KEGG   PATHWAY: cge04068
Entry
cge04068                    Pathway                                
Name
FoxO signaling pathway - Cricetulus griseus (Chinese hamster)
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
cge04068  FoxO signaling pathway
cge04068

Other DBs
GO: 0009267
Organism
Cricetulus griseus (Chinese hamster) [GN:cge]
Gene
100773359  Tgfb1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
100774918  Tgfb2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
100756831  Tgfb3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
100772727  Tgfbr1; TGF-beta receptor type-1 isoform X3 [KO:K04674] [EC:2.7.11.30]
100773953  Tgfbr2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
100770737  Smad4; mothers against decapentaplegic homolog 4 isoform X2 [KO:K04501]
100759220  Smad3; mothers against decapentaplegic homolog 3 isoform X3 [KO:K23605]
100765813  Stk11; serine/threonine-protein kinase STK11 isoform X4 [KO:K07298] [EC:2.7.11.1]
100767909  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X2 [KO:K07198] [EC:2.7.11.31]
100769574  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X2 [KO:K07198] [EC:2.7.11.31]
100755226  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
100772359  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
100758649  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X4 [KO:K07200]
100770459  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100765754  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
100768473  Nlk; serine/threonine-protein kinase NLK isoform X2 [KO:K04468] [EC:2.7.11.24]
100771396  Skp2; S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
100770120  Mdm2; E3 ubiquitin-protein ligase Mdm2 isoform X3 [KO:K06643] [EC:2.3.2.27]
100767175  Setd7; histone-lysine N-methyltransferase SETD7 isoform X2 [KO:K11431] [EC:2.1.1.364]
100762260  Ep300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
100770451  histone lysine acetyltransferase CREBBP isoform X3 [KO:K04498] [EC:2.3.1.48]
100763298  Sirt1; LOW QUALITY PROTEIN: NAD-dependent protein deacetylase sirtuin-1 isoform X2 [KO:K11411] [EC:2.3.1.286]
100769056  Usp7; ubiquitin carboxyl-terminal hydrolase 7 isoform X3 [KO:K11838] [EC:3.4.19.12]
100766656  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
100771734  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100754361  mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
100764964  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100757702  Stk4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
100751642  Igf1; insulin-like growth factor I isoform X1 [KO:K05459]
100768531  Igf1r; insulin-like growth factor 1 receptor isoform X2 [KO:K05087] [EC:2.7.10.1]
100760716  Ins; insulin [KO:K04526]
100766818  Insr; insulin receptor isoform X2 [KO:K04527] [EC:2.7.10.1]
100755710  Irs1; insulin receptor substrate 1 [KO:K16172]
100771848  Irs2; insulin receptor substrate 2 isoform X2 [KO:K07187]
100751390  insulin receptor substrate 1 [KO:K17445]
100773159  insulin receptor substrate 4 isoform X2 [KO:K17446]
100689251  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100769225  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100689252  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100771181  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
100750761  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100774067  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100772477  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 isoform X2 [KO:K06276] [EC:2.7.11.1]
100754432  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X5 [KO:K04467] [EC:2.7.11.10]
100750488  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
100764294  Pten; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X3 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
100768351  Akt2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100752454  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100769460  Akt1; RAC-alpha serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100771433  Sgk1; serine/threonine-protein kinase Sgk1 isoform X2 [KO:K13302] [EC:2.7.11.1]
100772733  Sgk2; serine/threonine-protein kinase Sgk2 isoform X3 [KO:K13303] [EC:2.7.11.1]
100767615  Sgk3; serine/threonine-protein kinase Sgk3 isoform X2 [KO:K13304] [EC:2.7.11.1]
100768647  Foxo1; forkhead box protein O1 isoform X2 [KO:K07201]
100770315  Foxo3; forkhead box protein O3 [KO:K09408]
100756577  Foxo4; forkhead box protein O4 [KO:K12358]
100758558  Foxo6; forkhead box protein O6 isoform X2 [KO:K17847]
100751598  Grm1; metabotropic glutamate receptor 1 isoform X2 [KO:K04603]
100771332  Homer2; homer protein homolog 2 isoform X1 [KO:K15010]
100760219  Homer1; homer protein homolog 1 [KO:K15010]
100764933  Homer3; homer protein homolog 3 isoform X2 [KO:K15010]
100764978  Agap2; arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 isoform X2 [KO:K17848]
100766643  casein kinase I isoform X4 [KO:K08960] [EC:2.7.11.1]
100689186  Il6; interleukin-6 [KO:K05405]
100759320  Il10; interleukin-10 isoform X1 [KO:K05443]
100755865  Stat3; signal transducer and activator of transcription 3 isoform X9 [KO:K04692]
100763146  Egf; pro-epidermal growth factor isoform X2 [KO:K04357]
100774580  Egfr; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100769627  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
100757521  Sos1; son of sevenless homolog 1 isoform X2 [KO:K03099]
100769325  Sos2; son of sevenless homolog 2 isoform X3 [KO:K03099]
100773737  Hras; GTPase HRas isoform X2 [KO:K02833]
100763178  Kras; GTPase KRas isoform X4 [KO:K07827]
113839127  GTPase KRas-like [KO:K07827]
113837935  GTPase KRas-like isoform X2 [KO:K07827]
113837956  GTPase KRas-like [KO:K07827]
113838653  GTPase KRas-like isoform X2 [KO:K07827]
113838692  GTPase KRas-like [KO:K07827]
113838722  GTPase KRas-like isoform X1 [KO:K07827]
113838818  GTPase KRas-like [KO:K07827]
113837633  GTPase KRas-like isoform X1 [KO:K07827]
113838146  GTPase KRas-like isoform X1 [KO:K07827]
113838876  GTPase KRas-like [KO:K07827]
113838228  GTPase KRas-like isoform X1 [KO:K07827]
113839011  GTPase KRas-like [KO:K07827]
100771078  GTPase KRas-like isoform X2 [KO:K07827]
113837960  GTPase KRas-like [KO:K07827]
113838098  GTPase KRas-like [KO:K07827]
113838326  GTPase KRas-like [KO:K07827]
113838417  GTPase KRas-like isoform X1 [KO:K07827]
113838488  GTPase KRas-like [KO:K07827]
113838583  GTPase KRas-like isoform X1 [KO:K07827]
113838676  GTPase KRas-like [KO:K07827]
113838679  GTPase KRas-like isoform X1 [KO:K07827]
113838746  GTPase KRas-like [KO:K07827]
113838796  GTPase KRas-like isoform X1 [KO:K07827]
113838871  GTPase KRas-like [KO:K07827]
113838872  GTPase KRas-like [KO:K07827]
113838892  GTPase KRas-like [KO:K07827]
113838898  GTPase KRas-like [KO:K07827]
113838914  GTPase KRas-like [KO:K07827]
113838921  GTPase KRas-like [KO:K07827]
113838942  GTPase KRas-like isoform X1 [KO:K07827]
113838943  GTPase KRas-like isoform X1 [KO:K07827]
113839007  GTPase HRas-like isoform X1 [KO:K07827]
118239746  GTPase KRas-like isoform X1 [KO:K07827]
118239767  GTPase KRas-like isoform X1 [KO:K07827]
118239768  GTPase KRas-like [KO:K07827]
118239770  GTPase KRas-like [KO:K07827]
118239801  GTPase KRas-like [KO:K07827]
118239825  GTPase KRas-like isoform X1 [KO:K07827]
100757614  Nras; GTPase NRas [KO:K07828]
100771486  Braf; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf isoform X6 [KO:K04365] [EC:2.7.11.1]
100769018  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
100751432  Araf; serine/threonine-protein kinase A-Raf isoform X5 [KO:K08845] [EC:2.7.11.1]
100689403  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
113835540  dual specificity mitogen-activated protein kinase kinase 1-like isoform X1 [KO:K04368] [EC:2.7.12.2]
103158537  dual specificity mitogen-activated protein kinase kinase 1-like isoform X2 [KO:K04368] [EC:2.7.12.2]
100774204  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X2 [KO:K04369] [EC:2.7.12.2]
100759514  Mapk1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
100753149  Mapk3; mitogen-activated protein kinase 3 isoform X2 [KO:K04371] [EC:2.7.11.24]
100689104  Mapk14; mitogen-activated protein kinase 14 isoform X3 [KO:K04441] [EC:2.7.11.24]
100759172  Mapk11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
100754042  Mapk12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100763519  Mapk13; mitogen-activated protein kinase 13 isoform X2 [KO:K04441] [EC:2.7.11.24]
100689039  Cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
100765197  Prmt1; protein arginine N-methyltransferase 1 isoform X3 [KO:K11434] [EC:2.1.1.319]
100762710  Foxg1; forkhead box protein G1 isoform X2 [KO:K09385]
100770842  Ccnb1; G2/mitotic-specific cyclin-B1 [KO:K05868]
100773656  Ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
100755282  Ccnb3; G2/mitotic-specific cyclin-B3 [KO:K21771]
100689063  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
100771544  Ccnd2; G1/S-specific cyclin-D2 [KO:K10151]
100753075  Ccng2; cyclin-G2 [KO:K10146]
113833995  cyclin-dependent kinase 4 inhibitor B [KO:K04685]
100758546  Cdkn2d; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
103160601  Cdkn1a; cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
100689401  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100770221  Rbl2; retinoblastoma-like protein 2 isoform X1 [KO:K16332]
100760676  Plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
100753472  Plk2; serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
100762491  Plk3; serine/threonine-protein kinase PLK3 isoform X2 [KO:K08862] [EC:2.7.11.21]
100774595  Plk4; serine/threonine-protein kinase PLK4 isoform X1 [KO:K08863] [EC:2.7.11.21]
103159266  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X2 [KO:K04402]
100759228  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100766127  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100773293  Faslg; tumor necrosis factor ligand superfamily member 6 isoform X1 [KO:K04389]
100771754  Bcl2l11; bcl-2-like protein 11 isoform X2 [KO:K16341]
100754968  Tnfsf10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
100773755  Bcl6; B-cell lymphoma 6 protein isoform X1 [KO:K15618]
100774634  Bnip3; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 isoform X2 [KO:K15464]
100760609  Atg12; ubiquitin-like protein ATG12 isoform X2 [KO:K08336]
100771320  Gabarapl1; gamma-aminobutyric acid receptor-associated protein-like 1 isoform X1 [KO:K08341]
100767236  Gabarap; gamma-aminobutyric acid receptor-associated protein [KO:K08341]
100767407  Gabarapl2; gamma-aminobutyric acid receptor-associated protein-like 2 isoform X3 [KO:K08341]
100773774  Cat; catalase isoform X1 [KO:K03781] [EC:1.11.1.6]
100760320  Sod2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
100754226  serine-protein kinase ATM isoform X6 [KO:K04728] [EC:2.7.11.1]
100758749  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100762618  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100762184  G6pc2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
100753219  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
100763214  G6pc; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100757700  Il7r; interleukin-7 receptor subunit alpha [KO:K05072]
113833401  Klf2; Krueppel-like factor 2 isoform X2 [KO:K17845]
100689198  S1pr1; sphingosine 1-phosphate receptor 1 [KO:K04288]
100770166  S1pr4; sphingosine 1-phosphate receptor 4 [KO:K04293]
100754292  Rag1; V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
100754577  Rag2; V(D)J recombination-activating protein 2 [KO:K10988]
103158884  Fbxo32; F-box only protein 32 isoform X2 [KO:K10305]
100758634  Fbxo25; F-box only protein 25 isoform X1 [KO:K10305]
Compound
C00008  ADP
C00020  AMP
C00025  L-Glutamate
C00031  D-Glucose
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:17470511
  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
PMID:17522590
  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
PMID:21440011
  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
PMID:23325358
  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
PMID:17569704
  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
PMID:19701188
  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
PMID:15516968
  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
PMID:22902436
  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
PMID:18403263
  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
PMID:23801966
  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
PMID:18045156
  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
PMID:22761423
  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
PMID:21238503
  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
PMID:16288288
  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
PMID:15084259
  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
PMID:18951090
  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
PMID:16964248
  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
PMID:21613825
  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
PMID:15005655
  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
cge00010  Glycolysis / Gluconeogenesis
cge00020  Citrate cycle (TCA cycle)
cge00190  Oxidative phosphorylation
cge04010  MAPK signaling pathway
cge04110  Cell cycle
cge04120  Ubiquitin mediated proteolysis
cge04140  Autophagy - animal
cge04151  PI3K-Akt signaling pathway
cge04210  Apoptosis
cge04350  TGF-beta signaling pathway
cge04630  JAK-STAT signaling pathway
cge04910  Insulin signaling pathway
KO pathway
ko04068   
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