FOXO1_ICTTR
ID FOXO1_ICTTR Reviewed; 653 AA.
AC Q810W5;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Forkhead box protein O1;
DE AltName: Full=Forkhead box protein O1A;
DE AltName: Full=Forkhead in rhabdomyosarcoma;
GN Name=FOXO1; Synonyms=FOXO1A;
OS Ictidomys tridecemlineatus (Thirteen-lined ground squirrel) (Spermophilus
OS tridecemlineatus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Sciuromorpha; Sciuridae;
OC Xerinae; Marmotini; Ictidomys.
OX NCBI_TaxID=43179;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PHOSPHORYLATION.
RC TISSUE=Brain;
RX PubMed=15563846; DOI=10.1016/j.gene.2004.09.003;
RA Cai D., McCarron R.M., Hallenbeck J.;
RT "Cloning and characterization of a forkhead transcription factor gene,
RT FoxO1a, from thirteen-lined ground squirrel.";
RL Gene 343:203-209(2004).
CC -!- FUNCTION: Transcription factor that is the main target of insulin
CC signaling and regulates metabolic homeostasis in response to oxidative
CC stress. Binds to the insulin response element (IRE) with consensus
CC sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding
CC element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'. Activity
CC suppressed by insulin. Main regulator of redox balance and osteoblast
CC numbers and controls bone mass. Orchestrates the endocrine function of
CC the skeleton in regulating glucose metabolism. Also acts as a key
CC regulator of chondrogenic commitment of skeletal progenitor cells in
CC 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.
CC Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity,
CC increasing glucose levels and triggering glucose intolerance and
CC insulin insensitivity. Also suppresses the transcriptional activity of
CC RUNX2, an upstream activator of osteocalcin/BGLAP. Acts as an inhibitor
CC of glucose sensing in pancreatic beta cells by acting as a
CC transcription repressor and suppressing expression of PDX1. In
CC hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A
CC and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and
CC PCK1 (By similarity). Also promotes gluconeogenesis by directly
CC promoting expression of PPARGC1A and G6PC1 (By similarity). Important
CC regulator of cell death acting downstream of CDK1, PKB/AKT1 and
CC STK4/MST1 (By similarity). Promotes neural cell death (By similarity).
CC Mediates insulin action on adipose tissue (By similarity). Regulates
CC the expression of adipogenic genes such as PPARG during preadipocyte
CC differentiation and, adipocyte size and adipose tissue-specific gene
CC expression in response to excessive calorie intake (By similarity).
CC Regulates the transcriptional activity of GADD45A and repair of nitric
CC oxide-damaged DNA in beta-cells (By similarity). Required for the
CC autophagic cell death induction in response to starvation or oxidative
CC stress in a transcription-independent manner (By similarity). Mediates
CC the function of MLIP in cardiomyocytes hypertrophy and cardiac
CC remodeling (By similarity). Regulates endothelial cell (EC) viability
CC and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2
CC and BCL2L11 which are involved in EC chemotaxis and apoptosis (By
CC similarity). {ECO:0000250|UniProtKB:A4L7N3,
CC ECO:0000250|UniProtKB:G3V7R4, ECO:0000250|UniProtKB:Q12778,
CC ECO:0000250|UniProtKB:Q9R1E0}.
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 254 leading to its nuclear import. Interacts with NLK. Interacts with
CC SIRT1; the interaction results in the deacetylation of FOXO1 leading to
CC activation of FOXO1-mediated transcription of genes involved in DNA
CC repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3
CC proteins, 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 (acetylated form) with PPARG. Interacts with XBP1; this
CC interaction is direct and leads to FOXO1 ubiquitination and degradation
CC via the proteasome pathway. Interacts with WDFY2. Forms a complex with
CC WDFY2 and AKT1 (By similarity). Interacts with CRY1 (By similarity).
CC Interacts with PPIA/CYPA; the interaction promotes FOXO1
CC dephosphorylation, nuclear accumulation and transcriptional activity
CC (By similarity). 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:Q12778,
CC ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9R1E0}. Nucleus
CC {ECO:0000250|UniProtKB:Q9R1E0}. Note=Shuttles between the cytoplasm and
CC nucleus (By similarity). Largely nuclear in unstimulated cells (By
CC similarity). In osteoblasts, colocalizes with ATF4 and RUNX2 in the
CC nucleus. Serum deprivation increases localization to the nucleus,
CC leading to activate expression of SOX9 and subsequent chondrogenesis
CC (By similarity). Insulin-induced phosphorylation at Ser-253 by PKB/AKT1
CC leads, via stimulation of Thr-24 phosphorylation, to binding of 14-3-3
CC proteins and nuclear export to the cytoplasm where it is degraded by
CC the ubiquitin-proteosomal pathway (By similarity). Phosphorylation at
CC Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes
CC nuclear accumulation (By similarity). Phosphorylation by NLK results in
CC nuclear export (By similarity). Translocates to the nucleus upon
CC oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (By
CC similarity). SGK1-mediated phosphorylation also results in nuclear
CC translocation. Retained in the nucleus under stress stimuli including
CC oxidative stress, nutrient deprivation or nitric oxide. Methylated form
CC is nuclear (By similarity). PPIA/CYPA stimulates its nuclear
CC accumulation (By similarity). Deacetylation by SIRT6, promotes its
CC translocation into the cytoplasm (By similarity).
CC {ECO:0000250|UniProtKB:Q12778, ECO:0000250|UniProtKB:Q9R1E0}.
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-254 and Ser-320 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-254 decreases DNA-binding activity and promotes
CC the phosphorylation of Thr-24 and Ser-317, permitting phosphorylation
CC of Ser-320 and Ser-323, 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-327 is independent of IGF1
CC and leads to reduced function. Dephosphorylated on Thr-24 and Ser-254
CC by PP2A in beta-cells under oxidative stress leading to nuclear
CC retention. Phosphorylation of Ser-247 by CDK1 disrupts binding of 14-3-
CC 3 proteins leading to nuclear accumulation and has no effect on DNA
CC binding nor transcriptional activity. Phosphorylation by STK4/MST1 on
CC Ser-210, upon oxidative stress, inhibits binding to 14-3-3 proteins and
CC nuclear export (By similarity). PPIA/CYPA promotes its
CC dephosphorylation on Ser-254 (By similarity).
CC {ECO:0000250|UniProtKB:Q12778, ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- PTM: Ubiquitinated by SKP2. Ubiquitination leads to proteasomal
CC degradation (By similarity). {ECO:0000250|UniProtKB:Q12778}.
CC -!- PTM: Methylation inhibits AKT1-mediated phosphorylation at Ser-254 and
CC is increased by oxidative stress. {ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- PTM: Acetylated. Acetylation at Lys-260 and Lys-272 are necessary for
CC autophagic cell death induction. Deacetylated by SIRT2 in response to
CC oxidative stress or serum deprivation, thereby negatively regulating
CC FOXO1-mediated autophagic cell death. Once in the nucleus, acetylated
CC by CREBBP/EP300. Acetylation diminishes the interaction with target DNA
CC and attenuates the transcriptional activity. It increases the
CC phosphorylation at Ser-254. Deacetylation by SIRT1 results in
CC reactivation of the transcriptional activity. Oxidative stress by
CC hydrogen peroxide treatment appears to promote deacetylation and
CC uncoupling of insulin-induced phosphorylation. By contrast, resveratrol
CC acts independently of acetylation. Acetylated at Lys-421, promoting its
CC localization to the nucleus and transcription factor activity.
CC Deacetylation at Lys-421 by SIRT6, promotes its translocation into the
CC cytoplasm, preventing its transcription factor activity. Deacetylation
CC and subsequent inhibition by SIRT6 has different effects depending on
CC cell types: it inhibits gluconeogenesis in hepatocytes, promotes
CC glucose sensing in pancreatic beta-cells and regulates lipid catabolism
CC in brown adipocytes. {ECO:0000250|UniProtKB:Q12778}.
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DR EMBL; AY255525; AAO72710.1; -; mRNA.
DR RefSeq; NP_001269185.1; NM_001282256.1.
DR AlphaFoldDB; Q810W5; -.
DR SMR; Q810W5; -.
DR STRING; 43179.ENSSTOP00000008695; -.
DR PRIDE; Q810W5; -.
DR GeneID; 101967490; -.
DR CTD; 2308; -.
DR eggNOG; KOG2294; Eukaryota.
DR InParanoid; Q810W5; -.
DR OrthoDB; 1160384at2759; -.
DR Proteomes; UP000005215; Unassembled WGS sequence.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
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; 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; ISS: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; 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:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0045722; P:positive regulation of gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0006473; P:protein acetylation; ISS:UniProtKB.
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 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; Autophagy; Cytoplasm; Differentiation;
KW DNA-binding; Methylation; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..653
FT /note="Forkhead box protein O1"
FT /id="PRO_0000250522"
FT DNA_BIND 157..233
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..64
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 117..156
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 209..216
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT REGION 232..335
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 232..235
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT REGION 281..561
FT /note="Sufficient for interaction with NLK"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT REGION 361..457
FT /note="Required for interaction with RUNX2"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOTIF 249..251
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT MOTIF 460..464
FT /note="Required for interaction with SIRT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT COMPBIAS 28..48
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 118..142
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 251..328
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 156
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT SITE 163
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT SITE 223
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 24
FT /note="Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 210
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 216
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 232
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 233
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 243
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 246
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 247
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 249
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 251
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 254
FT /note="Phosphoserine; by PKB/AKT1 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 260
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 263
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 272
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 285
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 296
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 317
FT /note="Phosphoserine; by PKB/AKT1 or PKB/AKT2"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 320
FT /note="Phosphoserine; by CK1 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 323
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 327
FT /note="Phosphoserine; by DYRK1A"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 331
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 421
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
SQ SEQUENCE 653 AA; 69444 MW; 31B6A6785F4F7E59 CRC64;
MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGGATA NPDASAGLPP
ASAAAVSADF MSNLSLLEES EDFPQAPGSV AAAVAAAAAA ATGGLCGDFQ GLEAGCLHPA
PPQPPPPGPL SQHPPVPPAA GPLAGQPRKS SSSRRNAWGN LSYADLITKA IESSAEKRLT
LSQIYEWMVK SVPYFKDKGD SNSSAGWKNS IRHNLSLHSK FIRVQNEGTG KSSWWMLNPE
GGKSGKSPRR RAASMDNNSK FAKSRGQAAK KKASLQSGQE GAGDSPGSQF SKWPASPGSH
SNDDFDNWST FRPRTSSNAS TISGRFSPIM TEQDDLGDGD VHSLVYPPSA SKMASTLPSL
SEISNPENME NLLDNLNLLS SPTSLTVSTQ SSPGSMMQQT PCYSFAPPST SLNSPSPNYQ
KYTYGQSSMS PLSQMPMQTL QDNKSSYGGL NQFNCAQGLL KELLTSDSPP HNDIMSSVDP
GVAQPNSRVL GQNVMLGPNS VMPAYGNQAS HNKMMNPSSH THPGHAQQTS VVNGRALPHT
VNTMPHTSGM NRLTPVKTPL QVPLLHHMQM SALGGYSSVS SCSGYGRMGV LHQEKLPSDL
DGMFIERLDC DMESIIRNDL MDGDALDFNF DNVLPNQSFP HGVKTTTHSW VSG
