methylates FOXO1, prevents
CC PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts
CC with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with
CC SIRT2; the interaction is disrupted in response to oxidative stress or
CC serum deprivation, leading to increased level of acetylated FOXO1,
CC which promotes stress-induced autophagy by stimulating E1-like
CC activating enzyme ATG7. Interacts (acetylated form) with ATG7; the
CC interaction is increased in response to oxidative stress or serum
CC deprivation and promotes the autophagic process leading to cell death.
CC Interacts (via the Fork-head domain) with CEBPA; the interaction
CC increases when FOXO1 is deacetylated. Interacts with WDFY2. Forms a
CC complex with WDFY2 and AKT1 (By similarity). Interacts with CRY1 (By
CC similarity). Interacts with PPIA/CYPA; the interaction promotes FOXO1
CC dephosphorylation, nuclear accumulation and transcriptional activity
CC (PubMed:31063815). Interacts with TOX4; FOXO1 is required for full
CC induction of TOX4-dependent activity and the interaction is inhibited
CC by insulin (By similarity). {ECO:0000250|UniProtKB:Q9R1E0,
CC ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:15220471,
CC ECO:0000269|PubMed:15668399, ECO:0000269|PubMed:15890677,
CC ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:18951090,
CC ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:31063815}.
CC -!- INTERACTION:
CC Q12778; P31749: AKT1; NbExp=2; IntAct=EBI-1108782, EBI-296087;
CC Q12778; P06493: CDK1; NbExp=5; IntAct=EBI-1108782, EBI-444308;
CC Q12778; Q92793: CREBBP; NbExp=3; IntAct=EBI-1108782, EBI-81215;
CC Q12778; P03372: ESR1; NbExp=2; IntAct=EBI-1108782, EBI-78473;
CC Q12778; P14921-3: ETS1; NbExp=2; IntAct=EBI-1108782, EBI-21403286;
CC Q12778; Q14192: FHL2; NbExp=8; IntAct=EBI-1108782, EBI-701903;
CC Q12778; Q01105: SET; NbExp=5; IntAct=EBI-1108782, EBI-1053182;
CC Q12778; Q96EB6: SIRT1; NbExp=4; IntAct=EBI-1108782, EBI-1802965;
CC Q12778; P63104: YWHAZ; NbExp=3; IntAct=EBI-1108782, EBI-347088;
CC Q12778; Q923E4: Sirt1; Xeno; NbExp=2; IntAct=EBI-1108782, EBI-1802585;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11237865,
CC ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231,
CC ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:20543840,
CC ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:25009184,
CC ECO:0000269|PubMed:31063815}. Nucleus {ECO:0000269|PubMed:11311120,
CC ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:20543840,
CC ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}.
CC Note=Shuttles between the cytoplasm and nucleus. Largely nuclear in
CC unstimulated cells (PubMed:11311120, PubMed:12228231, PubMed:19221179,
CC PubMed:21245099, PubMed:20543840, PubMed:25009184). In osteoblasts,
CC colocalizes with ATF4 and RUNX2 in the nucleus (By similarity). Serum
CC deprivation increases localization to the nucleus, leading to activate
CC expression of SOX9 and subsequent chondrogenesis (By similarity).
CC Insulin-induced phosphorylation at Ser-256 by PKB/AKT1 leads, via
CC stimulation of Thr-24 phosphorylation, to binding of 14-3-3 proteins
CC and nuclear export to the cytoplasm where it is degraded by the
CC ubiquitin-proteosomal pathway (PubMed:11237865, PubMed:12228231).
CC Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins
CC and promotes nuclear accumulation (PubMed:18356527). Phosphorylation by
CC NLK results in nuclear export (By similarity). Translocates to the
CC nucleus upon oxidative stress-induced phosphorylation at Ser-212 by
CC STK4/MST1 (PubMed:19221179, PubMed:21245099). SGK1-mediated
CC phosphorylation also results in nuclear translocation (By similarity).
CC Retained in the nucleus under stress stimuli including oxidative
CC stress, nutrient deprivation or nitric oxide (By similarity). Retained
CC in the nucleus on methylation (By similarity). PPIA/CYPA stimulates its
CC nuclear accumulation (PubMed:31063815). Deacetylation by SIRT6,
CC promotes its translocation into the cytoplasm (PubMed:25009184).
CC {ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:11237865,
CC ECO:0000269|PubMed:11311120, ECO:0000269|PubMed:12228231,
CC ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:19221179,
CC ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:21245099,
CC ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:31063815}.
CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:9479491}.
CC -!- INDUCTION: Expression is regulated by KRIT1. Levels of expression also
CC regulated by FOXC1 which binds to a conserved element in the FOXO1
CC promoter. {ECO:0000269|PubMed:20668652}.
CC -!- PTM: Phosphorylation by NLK promotes nuclear export and inhibits the
CC transcriptional activity. In response to growth factors,
CC phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes
CC nuclear export and inactivation of transactivational activity.
CC Phosphorylation on Thr-24 is required for binding 14-3-3 proteins.
CC Phosphorylation of Ser-256 decreases DNA-binding activity and promotes
CC the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation
CC of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion
CC and loss of function. Stress signals, such as response to oxygen or
CC nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading
CC to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1
CC and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256
CC by PP2A in beta-cells under oxidative stress leading to nuclear
CC retention (By similarity). Phosphorylation of Ser-249 by CDK1 disrupts
CC binding of 14-3-3 proteins leading to nuclear accumulation and has no
CC effect on DNA-binding nor transcriptional activity. Phosphorylation by
CC STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3
CC proteins and nuclear export. PPIA/CYPA promotes its dephosphorylation
CC on Ser-256 (PubMed:31063815). {ECO:0000250|UniProtKB:Q9R1E0,
CC ECO:0000269|PubMed:10358075, ECO:0000269|PubMed:10358076,
CC ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11311120,
CC ECO:0000269|PubMed:11980723, ECO:0000269|PubMed:18356527,
CC ECO:0000269|PubMed:18786403, ECO:0000269|PubMed:19221179,
CC ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:31063815}.
CC -!- PTM: Ubiquitinated by SKP2. Ubiquitination leads to proteasomal
CC degradation. {ECO:0000269|PubMed:15668399}.
CC -!- PTM: Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and
CC is increased by oxidative stress. {ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- PTM: Acetylated (PubMed:20543840, PubMed:15220471, PubMed:15890677,
CC PubMed:18786403). Acetylation at Lys-262, Lys-265 and Lys-274 are
CC necessary for autophagic cell death induction (PubMed:20543840).
CC Deacetylated by SIRT2 in response to oxidative stress or serum
CC deprivation, thereby negatively regulating FOXO1-mediated autophagic
CC cell death (PubMed:20543840). Once in the nucleus, acetylated by
CC CREBBP/EP300 (PubMed:15220471, PubMed:15890677, PubMed:18786403).
CC Acetylation diminishes the interaction with target DNA and attenuates
CC the transcriptional activity. It increases the phosphorylation at Ser-
CC 256 (PubMed:15220471, PubMed:15890677, PubMed:18786403). Deacetylation
CC by SIRT1 results in reactivation of the transcriptional activity
CC (PubMed:15220471, PubMed:15890677, PubMed:18786403). Oxidative stress
CC by hydrogen peroxide treatment appears to promote deacetylation and
CC uncoupling of insulin-induced phosphorylation (PubMed:15220471,
CC PubMed:15890677, PubMed:18786403). By contrast, resveratrol acts
CC independently of acetylation (PubMed:15220471, PubMed:15890677,
CC PubMed:18786403). Acetylated at Lys-423, promoting its localization to
CC the nucleus and transcription factor activity (PubMed:25009184).
CC Deacetylation at Lys-423 by SIRT6, promotes its translocation into the
CC cytoplasm, preventing its transcription factor activity
CC (PubMed:25009184). Deacetylation and subsequent inhibition by SIRT6 has
CC different effects depending on cell types: it inhibits gluconeogenesis
CC in hepatocytes, promotes glucose sensing in pancreatic beta-cells and
CC regulates lipid catabolism in brown adipocytes (By similarity).
CC {ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:15220471,
CC ECO:0000269|PubMed:15890677, ECO:0000269|PubMed:18786403,
CC ECO:0000269|PubMed:20543840, ECO:0000269|PubMed:25009184}.
CC -!- DISEASE: Rhabdomyosarcoma 2 (RMS2) [MIM:268220]: A form of
CC rhabdomyosarcoma, a highly malignant tumor of striated muscle derived
CC from primitive mesenchymal cells and exhibiting differentiation along
CC rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently
CC occurring soft tissue sarcomas and the most common in children. It
CC occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal
CC rhabdomyosarcomas. Note=The gene represented in this entry may be
CC involved in disease pathogenesis. Chromosomal aberrations involving
CC FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with
CC PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting
CC protein is a transcriptional activator. {ECO:0000269|PubMed:8275086}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FOXO1ID83ch13q14.html";
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; U02310; AAA03629.1; -; mRNA.
DR EMBL; AF032885; AAC39591.1; -; mRNA.
DR EMBL; BT007455; AAP36123.1; -; mRNA.
DR EMBL; AL355132; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL133318; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC021981; AAH21981.1; -; mRNA.
DR EMBL; BC070065; AAH70065.3; -; mRNA.
DR CCDS; CCDS9371.1; -.
DR PIR; S40521; S40521.
DR RefSeq; NP_002006.2; NM_002015.3.
DR PDB; 3CO6; X-ray; 2.10 A; C=151-249.
DR PDB; 3CO7; X-ray; 2.91 A; C/F=151-266.
DR PDB; 3COA; X-ray; 2.20 A; C/F=151-266.
DR PDB; 4LG0; X-ray; 2.19 A; A=143-270.
DR PDB; 5DUI; X-ray; 2.31 A; A/B=151-259.
DR PDB; 6LBI; X-ray; 3.07 A; C/D/G/H/K/L=151-265.
DR PDB; 6QVW; NMR; -; A=159-272.
DR PDB; 6QZR; X-ray; 2.30 A; J/M/N/O/P/R/T/U=19-29.
DR PDB; 6QZS; X-ray; 1.90 A; C/P=251-262.
DR PDBsum; 3CO6; -.
DR PDBsum; 3CO7; -.
DR PDBsum; 3COA; -.
DR PDBsum; 4LG0; -.
DR PDBsum; 5DUI; -.
DR PDBsum; 6LBI; -.
DR PDBsum; 6QVW; -.
DR PDBsum; 6QZR; -.
DR PDBsum; 6QZS; -.
DR AlphaFoldDB; Q12778; -.
DR SMR; Q12778; -.
DR BioGRID; 108597; 85.
DR CORUM; Q12778; -.
DR DIP; DIP-35654N; -.
DR IntAct; Q12778; 38.
DR MINT; Q12778; -.
DR STRING; 9606.ENSP00000368880; -.
DR BindingDB; Q12778; -.
DR ChEMBL; CHEMBL5294; -.
DR GlyConnect; 2844; 1 O-Linked glycan (4 sites).
DR GlyGen; Q12778; 7 sites, 1 O-linked glycan (7 sites).
DR iPTMnet; Q12778; -.
DR PhosphoSitePlus; Q12778; -.
DR BioMuta; FOXO1; -.
DR DMDM; 116241368; -.
DR CPTAC; CPTAC-1323; -.
DR EPD; Q12778; -.
DR jPOST; Q12778; -.
DR MassIVE; Q12778; -.
DR MaxQB; Q12778; -.
DR PaxDb; Q12778; -.
DR PeptideAtlas; Q12778; -.
DR PRIDE; Q12778; -.
DR ProteomicsDB; 58922; -.
DR Antibodypedia; 645; 2175 antibodies from 53 providers.
DR CPTC; Q12778; 3 antibodies.
DR DNASU; 2308; -.
DR Ensembl; ENST00000379561.6; ENSP00000368880.4; ENSG00000150907.10.
DR GeneID; 2308; -.
DR KEGG; hsa:2308; -.
DR MANE-Select; ENST00000379561.6; ENSP00000368880.4; NM_002015.4; NP_002006.2.
DR UCSC; uc001uxl.5; human.
DR CTD; 2308; -.
DR DisGeNET; 2308; -.
DR GeneCards; FOXO1; -.
DR HGNC; HGNC:3819; FOXO1.
DR HPA; ENSG00000150907; Tissue enhanced (skeletal).
DR MalaCards; FOXO1; -.
DR MIM; 136533; gene.
DR MIM; 268220; phenotype.
DR neXtProt; NX_Q12778; -.
DR OpenTargets; ENSG00000150907; -.
DR Orphanet; 99756; Alveolar rhabdomyosarcoma.
DR PharmGKB; PA28237; -.
DR VEuPathDB; HostDB:ENSG00000150907; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000161558; -.
DR HOGENOM; CLU_023456_1_1_1; -.
DR InParanoid; Q12778; -.
DR OMA; SMNPLPQ; -.
DR OrthoDB; 1160384at2759; -.
DR PhylomeDB; Q12778; -.
DR TreeFam; TF315583; -.
DR PathwayCommons; Q12778; -.
DR Reactome; R-HSA-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-HSA-210745; Regulation of gene expression in beta cells.
DR Reactome; R-HSA-211163; AKT-mediated inactivation of FOXO1A.
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-9614399; Regulation of localization of FOXO transcription factors.
DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes.
DR Reactome; R-HSA-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR Reactome; R-HSA-9617629; Regulation of FOXO transcriptional activity by acetylation.
DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes.
DR SignaLink; Q12778; -.
DR SIGNOR; Q12778; -.
DR BioGRID-ORCS; 2308; 18 hits in 1096 CRISPR screens.
DR ChiTaRS; FOXO1; human.
DR EvolutionaryTrace; Q12778; -.
DR GeneWiki; FOXO1; -.
DR GenomeRNAi; 2308; -.
DR Pharos; Q12778; Tbio.
DR PRO; PR:Q12778; -.
DR Proteomes; UP000005640; Chromosome 13.
DR RNAct; Q12778; protein.
DR Bgee; ENSG00000150907; Expressed in decidua and 217 other tissues.
DR Genevisible; Q12778; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; IEA:Ensembl.
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; IMP: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; IEA:Ensembl.
DR GO; GO:1990841; F:promoter-specific chromatin binding; IEA:Ensembl.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0001678; P:cellular glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0070417; P:cellular response to cold; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071455; P:cellular response to hyperoxia; IDA:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB.
DR GO; GO:0071732; P:cellular response to nitric oxide; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; IDA:UniProtKB.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0045444; P:fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:1903243; P:negative regulation of cardiac muscle hypertrophy in response to stress; ISS:UniProtKB.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0046676; P:negative regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0032873; P:negative regulation of stress-activated MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0097150; P:neuronal stem cell population maintenance; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR GO; GO:0045722; P:positive regulation of gluconeogenesis; IDA:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IMP: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:0006473; P:protein acetylation; ISS:UniProtKB.
DR GO; GO:2000177; P:regulation of neural precursor cell proliferation; IEA:Ensembl.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0070542; P:response to fatty acid; ISS:UniProtKB.
DR GO; GO:0001659; P:temperature homeostasis; ISS:UniProtKB.
DR CDD; cd00059; FH; 1.
DR DisProt; DP01132; -.
DR Gene3D; 1.10.10.10; -; 1.
DR IDEAL; IID00464; -.
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; Apoptosis; Autophagy;
KW Chromosomal rearrangement; Cytoplasm; Differentiation; DNA-binding;
KW Methylation; Nucleus; Phosphoprotein; Proto-oncogene; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..655
FT /note="Forkhead box protein O1"
FT /id="PRO_0000091872"
FT DNA_BIND 159..235
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..63
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 116..158
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 211..218
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:18786403"
FT REGION 234..344
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 234..237
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:18786403"
FT REGION 283..563
FT /note="Sufficient for interaction with NLK"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT REGION 363..459
FT /note="Required for interaction with RUNX2"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT REGION 507..537
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 251..253
FT /note="Nuclear localization signal"
FT MOTIF 462..466
FT /note="Required for interaction with SIRT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT COMPBIAS 28..47
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 118..143
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 280..330
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 158
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:18786403"
FT SITE 165
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:18786403"
FT SITE 225
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:18786403"
FT MOD_RES 24
FT /note="Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1"
FT /evidence="ECO:0000269|PubMed:10358075,
FT ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11980723"
FT MOD_RES 212
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000269|PubMed:18786403,
FT ECO:0000269|PubMed:19221179, ECO:0000269|PubMed:21245099"
FT MOD_RES 218
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000269|PubMed:18786403"
FT MOD_RES 234
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000269|PubMed:18786403"
FT MOD_RES 235
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000269|PubMed:18786403"
FT MOD_RES 245
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 248
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 249
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000269|PubMed:18356527"
FT MOD_RES 251
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 253
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 256
FT /note="Phosphoserine; by PKB/AKT1 and SGK1"
FT /evidence="ECO:0000269|PubMed:10358075,
FT ECO:0000269|PubMed:10358076, ECO:0000269|PubMed:11237865,
FT ECO:0000269|PubMed:11980723, ECO:0000269|PubMed:31063815"
FT MOD_RES 262
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:20543840"
FT MOD_RES 265
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:20543840"
FT MOD_RES 274
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:20543840"
FT MOD_RES 287
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692"
FT MOD_RES 298
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 319
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:10358075,
FT ECO:0000269|PubMed:11237865, ECO:0000269|PubMed:11980723"
FT MOD_RES 322
FT /note="Phosphoserine; by CK1 and SGK1"
FT /evidence="ECO:0000269|PubMed:11980723"
FT MOD_RES 325
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000269|PubMed:11980723"
FT MOD_RES 329
FT /note="Phosphoserine; by DYRK1A"
FT /evidence="ECO:0000269|PubMed:11311120,
FT ECO:0000269|PubMed:11980723"
FT MOD_RES 333
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 423
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:25009184"
FT MUTAGEN 24
FT /note="T->A: Abolishes PKB/AKT1-mediated phosphorylation
FT but does not prevent phosphorylation of Ser-256 or Ser-319.
FT Also inhibits binding of 14-3-3 proteins. Nuclear in
FT unstimulated cells, and little export to cytoplasm on IGF1
FT stimulation. Inhibits the PKB/AKT1-mediated activity
FT towards other substrates but does not block the IGF1-
FT activated 'T-308' of phosphorylation of PKB/AKT1; when
FT associated with A-256 and A-319. Targeted to the nucleus
FT and enhances transactivation; when associated with A-319."
FT /evidence="ECO:0000269|PubMed:11237865,
FT ECO:0000269|PubMed:12228231"
FT MUTAGEN 212
FT /note="S->A: Abolishes STK4/MST1-mediated phosphorylation."
FT /evidence="ECO:0000269|PubMed:19221179"
FT MUTAGEN 245
FT /note="K->A: Disrupts DNA-binding; when associated with A-
FT 248."
FT /evidence="ECO:0000269|PubMed:12228231"
FT MUTAGEN 248
FT /note="K->A: Disrupts DNA-binding; when associated with A-
FT 245."
FT /evidence="ECO:0000269|PubMed:12228231"
FT MUTAGEN 249
FT /note="S->A: Impaired phosphorylation by CDK1."
FT /evidence="ECO:0000269|PubMed:18356527,
FT ECO:0000269|PubMed:18786403"
FT MUTAGEN 249
FT /note="S->E: No effect on DNA-binding."
FT /evidence="ECO:0000269|PubMed:18356527,
FT ECO:0000269|PubMed:18786403"
FT MUTAGEN 251..253
FT /note="RRR->SAS: No targeting to the nucleus and disruption
FT of DNA-binding."
FT /evidence="ECO:0000269|PubMed:12228231"
FT MUTAGEN 256
FT /note="S->A: Completely abolishes PKB/AKT1-mediated
FT phosphorylation at all three sites, and inhibits binding of
FT 14-3-3 proteins. Inhibits the PKB/AKT1-mediated activity
FT towards other substrates but does not block the IGF1-
FT activated 'T-308' of phosphorylation of PKB/AKT1; when
FT associated with or without A-24 and A-319. Nuclear in
FT unstimulated cells, and little export to cytoplasm on IGF1
FT stimulation. Abolishes the ability of IGF1 to suppress
FT transactivation. Prevents T-24 and S-319 phosphorylation.
FT Enhances transactivation; when associated with A-24 and A-
FT 319."
FT /evidence="ECO:0000269|PubMed:11237865,
FT ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:15668399"
FT MUTAGEN 256
FT /note="S->D: Reduces DNA binding, promotes nuclear
FT exclusion and partially promotes T-24 and S-319
FT phosphorylation. Reduces DNA binding, does not promote
FT nuclear exclusion but reduces transactivation; when
FT associated with A-24 and A-319."
FT /evidence="ECO:0000269|PubMed:11237865,
FT ECO:0000269|PubMed:12228231, ECO:0000269|PubMed:15668399"
FT MUTAGEN 262
FT /note="K->R: Inhibits interaction with ATG7 and FOXO1-
FT acetylation-induced autophagic cell death; when associated
FT with R-265 and R-274."
FT /evidence="ECO:0000269|PubMed:12228231"
FT MUTAGEN 265
FT /note="K->R: Inhibits interaction with ATG7 and FOXO1-
FT acetylation-induced autophagic cell death; when associated
FT with R-262 and R-274."
FT /evidence="ECO:0000269|PubMed:12228231"
FT MUTAGEN 274
FT /note="K->R: Inhibits interaction with ATG7 and FOXO1-
FT acetylation-induced autophagic cell death; when associated
FT with R-262 and R-265."
FT /evidence="ECO:0000269|PubMed:12228231"
FT MUTAGEN 319
FT /note="S->A: Abolishes PKB/AKT1-mediated phosphorylation
FT but does not prevent phosphorylation of Ser-24 or Ser-256.
FT Inhibits the PKB/AKT1-mediated activity towards other
FT substrates but does not block the IGF1-activated 'T-308' of
FT phosphorylation of PKB/AKT1; when associated with A-24 and
FT A-256. Targeted to the nucleus and enhances
FT transactivation; when associated with A-24."
FT /evidence="ECO:0000269|PubMed:11237865,
FT ECO:0000269|PubMed:12228231"
FT MUTAGEN 329
FT /note="S->A: Targeted to the nucleus and enhances
FT transactivation."
FT /evidence="ECO:0000269|PubMed:11311120"
FT MUTAGEN 423
FT /note="K->R: Abolished deacetylation by SIRT6."
FT /evidence="ECO:0000269|PubMed:25009184"
FT MUTAGEN 446
FT /note="K->R: Does not affect deacetylation by SIRT6."
FT /evidence="ECO:0000269|PubMed:25009184"
FT MUTAGEN 463
FT /note="K->R: Does not affect deacetylation by SIRT6."
FT /evidence="ECO:0000269|PubMed:25009184"
FT MUTAGEN 515
FT /note="K->R: Does not affect deacetylation by SIRT6."
FT /evidence="ECO:0000269|PubMed:25009184"
FT CONFLICT 131
FT /note="L -> V (in Ref. 1; AAA03629)"
FT /evidence="ECO:0000305"
FT CONFLICT 343
FT /note="V -> M (in Ref. 5; AAH70065)"
FT /evidence="ECO:0000305"
FT STRAND 156..158
FT /evidence="ECO:0007829|PDB:3CO6"
FT HELIX 165..175
FT /evidence="ECO:0007829|PDB:3CO6"
FT STRAND 176..181
FT /evidence="ECO:0007829|PDB:5DUI"
FT HELIX 183..193
FT /evidence="ECO:0007829|PDB:3CO6"
FT HELIX 195..197
FT /evidence="ECO:0007829|PDB:3CO6"
FT HELIX 203..219
FT /evidence="ECO:0007829|PDB:3CO6"
FT STRAND 223..226
FT /evidence="ECO:0007829|PDB:3CO6"
FT TURN 230..232
FT /evidence="ECO:0007829|PDB:3CO6"
FT STRAND 236..239
FT /evidence="ECO:0007829|PDB:3CO6"
SQ SEQUENCE 655 AA; 69662 MW; 6DEF6C994BDFDBAB CRC64;
MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGSAAA NPDAAAGLPS
ASAAAVSADF MSNLSLLEES EDFPQAPGSV AAAVAAAAAA AATGGLCGDF QGPEAGCLHP
APPQPPPPGP LSQHPPVPPA AAGPLAGQPR KSSSSRRNAW GNLSYADLIT KAIESSAEKR
LTLSQIYEWM VKSVPYFKDK GDSNSSAGWK NSIRHNLSLH SKFIRVQNEG TGKSSWWMLN
PEGGKSGKSP RRRAASMDNN SKFAKSRSRA AKKKASLQSG QEGAGDSPGS QFSKWPASPG
SHSNDDFDNW STFRPRTSSN ASTISGRLSP IMTEQDDLGE GDVHSMVYPP SAAKMASTLP
SLSEISNPEN MENLLDNLNL LSSPTSLTVS TQSSPGTMMQ QTPCYSFAPP NTSLNSPSPN
YQKYTYGQSS MSPLPQMPIQ TLQDNKSSYG GMSQYNCAPG LLKELLTSDS PPHNDIMTPV
DPGVAQPNSR VLGQNVMMGP NSVMSTYGSQ ASHNKMMNPS SHTHPGHAQQ TSAVNGRPLP
HTVSTMPHTS GMNRLTQVKT PVQVPLPHPM QMSALGGYSS VSSCNGYGRM GLLHQEKLPS
DLDGMFIERL DCDMESIIRN DLMDGDTLDF NFDNVLPNQS FPHSVKTTTH SWVSG
