KEGG   PATHWAY: panu04068
Entry
panu04068                   Pathway                                
Name
FoxO signaling pathway - Papio anubis (olive baboon)
Description
The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, methylation and ubiquitylation.
Class
Environmental Information Processing; Signal transduction
Pathway map
panu04068  FoxO signaling pathway
panu04068

Other DBs
GO: 0009267
Organism
Papio anubis (olive baboon) [GN:panu]
Gene
100126735  IGF1R; insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
100137163  STK4; serine/threonine-protein kinase 4 [KO:K04411]
100381179  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100381195  IL6; interleukin-6 precursor [KO:K05405]
100510873  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X4 [KO:K02649]
100997116  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
100997156  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
100997308  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100997339  IL7R; interleukin-7 receptor subunit alpha [KO:K05072]
100997562  ATG12; LOW QUALITY PROTEIN: ubiquitin-like protein ATG12 [KO:K08336]
100997634  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100997985  INS; insulin isoform X2 [KO:K04526]
100998492  CDKN2D; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
100998724  USP7; ubiquitin carboxyl-terminal hydrolase 7 isoform X1 [KO:K11838] [EC:3.4.19.12]
100998877  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
100998929  STAT3; signal transducer and activator of transcription 3 isoform X9 [KO:K04692]
100999335  HOMER2; homer protein homolog 2 isoform X4 [KO:K15010]
100999369  IRS1; insulin receptor substrate 1 [KO:K16172]
100999911  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
101000053  [KO:K13304] [EC:2.7.11.1]
101000127  SETD7; histone-lysine N-methyltransferase SETD7 isoform X1 [KO:K11431] [EC:2.1.1.364]
101000210  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
101000264  SKP2; S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
101000402  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101000449  RAG1; V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
101000707  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
101000786  RAG2; V(D)J recombination-activating protein 2 [KO:K10988]
101001103  MAPK12; mitogen-activated protein kinase 12 isoform X2 [KO:K04441] [EC:2.7.11.24]
101001218  [KO:K08960] [EC:2.7.11.1]
101001461  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
101002160  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
101002278  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
101002393  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
101002586  CREBBP; CREB-binding protein isoform X5 [KO:K04498] [EC:2.3.1.48]
101002675  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101002971  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101002992  HRAS; GTPase HRas isoform X2 [KO:K02833]
101003588  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
101003602  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
101003612  CCNG2; cyclin-G2 isoform X2 [KO:K10146]
101003749  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101004074  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
101004371  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
101004903  PLK2; serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
101004976  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101005010  MAPK10; mitogen-activated protein kinase 10 isoform X3 [KO:K04440] [EC:2.7.11.24]
101005034  FOXG1; forkhead box protein G1 [KO:K09385]
101005407  SGK2; serine/threonine-protein kinase Sgk2 isoform X2 [KO:K13303] [EC:2.7.11.1]
101005483  GRM1; metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
101005652  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101006391  NLK; serine/threonine-protein kinase NLK isoform X1 [KO:K04468] [EC:2.7.11.24]
101006436  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101006627  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
101006670  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
101006756  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101006845  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X8 [KO:K07200]
101007472  AGAP2; arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 isoform X1 [KO:K17848]
101007559  FOXO4; forkhead box protein O4 [KO:K12358]
101007909  CCNB1; G2/mitotic-specific cyclin-B1 [KO:K05868]
101008150  RBL2; retinoblastoma-like protein 2 isoform X1 [KO:K16332]
101008313  G6PC2; LOW QUALITY PROTEIN: glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
101008394  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
101008699  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101009029  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101009200  PLK1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
101009253  TGFB2; transforming growth factor beta-2 proprotein isoform X2 [KO:K13376]
101009981  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101010276  IGF1; insulin-like growth factor I isoform X2 [KO:K05459]
101010652  BCL2L11; bcl-2-like protein 11 isoform X1 [KO:K16341]
101010952  PLK4; serine/threonine-protein kinase PLK4 [KO:K08863] [EC:2.7.11.21]
101011002  GABARAPL1; gamma-aminobutyric acid receptor-associated protein-like 1 [KO:K08341]
101011176  IRS2; insulin receptor substrate 2 [KO:K07187]
101011570  BNIP3; LOW QUALITY PROTEIN: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [KO:K15464]
101012041  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101012106  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta isoform X2 [KO:K04402]
101012351  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
101013013  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
101013089  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
101013448  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101013655  CAT; LOW QUALITY PROTEIN: catalase [KO:K03781] [EC:1.11.1.6]
101013750  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
101014127  CDKN2B; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
101014172  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
101014322  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
101014774  FBXO25; F-box only protein 25 isoform X3 [KO:K10305]
101014806  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
101015024  FBXO32; F-box only protein 32 [KO:K10305]
101015152  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
101015293  FOXO6; forkhead box protein O6 [KO:K17847]
101015356  PRMT1; protein arginine N-methyltransferase 1 isoform X1 [KO:K11434] [EC:2.1.1.319]
101015676  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
101016447  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X5 [KO:K07209] [EC:2.7.11.10]
101016512  TGFBR1; TGF-beta receptor type-1 isoform X2 [KO:K04674] [EC:2.7.11.30]
101016586  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X1 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
101016626  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
101016712  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
101017109  FOXO1; forkhead box protein O1 [KO:K07201]
101017114  SGK1; serine/threonine-protein kinase Sgk1 isoform X3 [KO:K13302] [EC:2.7.11.1]
101017528  KRAS; GTPase KRas isoform X2 [KO:K07827]
101017830  KLF2; Krueppel-like factor 2 [KO:K17845]
101019119  BCL6; B-cell lymphoma 6 protein isoform X1 [KO:K15618]
101019266  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
101019608  [KO:K15464]
101019640  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101019884  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101019923  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
101020320  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
101020446  GABARAPL2; gamma-aminobutyric acid receptor-associated protein-like 2 isoform X4 [KO:K08341]
101020739  PLK3; serine/threonine-protein kinase PLK3 isoform X1 [KO:K08862] [EC:2.7.11.21]
101021695  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
101021830  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
101021880  [KO:K17445]
101022024  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
101022320  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101022550  FOXO3; LOW QUALITY PROTEIN: forkhead box protein O3 [KO:K09408]
101022780  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
101023107  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
101023749  [KO:K15464]
101024189  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101024270  IL10; interleukin-10 [KO:K05443]
101024667  HOMER3; homer protein homolog 3 [KO:K15010]
101024771  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
101024929  CCNB3; G2/mitotic-specific cyclin-B3 isoform X1 [KO:K21771]
101025519  GABARAP; gamma-aminobutyric acid receptor-associated protein [KO:K08341]
101025892  CDK2; cyclin-dependent kinase 2 isoform X2 [KO:K02206] [EC:2.7.11.22]
101025984  [KO:K21770]
101026002  DEPP1; protein DEPP1 [KO:K27679]
101026253  NRAS; GTPase NRas isoform X2 [KO:K07828]
101026665  EGF; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
101027041  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
101027061  EP300; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
116272568  [KO:K21770]
Compound
C00008  ADP
C00020  AMP
C00025  L-Glutamate
C00031  D-Glucose
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Glauser DA, Schlegel W
  Title
The emerging role of FOXO transcription factors in pancreatic beta cells.
  Journal
J Endocrinol 193:195-207 (2007)
DOI:10.1677/JOE-06-0191
Reference
  Authors
van der Horst A, Burgering BM
  Title
Stressing the role of FoxO proteins in lifespan and disease.
  Journal
Nat Rev Mol Cell Biol 8:440-50 (2007)
DOI:10.1038/nrm2190
Reference
  Authors
Zhang X, Tang N, Hadden TJ, Rishi AK
  Title
Akt, FoxO and regulation of apoptosis.
  Journal
Biochim Biophys Acta 1813:1978-86 (2011)
DOI:10.1016/j.bbamcr.2011.03.010
Reference
  Authors
Eijkelenboom A, Burgering BM
  Title
FOXOs: signalling integrators for homeostasis maintenance.
  Journal
Nat Rev Mol Cell Biol 14:83-97 (2013)
DOI:10.1038/nrm3507
Reference
  Authors
Daitoku H, Fukamizu A
  Title
FOXO transcription factors in the regulatory networks of longevity.
  Journal
J Biochem 141:769-74 (2007)
DOI:10.1093/jb/mvm104
Reference
  Authors
Hedrick SM
  Title
The cunning little vixen: Foxo and the cycle of life and death.
  Journal
Nat Immunol 10:1057-63 (2009)
DOI:10.1038/ni.1784
Reference
  Authors
Coffer PJ, Burgering BM
  Title
Forkhead-box transcription factors and their role in the immune system.
  Journal
Nat Rev Immunol 4:889-99 (2004)
DOI:10.1038/nri1488
Reference
  Authors
Ro SH, Liu D, Yeo H, Paik JH
  Title
FoxOs in neural stem cell fate decision.
  Journal
Arch Biochem Biophys 534:55-63 (2013)
DOI:10.1016/j.abb.2012.07.017
Reference
  Authors
Maiese K, Chong ZZ, Shang YC
  Title
OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins.
  Journal
Trends Mol Med 14:219-27 (2008)
DOI:10.1016/j.molmed.2008.03.002
Reference
  Authors
Hagenbuchner J, Ausserlechner MJ
  Title
Mitochondria and FOXO3: breath or die.
  Journal
Front Physiol 4:147 (2013)
DOI:10.3389/fphys.2013.00147
Reference
  Authors
Maiese K, Chong ZZ, Shang YC
  Title
"Sly as a FOXO": new paths with Forkhead signaling in the brain.
  Journal
Curr Neurovasc Res 4:295-302 (2007)
DOI:10.2174/156720207782446306
Reference
  Authors
Oh HM, Yu CR, Dambuza I, Marrero B, Egwuagu CE
  Title
STAT3 protein interacts with Class O Forkhead transcription factors in the cytoplasm and regulates nuclear/cytoplasmic localization of FoxO1 and FoxO3a proteins in CD4(+) T cells.
  Journal
J Biol Chem 287:30436-43 (2012)
DOI:10.1074/jbc.M112.359661
Reference
  Authors
Huang H, Tindall DJ
  Title
Regulation of FOXO protein stability via ubiquitination and proteasome degradation.
  Journal
Biochim Biophys Acta 1813:1961-4 (2011)
DOI:10.1016/j.bbamcr.2011.01.007
Reference
  Authors
Greer EL, Brunet A
  Title
FOXO transcription factors at the interface between longevity and tumor suppression.
  Journal
Oncogene 24:7410-25 (2005)
DOI:10.1038/sj.onc.1209086
Reference
  Authors
Seoane J, Le HV, Shen L, Anderson SA, Massague J
  Title
Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.
  Journal
Cell 117:211-23 (2004)
DOI:10.1016/S0092-8674(04)00298-3
Reference
  Authors
Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y, Fukamizu A
  Title
Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.
  Journal
Mol Cell 32:221-31 (2008)
DOI:10.1016/j.molcel.2008.09.013
Reference
  Authors
van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM
  Title
FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP.
  Journal
Nat Cell Biol 8:1064-73 (2006)
DOI:10.1038/ncb1469
Reference
  Authors
Zhang Y, Gan B, Liu D, Paik JH
  Title
FoxO family members in cancer.
  Journal
Cancer Biol Ther 12:253-9 (2011)
DOI:10.4161/cbt.12.4.15954
Reference
  Authors
Van Der Heide LP, Hoekman MF, Smidt MP
  Title
The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.
  Journal
Biochem J 380:297-309 (2004)
DOI:10.1042/BJ20040167
Related
pathway
panu00010  Glycolysis / Gluconeogenesis
panu00020  Citrate cycle (TCA cycle)
panu00190  Oxidative phosphorylation
panu04010  MAPK signaling pathway
panu04110  Cell cycle
panu04120  Ubiquitin mediated proteolysis
panu04140  Autophagy - animal
panu04151  PI3K-Akt signaling pathway
panu04210  Apoptosis
panu04350  TGF-beta signaling pathway
panu04630  JAK-STAT signaling pathway
panu04910  Insulin signaling pathway
KO pathway
ko04068   

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