BioPAX pathway converted from "Phosphorylated FOXO1A is excluded from the nucleus" in the Reactome database.LEFT-TO-RIGHTPhosphorylated FOXO1A is excluded from the nucleusThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Q9R1E0phospho-Foxo1p-T24,S256,S319-FOXO1Reactome DB_ID: 9726702nucleoplasmGENE ONTOLOGYGO:0005654UniProt:Q9R1E0 Foxo1Foxo1FkhrFoxo1aFUNCTION Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (PubMed:12754525, PubMed:15184386, PubMed:15220471, PubMed:16917544, PubMed:17090532, PubMed:17627282, PubMed:17681146, PubMed:20519497, PubMed:20668652, PubMed:21196578, PubMed:21335550, PubMed:21471200, PubMed:22298775, PubMed:22417654, PubMed:22510882). Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3' (PubMed:17090532, PubMed:21335550). Activity suppressed by insulin (PubMed:12754525, PubMed:17627282). Main regulator of redox balance and osteoblast numbers and controls bone mass (PubMed:21471200, PubMed:22298775). Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (PubMed:21471200, PubMed:22298775). Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (PubMed:32103177). Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (PubMed:22298775). Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (PubMed:21471200). In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC and PCK1 (PubMed:12754525). Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (By similarity). Promotes neural cell death (By similarity). Mediates insulin action on adipose tissue (By similarity). Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake (By similarity). Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells (PubMed:21196578). Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (By similarity). Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity). Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (By similarity).SUBUNIT Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteosomal degradation. Interacts with PMRT1; methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus (By similarity). Interacts (via an N-terminal domain) with FCOR; the interaction is direct, occurs in a forskolin-independent manner and prevents SIRT1 binding to FOXO1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts. Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-253 leading to its nuclear import. Binds to CDK1. Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts. Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. The interaction requires the presence of KRIT1 and is inhibited by FCOR. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (acetylated form) with PPARG (PubMed:12754525, PubMed:15220471, PubMed:16917544, PubMed:17050673, PubMed:17681146, PubMed:19037106, PubMed:20061393, PubMed:20668652, PubMed:21471200, PubMed:22298775, PubMed:22417654, PubMed:22510882). Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (PubMed:21317886). Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated (PubMed:17090532, PubMed:17627282). Interacts with WDFY2 (PubMed:18388859). Forms a complex with WDFY2 and AKT1 (PubMed:18388859). Interacts with CRY1 (PubMed:28790135). Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (By similarity).TISSUE SPECIFICITY Expressed in liver, white and brown adipose tissues (at protein level).DEVELOPMENTAL STAGE In liver, barely expressed at 14.5 dpc, expression dramatically increases at 18.5 dpc. Abundantly expressed in neonate liver but levels strongly decrease in adult liver (at protein level).INDUCTION Expression is regulated by KRIT1 (PubMed:20668652). Transiently up-regulated during adipogenesis (at protein level) (PubMed:18388859).PTM Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-253 and Ser-319 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-253 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-316, permitting phosphorylation of Ser-319 and Ser-322, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-326 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-253 by PP2A in beta-cells under oxidative stress leading to nuclear retention (By similarity). Phosphorylation of Ser-246 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-209, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export (By similarity). PPIA/CYPA promotes its dephosphorylation on Ser-253 (By similarity).PTM Ubiquitinated, leading to proteasomal degradation (PubMed:28790135). Ubiquitinated by SKP2 (By similarity).PTM Methylation inhibits PKB/AKT1-mediated phosphorylation at Ser-253, promoting nuclear retention and increasing the transcriptional activity and cell death. Methylation increased by oxidative stress.PTM Acetylation at Lys-259 and Lys-271 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death (By similarity). Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-253, and is required for the transcriptional inhibition by FCOR. Deacetylation by SIRT1 results in reactivation of the transcriptional activity (PubMed:17090532). Acetylation of FOXO1 diminishes its binding to PPARG in adipocytes. Deacetylated by SIRT2; deacetylation of FOXO1 directly increases its repressive binding to PPARG and inhibits adipocyte differentiation. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation.DISRUPTION PHENOTYPE Null mice die around embryonic day 11 and exhibit abnormal angiogenesis. Defects are observed in branchial arches and there is remarkably impaired vascular development of embryos and yolk sacs. Exogeneous VEGF on FOX1-deficient endothelial cells show markedly different morphological response. Active osteocalcin/BGLAP as well as serum insulin and beta-cell and gonadal fat levels were increased, but there is no change in total fat content, lean mass, and body weight. Effect on RUNX2 activity was inhibited. FOXO1 and ATF4 double happlo-insufficient mice exhibit also an increase in insulin levels and beta cell proliferation, but there is an increase in insulin sensitivity demonstrated by an increase in expression of insulin-sensitizing hormone adiponectin. Gonadal fat levels and adipocyte numbers were decreased. Osteocalcin/BGLAP levels were unchanged.MISCELLANEOUS In an animal model of diabetes mellitus type 2 (db/db mice), beta-cell islets exhibit increased levels of PPP2R1A leading to increased dephosphorylation at Thr-24 and Ser-253 and nuclear retention of FOXO1.Mus musculusNCBI Taxonomy10090UniProtQ9R1E024EQUALO-phospho-L-threonineMODMOD:00047256EQUALO-phospho-L-serineMODMOD:00046319EQUAL1EQUAL655EQUALReactome Database ID Release 759726702Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9726702ReactomeR-MMU-1993061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199306.1Reactomehttp://www.reactome.orgQ9R1E0phospho-Foxo1p-T24,S256,S319-FOXO1Reactome DB_ID: 9730004cytosolGENE ONTOLOGYGO:00058291EQUAL655EQUALReactome Database ID Release 759730004Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9730004ReactomeR-MMU-2111581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-211158.1Reactome Database ID Release 759730006Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9730006ReactomeR-MMU-2111781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-211178.1Phosphorylated FOXO1A is transported from the nucleoplasm to the cytosol (Zhang et al. 2002).12228231Pubmed2002Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA bindingZhang, XGan, LPan, HGuo, SHe, XOlson, STMesecar, AAdam, SUnterman, TGJ Biol Chem 277:45276-84inferred from electronic annotationEVIDENCE CODEECO:0000203