FOXO-mediated transcription (Homo sapiens)

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11, 78, 867514, 30, 64, 8514, 30, 33, 4922, 33, 5414, 634, 2543cytosolnucleoplasmFOXO-mediatedtranscription ofcell cycle genesSIRT3 2'-O-acetyl-ADP-ribosep-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4,(p-T26,S184-FOXO6)EP300-S-S-FOXO4 CREBBPCREBBP-S-S-FOXO4 2'-O-acetyl-ADP-ribosep-T32,S253,S315-FOXO3 p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4FOXO4FOXO-mediatedtranscription ofoxidative stress,metabolic andneuronal genesp-T32,S253,S315-FOXO3 YWHAZ p-T309,S474-AKT2 NAMFOXO-mediatedtranscription ofcell death genesp-T,p-S-AKTp-T32,S253,S315-FOXO3 p-T24,S256,S319-FOXO1 FOXO3 SFN p-T26,S184-FOXO6 YWHAZ dimer,YWHAQdimer,YWHAGdimer,YWHAB dimerp-T32,S197,S262-FOXO4 KAT2B p-T32,S197,S262-FOXO4 SFN EP300-S-S-FOXO4 p-T32,S197,S262-FOXO4 NAD+YWHAZ Ac-K242,K259,K271,K290,K569-FOXO3p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4ATPYWHAQ CREBBP FOXO6 EP300-S-S-FOXO4:FOXO4-S-S-EP300SIRT1ROSYWHAB Ac-CoAp-T24,S256,S319-FOXO1:YWHAZ,YWHAQ,YWHAG,YWHABCREBBP CoA-SHCREBPP-S-S-FOXO4:FOXO4-S-S-CREBBP,EP300-S-S-FOXO4:FOXO4-S-S-EP300p-T32,S253,S315-FOXO3:YWHAZ,YWHAQ,SFNFOXO1,FOXO3,FOXO4,(FOXO6)TXNp-T24,S256,S319-FOXO1 p-T24,S256,S319-FOXO1 SIRT1 Ac-K245,K248,K265-FOXO1Ac-K-FOXO4YWHAB p-T308,S473-AKT1 EP300 YWHAZ EP300FOXO1 TXNIPFOXO1 p-T32,S253,S315-FOXO3 YWHAZ dimer,YWHAQdimer,SFN dimerp-T24,S256,S319-FOXO12xHC-TXNADPFOXO4-S-S-EP300 FOXO4-S-S-EP300 p-T24,S256,S319-FOXO1 CREBBP,EP300EP300 SOH-C481-FOXO4p-T32,S197,S262-FOXO4:YWHAZ dimerFOXO3YWHAQ FOXO1:CREBBPYWHAG YWHAG FOXO4 YWHAZ p-T305,S472-AKT3 p-T32,S253,S315-FOXO3SIRT1,SIRT3YWHAZ dimerFOXO1NAMCoA-SHKAT2B,(EP300)p-T32,S197,S262-FOXO4 FOXO4-S-S-CREBBP YWHAQ PIP3 activates AKTsignalingNAD+YWHAQ p-T32,S197,S262-FOXO4YWHAZ Ac-CoAYWHAZ 3758, 9, 14, 19, 29...1, 5, 7, 10, 12...14, 63272, 6, 13, 15, 17...27


Description

The family of FOXO transcription factors includes FOXO1, FOXO3, FOXO4 and FOXO6. FOXO transcription factors integrate pathways that regulate cell survival, growth, differentiation and metabolism in response to environmental changes, such as growth factor deprivation, starvation and oxidative stress (reviewed by Accili and Arden 2004, Calnan and Brunet 2008, Eijkelenboom and Burgering 2013). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9614085
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  14. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME.; ''Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.''; PubMed Europe PMC Scholia
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  21. Lees SJ, Childs TE, Booth FW.; ''Age-dependent FOXO regulation of p27Kip1 expression via a conserved binding motif in rat muscle precursor cells.''; PubMed Europe PMC Scholia
  22. Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T.; ''Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding.''; PubMed Europe PMC Scholia
  23. Hughes KJ, Meares GP, Hansen PA, Corbett JA.; ''FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide.''; PubMed Europe PMC Scholia
  24. Medema RH, Kops GJ, Bos JL, Burgering BM.; ''AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.''; PubMed Europe PMC Scholia
  25. Tseng AH, Shieh SS, Wang DL.; ''SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage.''; PubMed Europe PMC Scholia
  26. Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N.; ''FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress.''; PubMed Europe PMC Scholia
  27. Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMed Europe PMC Scholia
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  30. Rena G, Guo S, Cichy SC, Unterman TG, Cohen P.; ''Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B.''; PubMed Europe PMC Scholia
  31. Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM.; ''Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress.''; PubMed Europe PMC Scholia
  32. Urbich C, Knau A, Fichtlscherer S, Walter DH, Brühl T, Potente M, Hofmann WK, de Vos S, Zeiher AM, Dimmeler S.; ''FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells.''; PubMed Europe PMC Scholia
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  49. Matsuzaki H, Ichino A, Hayashi T, Yamamoto T, Kikkawa U.; ''Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family.''; PubMed Europe PMC Scholia
  50. Liao L, Su X, Yang X, Hu C, Li B, Lv Y, Shuai Y, Jing H, Deng Z, Jin Y.; ''TNF-α Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis.''; PubMed Europe PMC Scholia
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  52. Araujo J, Breuer P, Dieringer S, Krauss S, Dorn S, Zimmermann K, Pfeifer A, Klockgether T, Wuellner U, Evert BO.; ''FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.''; PubMed Europe PMC Scholia
  53. Chen L, Tang Y, Wang J, Yan Z, Xu R.; ''miR-421 induces cell proliferation and apoptosis resistance in human nasopharyngeal carcinoma via downregulation of FOXO4.''; PubMed Europe PMC Scholia
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  56. Liu ZQ, Shen M, Wu WJ, Li BJ, Weng QN, Li M, Liu HL.; ''Expression of PUMA in Follicular Granulosa Cells Regulated by FoxO1 Activation During Oxidative Stress.''; PubMed Europe PMC Scholia
  57. Rangarajan P, Karthikeyan A, Lu J, Ling EA, Dheen ST.; ''Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia.''; PubMed Europe PMC Scholia
  58. Langlet F, Haeusler RA, Lindén D, Ericson E, Norris T, Johansson A, Cook JR, Aizawa K, Wang L, Buettner C, Accili D.; ''Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling.''; PubMed Europe PMC Scholia
  59. Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, O'Prey J, Ryan KM, Espinosa JM, Morgan MJ, Thorburn A.; ''Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover.''; PubMed Europe PMC Scholia
  60. Hori YS, Kuno A, Hosoda R, Horio Y.; ''Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress.''; PubMed Europe PMC Scholia
  61. Guo F, Wang Q, Zhou Y, Wu L, Ma X, Liu F, Huang F, Qin G.; ''Lentiviral Vector-Mediated FoxO1 Overexpression Inhibits Extracellular Matrix Protein Secretion Under High Glucose Conditions in Mesangial Cells.''; PubMed Europe PMC Scholia
  62. Liu T, Chen X, Li T, Li X, Lyu Y, Fan X, Zhang P, Zeng W.; ''Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.''; PubMed Europe PMC Scholia
  63. Arimoto-Ishida E, Ohmichi M, Mabuchi S, Takahashi T, Ohshima C, Hayakawa J, Kimura A, Takahashi K, Nishio Y, Sakata M, Kurachi H, Tasaka K, Murata Y.; ''Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin.''; PubMed Europe PMC Scholia
  64. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.''; PubMed Europe PMC Scholia
  65. Seoane J, Le HV, Shen L, Anderson SA, Massagué J.; ''Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.''; PubMed Europe PMC Scholia
  66. Li J, Hu L, Tian C, Lu F, Wu J, Liu L.; ''microRNA-150 promotes cervical cancer cell growth and survival by targeting FOXO4.''; PubMed Europe PMC Scholia
  67. Gilley J, Coffer PJ, Ham J.; ''FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.''; PubMed Europe PMC Scholia
  68. Awad H, Nolette N, Hinton M, Dakshinamurti S.; ''AMPK and FoxO1 regulate catalase expression in hypoxic pulmonary arterial smooth muscle.''; PubMed Europe PMC Scholia
  69. Yang Z, Whelan J, Babb R, Bowen BR.; ''An mRNA splice variant of the AFX gene with altered transcriptional activity.''; PubMed Europe PMC Scholia
  70. Chuang PY, Yu Q, Fang W, Uribarri J, He JC.; ''Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor.''; PubMed Europe PMC Scholia
  71. Liu CW, Yang SY, Lin CK, Liu HS, Ho LT, Wu LY, Lee MJ, Ku HC, Chang HH, Huang RN, Kao YH.; ''The forkhead transcription factor FOXO1 stimulates the expression of the adipocyte resistin gene.''; PubMed Europe PMC Scholia
  72. Tang ED, Nuñez G, Barr FG, Guan KL.; ''Negative regulation of the forkhead transcription factor FKHR by Akt.''; PubMed Europe PMC Scholia
  73. Ciechomska I, Pyrzynska B, Kazmierczak P, Kaminska B.; ''Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells.''; PubMed Europe PMC Scholia
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  75. Rena G, Prescott AR, Guo S, Cohen P, Unterman TG.; ''Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting.''; PubMed Europe PMC Scholia
  76. Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM.; ''Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors.''; PubMed Europe PMC Scholia
  77. Roy UK, Henkhaus RS, Ignatenko NA, Mora J, Fultz KE, Gerner EW.; ''Wild-type APC regulates caveolin-1 expression in human colon adenocarcinoma cell lines via FOXO1a and C-myc.''; PubMed Europe PMC Scholia
  78. Calnan DR, Brunet A.; ''The FoxO code.''; PubMed Europe PMC Scholia
  79. Wang W, Zhou PH, Hu W.; ''Overexpression of FOXO4 induces apoptosis of clear-cell renal carcinoma cells through downregulation of Bim.''; PubMed Europe PMC Scholia
  80. Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ.; ''Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1).''; PubMed Europe PMC Scholia
  81. Hong SH, Lee KS, Kwak SJ, Kim AK, Bai H, Jung MS, Kwon OY, Song WJ, Tatar M, Yu K.; ''Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals.''; PubMed Europe PMC Scholia
  82. Mei Y, Zhang Y, Yamamoto K, Xie W, Mak TW, You H.; ''FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation.''; PubMed Europe PMC Scholia
  83. Ju Y, Xu T, Zhang H, Yu A.; ''FOXO1-dependent DNA damage repair is regulated by JNK in lung cancer cells.''; PubMed Europe PMC Scholia
  84. Shore AM, White PC, Hui RC, Essafi A, Lam EW, Rowe M, Brennan P.; ''Epstein-Barr virus represses the FoxO1 transcription factor through latent membrane protein 1 and latent membrane protein 2A.''; PubMed Europe PMC Scholia
  85. van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.''; PubMed Europe PMC Scholia
  86. Accili D, Arden KC.; ''FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.''; PubMed Europe PMC Scholia
  87. Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE.; ''FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress.''; PubMed Europe PMC Scholia
  88. Raffaello A, Milan G, Masiero E, Carnio S, Lee D, Lanfranchi G, Goldberg AL, Sandri M.; ''JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy.''; PubMed Europe PMC Scholia
  89. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM.; ''Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114996view16:52, 25 January 2021ReactomeTeamReactome version 75
113440view11:51, 2 November 2020ReactomeTeamReactome version 74
112827view18:33, 9 October 2020DeSlOntology Term : 'forkhead class O signaling pathway' added !
112774view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseMetaboliteCHEBI:76279 (ChEBI)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-K-FOXO4ProteinP98177 (Uniprot-TrEMBL)
Ac-K242,K259,K271,K290,K569-FOXO3ProteinO43524 (Uniprot-TrEMBL)
Ac-K245,K248,K265-FOXO1ProteinQ12778 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBP,EP300ComplexR-HSA-1027362 (Reactome)
CREBBP-S-S-FOXO4 ProteinP98177 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CREBPP-S-S-FOXO4:FOXO4-S-S-CREBBP,EP300-S-S-FOXO4:FOXO4-S-S-EP300ComplexR-HSA-9617678 (Reactome)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300-S-S-FOXO4 ProteinP98177 (Uniprot-TrEMBL)
EP300-S-S-FOXO4:FOXO4-S-S-EP300ComplexR-HSA-9617686 (Reactome)
EP300ProteinQ09472 (Uniprot-TrEMBL)
FOXO-mediated

transcription of

cell cycle genes		PathwayR-HSA-9617828 (Reactome) FOXO transcription factors induce expression of several genes that negatively regulate proliferation of different cell types, such as erythroid progenitors (Bakker et al. 2004, Wang et al. 2015) and neuroepithelial progenitor cells in the telencephalon (Seoane et al. 2004).
Transcription of cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip1) is directly stimulated by FOXO1, FOXO3 and FOXO4 (Seoane et al. 2004, Tinkum et al. 2013). FOXO transcription factors can cooperate with the SMAD2/3:SMAD4 complex to induce CDKN1A transcription in response to TGF-beta signaling (Seoane et al. 2004).
FOXO transcription factors FOXO1, FOXO3 and FOXO4 stimulate transcription of the CDKN1B (p27Kip1) gene, but direct binding of FOXOs to the CDKN1B gene locus has not been demonstrated (Dijkers et al. 2000, Medema et al. 2000, Lees et al. 2008).
FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the GADD45A gene (Tran et al. 2002, Furukawa Hibi et al. 2002, Hughes et al. 2011, Sengupta et al. 2011, Ju et al. 2014).
Transcription of the retinoblastoma family protein RBL2 (p130), involved in the maintenance of quiescent (G0) state, is directly stimulated by FOXO1, FOXO3 and FOXO4 (Kops et al. 2002, Chen et al. 2006).
Transcription of the anti-proliferative protein CCNG2 is directly stimulated by FOXO1 and FOXO3, and possibly FOXO4 (Martinez Gac et al. 2004, Chen et al. 2006). Transcription of the anti-proliferative protein BTG1 is directly stimulated by FOXO3 (Bakker et al. 2004, Bakker et al. 2007, Wang et al. 2015).
Transcription of CAV1, encoding caveolin-1, involved in negative regulation of growth factor receptor signaling and establishment of quiescent cell phenotype, is directly stimulated by FOXO1 and FOXO3 (van den Heuvel et al. 2005, Roy et al. 2008, Nho et al. 2013, Sisci et al. 2013).
FOXO1 and FOXO3 promote transcription of the KLF4 gene, encoding a transcription factor Krueppel-like factor 4, which inhibits proliferation of mouse B cells (Yusuf et al. 2008).
FOXO1, together with the p-2S-SMAD2/3:SMAD4 complex, stimulates transcription of the MSTN gene, encoding myostatin, a TGF-beta family member that stimulates differentiation of myoblasts (Allen and Unterman 2007).
FOXO-mediated

transcription of

cell death genes		PathwayR-HSA-9614657 (Reactome) FOXO transcription factors promote expression of several pro-apoptotic genes, such as FASLG (Brunet et al. 1999, Ciechomska et al. 2003, Chen et al. 2013, Li et al. 2015), PINK1 (Mei et al. 2009, Sengupta et al. 2011), BCL2L11 (BIM) (Gilley et al. 2003, Urbich et al. 2005, Chuang et al. 2007, Hughes et al. 2011, Chen et al. 2013, Wang et al. 2016), BCL6 (Tang et al. 2002, Fernandez de Mattos et al. 2004, Shore et al. 2006) and BBC3 (PUMA) (Dudgeon et al. 2010, Hughes et al. 2011, Liu et al. 2015, Wu et al. 2016, Liu et al. 2017, Fitzwalter et al. 2018). FOXO-mediated induction of cell death genes is important during development, for example during nervous system development, where FOXO promotes neuronal death upon NGF withdrawal (Gilley et al. 2003), and also contributes to the tumor-suppressive role of FOXO factors (Arimoto Ishida et al. 2004). FOXO1 transcriptional activity is implicated in the cell death of enteric nervous system (ENS) precursors. RET signaling, which activates PI3K/AKT signaling, leading to inhibition of FOXO mediated transcription, ensures survival of ENS precursors (Srinivasan et al. 2005).
Transcription of the STK11 (LKB1) gene, encoding Serine/threonine-protein kinase STK11 (also known as Liver kinase B1), which regulates diverse cellular processes, including apoptosis, is directly stimulated by FOXO3 and FOXO4 (Lutzner et al. 2012).
FOXO-mediated

transcription of oxidative stress, metabolic and

neuronal genes		PathwayR-HSA-9615017 (Reactome) FOXO6, the least studied member of the FOXO family, directly stimulates transcription of PLXNA4 gene, encoding a co-factor for the semaphorin SEMA3A receptor. FOXO6-mediated regulation of PLXNA4 expression plays an important role in radial glia migration during cortical development (Paap et al. 2016).
FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).
FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.
In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.
FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.
FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).
Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).
FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
FOXO1,FOXO3,FOXO4,(FOXO6)ComplexR-HSA-199272 (Reactome)
FOXO1:CREBBPComplexR-HSA-9626931 (Reactome)
FOXO1ProteinQ12778 (Uniprot-TrEMBL)
FOXO3 ProteinO43524 (Uniprot-TrEMBL)
FOXO3ProteinO43524 (Uniprot-TrEMBL)
FOXO4 ProteinP98177 (Uniprot-TrEMBL)
FOXO4-S-S-CREBBP ProteinQ92793 (Uniprot-TrEMBL)
FOXO4-S-S-EP300 ProteinQ09472 (Uniprot-TrEMBL)
FOXO4ProteinP98177 (Uniprot-TrEMBL)
FOXO6 ProteinA8MYZ6 (Uniprot-TrEMBL)
KAT2B ProteinQ92831 (Uniprot-TrEMBL)
KAT2B,(EP300)ComplexR-HSA-9620507 (Reactome)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
ROSMetaboliteCHEBI:26523 (ChEBI)
SFN ProteinP31947 (Uniprot-TrEMBL)
SIRT1 ProteinQ96EB6 (Uniprot-TrEMBL)
SIRT1,SIRT3ComplexR-HSA-9622899 (Reactome)
SIRT1ProteinQ96EB6 (Uniprot-TrEMBL)
SIRT3 ProteinQ9NTG7 (Uniprot-TrEMBL)
SOH-C481-FOXO4ProteinP98177 (Uniprot-TrEMBL)
TXNIPProteinQ9H3M7 (Uniprot-TrEMBL)
TXNProteinP10599 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
YWHAZ dimer,YWHAQ dimer,SFN dimerComplexR-HSA-9614627 (Reactome)
YWHAZ dimer,YWHAQ

dimer,YWHAG

dimer,YWHAB dimer		ComplexR-HSA-9614573 (Reactome)
YWHAZ dimerComplexR-HSA-206751 (Reactome)
p-T,p-S-AKTComplexR-HSA-202072 (Reactome)
p-T24,S256,S319-FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4,(p-T26,S184-FOXO6)ComplexR-HSA-9614997 (Reactome)
p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4ComplexR-HSA-199269 (Reactome)
p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4ComplexR-HSA-9614416 (Reactome)
p-T24,S256,S319-FOXO1:YWHAZ,YWHAQ,YWHAG,YWHABComplexR-HSA-9614572 (Reactome)
p-T24,S256,S319-FOXO1ProteinQ12778 (Uniprot-TrEMBL)
p-T26,S184-FOXO6 ProteinA8MYZ6 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T32,S197,S262-FOXO4 ProteinP98177 (Uniprot-TrEMBL)
p-T32,S197,S262-FOXO4:YWHAZ dimerComplexR-HSA-9614653 (Reactome)
p-T32,S197,S262-FOXO4ProteinP98177 (Uniprot-TrEMBL)
p-T32,S253,S315-FOXO3 ProteinO43524 (Uniprot-TrEMBL)
p-T32,S253,S315-FOXO3:YWHAZ,YWHAQ,SFNComplexR-HSA-9614628 (Reactome)
p-T32,S253,S315-FOXO3ProteinO43524 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseArrowR-HSA-9620532 (Reactome)
2'-O-acetyl-ADP-riboseArrowR-HSA-9626962 (Reactome)
2xHC-TXNArrowR-HSA-9617735 (Reactome)
ADPArrowR-HSA-199299 (Reactome)
ATPR-HSA-199299 (Reactome)
Ac-CoAR-HSA-9617758 (Reactome)
Ac-CoAR-HSA-9620515 (Reactome)
Ac-CoAR-HSA-9626945 (Reactome)
Ac-K-FOXO4ArrowR-HSA-9617758 (Reactome)
Ac-K242,K259,K271,K290,K569-FOXO3ArrowR-HSA-9620515 (Reactome)
Ac-K242,K259,K271,K290,K569-FOXO3R-HSA-9620532 (Reactome)
Ac-K245,K248,K265-FOXO1ArrowR-HSA-9626945 (Reactome)
Ac-K245,K248,K265-FOXO1R-HSA-9626962 (Reactome)
CREBBP,EP300ArrowR-HSA-9617758 (Reactome)
CREBBP,EP300R-HSA-9617683 (Reactome)
CREBBPArrowR-HSA-9626945 (Reactome)
CREBBPR-HSA-9626928 (Reactome)
CREBPP-S-S-FOXO4:FOXO4-S-S-CREBBP,EP300-S-S-FOXO4:FOXO4-S-S-EP300ArrowR-HSA-9617683 (Reactome)
CREBPP-S-S-FOXO4:FOXO4-S-S-CREBBP,EP300-S-S-FOXO4:FOXO4-S-S-EP300R-HSA-9617758 (Reactome)
CREBPP-S-S-FOXO4:FOXO4-S-S-CREBBP,EP300-S-S-FOXO4:FOXO4-S-S-EP300mim-catalysisR-HSA-9617758 (Reactome)
CoA-SHArrowR-HSA-9617758 (Reactome)
CoA-SHArrowR-HSA-9620515 (Reactome)
CoA-SHArrowR-HSA-9626945 (Reactome)
EP300-S-S-FOXO4:FOXO4-S-S-EP300R-HSA-9617735 (Reactome)
EP300ArrowR-HSA-9617735 (Reactome)
FOXO1,FOXO3,FOXO4,(FOXO6)R-HSA-199299 (Reactome)
FOXO1:CREBBPArrowR-HSA-9626928 (Reactome)
FOXO1:CREBBPR-HSA-9626945 (Reactome)
FOXO1:CREBBPmim-catalysisR-HSA-9626945 (Reactome)
FOXO1ArrowR-HSA-9626962 (Reactome)
FOXO1R-HSA-9626928 (Reactome)
FOXO3ArrowR-HSA-9620532 (Reactome)
FOXO3R-HSA-9620515 (Reactome)
FOXO4ArrowR-HSA-9617735 (Reactome)
FOXO4R-HSA-9617660 (Reactome)
KAT2B,(EP300)mim-catalysisR-HSA-9620515 (Reactome)
NAD+R-HSA-9620532 (Reactome)
NAD+R-HSA-9626962 (Reactome)
NAMArrowR-HSA-9620532 (Reactome)
NAMArrowR-HSA-9626962 (Reactome)
R-HSA-199299 (Reactome) AKT-mediated phosphorylation of Forkhead box (FOX) transcription factors of the FOXO family, FOXO1 (FKHR), FOXO3 (FoxO3a, also known as FKHRL1) and FOXO4 (AFX) contributes to PI3K/AKT signaling-stimulated cell survival and growth. Activated AKT1 phosphorylates FOXO1 on threonine residue T24 and serine residues S256 and S319 (Rena et al. 1999), FOXO3 on threonine residue T32 and serine residues S253 and S315 (Brunet et al. 1999), and FOXO4 on threonine residue T32 and serine residues S197 and S262 (Kops et al. 1999).
Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005).
Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017).
R-HSA-9614414 (Reactome) AKT-mediated phosphorylation results in exclusion of FOXO1 (Rena et al. 2001), FOXO3 (Brunet et al. 1999) and FOXO4 (Obslova et al. 2005) from the nucleus. In the absence of PI3K/AKT signaling, FOXO1 (Rena et al. 2001), FOXO3 (Brunet et al. 1999) and FOXO4 (Matsuzaki et al. 2005) are mainly nuclear, but after activation of PI3K/AKT signaling, they become cytoplasmic. One of the conserved AKT phosphorylation sites is within the nuclear localization signal (NLS) of FOXO1, FOXO3 and FOXO4.
In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of FOXO6 phosphorylated on putative AKT sites may shuttle to the nucleus (Jacobs et al. 2003, van der Heide et al. 2005).
R-HSA-9614423 (Reactome) Nuclear exclusion and cytoplasmic retention of AKT-phosphorylated FOXO1 is promoted by binding of FOXO1 to 14-3-3 proteins: YWHAZ (14-3-3 zeta), YWHAQ (14-3-3 theta), YWHAB (14-3-3 beta) and YWHAG (14-3-3 gamma) (Rena et al. 2001).
R-HSA-9614562 (Reactome) Nuclear exclusion and cytoplasmic retention of AKT-phosphorylated FOXO3 is promoted by binding of FOXO3 to 14-3-3 proteins: YWHAZ (14-3-3 zeta), YWHAQ (14-3-3 theta), and SFN (14-3-3 sigma) (Brunet et al. 1999, Arimoto-Ishida et al. 2004).
R-HSA-9614564 (Reactome) Nuclear exclusion and cytoplasmic retention of AKT-phosphorylated FOXO4 is promoted by binding of FOXO4 to 14-3-3 zeta (YWHAZ) (Obsilova et al. 2005, Boura et al. 2007, Silhan et al. 2009).
R-HSA-9617660 (Reactome) Reactive oxygen species (ROS) oxidize cysteine residue(s) of FOXO4. There are five cysteine residues in FOXO4, of which two residues, C31 (corresponds to C27 in mouse Foxo4) and C481 (corresponds to C477 of mouse Foxo4) are conserved in other FOXO family members. Oxidation of C481 of FOXO4 has the most significant functional implications (Dansen et al. 2009).
R-HSA-9617683 (Reactome) After oxidation of FOXO4 cysteine residues by reactive oxygen species (ROS), FOXO4 forms a complex with a protein acetyltransferase EP300 (p300) or CREBBP (CBP). A covalent disulfide bond between FOXO4 and EP300 or CREBBP facilitates complex formation (Dansen et al. 2009).
R-HSA-9617735 (Reactome) Thioredoxin (TXN) reduces oxidized FOXO4 and disrupts interaction between FOXO4 and EP300 (p300). TXN-mediated disruption of FOXO4:EP300 complexes is negatively regulated by TXNIP (TBP-2), a TXN binding protein (Dansen et al. 2009).
R-HSA-9617758 (Reactome) EP300 and CREBBP histone acetyltransferases acetylate FOXO4 (Dansen et al. 2009).
R-HSA-9620515 (Reactome) KAT2B (PCAF) and possibly EP300 (p300) acetylate FOXO3 under conditions of oxidative stress (Brunet et al. 2004).
R-HSA-9620532 (Reactome) SIRT1, an NAD-dependent histone deacetylase, deacetylates FOXO3. SIRT1-mediated deacetylation of FOXO3 inhibits FOXO3-mediated cell death induced by oxidative stress while promoting FOXO3-mediated cell cycle arrest, which increases resistance to oxidative stress (Brunet et al. 2004).
FOXO3 can similarly be deacetylated by SIRT3, also an NAD-dependent histone deacetylase. Deacetylation of FOXO3 by SIRT3 in response to oxidative stress increases FOXO3 nuclear localization by interfering with AKT-mediated phosphorylation of FOXO3. SIRT3-mediated deacetylation of FOXO3 positively regulates FOXO3-mediated transcription of SOD2 and CAT genes which encode enzymes that process reactive oxygen species and reduce oxidative stress to the cell (Kim et al. 2010, Tseng et al. 2013).
R-HSA-9626928 (Reactome) Endogenous human histone acetyltransferase CREBBP (CBP) binds to endogenous human FOXO1. The C-terminus of FOXO1 is needed for this interaction (Daitoku et al. 2004).
R-HSA-9626945 (Reactome) Based on experiments using recombinant human CREBBP and recombinant mouse Foxo1, CREBBP phosphorylates FOXO1 on conserved lysine residues K245, K248 and K265 (these residues correspond to K242, K245 and K262, respectively, in mouse Foxo1) (Daitoku et al. 2004).
R-HSA-9626962 (Reactome) A histone deacetylase SIRT1 deacetylates FOXO1. Deacetylation increases FOXO1-mediated upregulation of SOD2 and CDKN1B (Diatoku et al. 2004). SIRT-dependent deacetylation leads to retention of FOXO1 in the nucleus (Frescas et al. 2005).
ROSArrowR-HSA-9620515 (Reactome)
ROSR-HSA-9617660 (Reactome)
SIRT1,SIRT3mim-catalysisR-HSA-9620532 (Reactome)
SIRT1mim-catalysisR-HSA-9626962 (Reactome)
SOH-C481-FOXO4ArrowR-HSA-9617660 (Reactome)
SOH-C481-FOXO4R-HSA-9617683 (Reactome)
TXNIPTBarR-HSA-9617735 (Reactome)
TXNR-HSA-9617735 (Reactome)
TXNmim-catalysisR-HSA-9617735 (Reactome)
YWHAZ dimer,YWHAQ dimer,SFN dimerR-HSA-9614562 (Reactome)
YWHAZ dimer,YWHAQ

dimer,YWHAG

dimer,YWHAB dimer		R-HSA-9614423 (Reactome)
YWHAZ dimerR-HSA-9614564 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-199299 (Reactome)
p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4,(p-T26,S184-FOXO6)ArrowR-HSA-199299 (Reactome)
p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4ArrowR-HSA-9614414 (Reactome)
p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4R-HSA-9614414 (Reactome)
p-T24,S256,S319-FOXO1:YWHAZ,YWHAQ,YWHAG,YWHABArrowR-HSA-9614423 (Reactome)
p-T24,S256,S319-FOXO1R-HSA-9614423 (Reactome)
p-T32,S197,S262-FOXO4:YWHAZ dimerArrowR-HSA-9614564 (Reactome)
p-T32,S197,S262-FOXO4R-HSA-9614564 (Reactome)
p-T32,S253,S315-FOXO3:YWHAZ,YWHAQ,SFNArrowR-HSA-9614562 (Reactome)
p-T32,S253,S315-FOXO3R-HSA-9614562 (Reactome)
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