KEGG   PATHWAY: aful04068
Entry
aful04068                   Pathway                                
Name
FoxO signaling pathway - Aythya fuligula (tufted duck)
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
aful04068  FoxO signaling pathway
aful04068

Other DBs
GO: 0009267
Organism
Aythya fuligula (tufted duck) [GN:aful]
Gene
116488326  TGFB2; LOW QUALITY PROTEIN: transforming growth factor beta-2 proprotein [KO:K13376]
116490182  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
116485537  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
116490458  TGF-beta receptor type-2-like [KO:K04388] [EC:2.7.11.30]
116486426  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
116499524  mothers against decapentaplegic homolog 4-like [KO:K04501]
116500438  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
116493384  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
116498971  STK11; serine/threonine-protein kinase STK11 [KO:K07298] [EC:2.7.11.1]
116492219  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
116500605  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
116491946  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
116496284  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
116499919  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
116485518  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
116490906  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
116497142  NLK; serine/threonine-protein kinase NLK isoform X1 [KO:K04468] [EC:2.7.11.24]
116500511  SKP2; S-phase kinase-associated protein 2 [KO:K03875]
116486905  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
116488501  SETD7; histone-lysine N-methyltransferase SETD7 [KO:K11431] [EC:2.1.1.364]
116488293  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
116495102  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
116491373  SIRT1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
116495116  USP7; ubiquitin carboxyl-terminal hydrolase 7 [KO:K11838] [EC:3.4.19.12]
116489162  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
116495022  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
116491194  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
116495676  STK4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
116494460  IGF1; insulin-like growth factor I [KO:K05459]
116493472  IGF1R; insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
116489355  INS; insulin [KO:K04526]
116499030  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
116492767  IRS1; insulin receptor substrate 1 [KO:K16172]
116493009  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
116494470  IRS4; insulin receptor substrate 4 [KO:K07187]
116492299  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
116492415  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
116497623  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
116499089  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
116501170  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
116491758  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
116495306  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
116491240  CHUK; LOW QUALITY PROTEIN: inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
116499350  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
116491269  PTEN; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
116488009  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
116489712  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
116487835  SGK1; serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
116495655  SGK2; serine/threonine-protein kinase Sgk2 [KO:K13303] [EC:2.7.11.1]
116485553  serine/threonine-protein kinase Sgk3 isoform X1 [KO:K13304] [EC:2.7.11.1]
116501846  FOXO1; forkhead box protein O1 [KO:K07201]
116488152  FOXO3; forkhead box protein O3 [KO:K09408]
116494517  FOXO4; forkhead box protein O4 [KO:K12358]
116498137  FOXO6; forkhead box protein O6 [KO:K17847]
116487901  GRM1; metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
116493276  HOMER2; homer protein homolog 2 [KO:K15010]
116499090  HOMER3; homer protein homolog 3 [KO:K15010]
116501094  HOMER1; homer protein homolog 1 [KO:K15010]
116501384  homer protein homolog 1-like [KO:K15010]
116501951  CSNK1E; casein kinase I [KO:K08960] [EC:2.7.11.1]
116486491  IL6; interleukin-6 [KO:K05405]
116498884  IL10; interleukin-10 [KO:K05443]
116498455  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
116488496  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
116485864  EGFR; LOW QUALITY PROTEIN: epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
116496483  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
116487382  SOS1; son of sevenless homolog 1 [KO:K03099]
116489737  SOS2; son of sevenless homolog 2 [KO:K03099]
116490064  HRAS; GTPase HRas [KO:K02833]
116486326  KRAS; LOW QUALITY PROTEIN: GTPase KRas [KO:K07827]
116498924  NRAS; GTPase NRas [KO:K07828]
116492488  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
116493064  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
116493377  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
116499043  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116496022  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
116498684  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
116489834  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
116489843  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
116499925  CDK2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
116490369  FOXG1; forkhead box protein G1 [KO:K09385]
116493403  CCNB2; G2/mitotic-specific cyclin-B2 [KO:K21770]
116494608  CCNB3; G2/mitotic-specific cyclin-B3 isoform X1 [KO:K21771]
116490240  CCND1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
116494310  CCND2; LOW QUALITY PROTEIN: G1/S-specific cyclin-D2 [KO:K10151]
116489019  CCNG2; cyclin-G2 [KO:K10146]
116500967  cyclin-dependent kinase 4 inhibitor B-like [KO:K04685]
116500968  cyclin-dependent kinase 4 inhibitor B-like [KO:K04685]
116498917  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
116488021  cyclin-dependent kinase inhibitor 1-like [KO:K06625]
116501761  CDKN1B; LOW QUALITY PROTEIN: cyclin-dependent kinase inhibitor 1B [KO:K06624]
116493890  RBL2; retinoblastoma-like protein 2 [KO:K16332]
116495259  PLK1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
116500932  PLK2; serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
116491989  PLK3; serine/threonine-protein kinase PLK3 [KO:K08862] [EC:2.7.11.21]
116489299  PLK4; serine/threonine-protein kinase PLK4 [KO:K08863] [EC:2.7.11.21]
116492040  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
116500801  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
116491691  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
116487567  BCL2L11; bcl-2-like protein 11 [KO:K16341]
116492693  TNFSF10; tumor necrosis factor ligand superfamily member 10 isoform X1 [KO:K04721]
116492572  BCL6; B-cell lymphoma 6 protein [KO:K15618]
116491532  BNIP3; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [KO:K15464]
116501200  ATG12; ubiquitin-like protein ATG12 [KO:K08336]
116493823  GABARAPL2; gamma-aminobutyric acid receptor-associated protein-like 2 [KO:K08341]
116489669  GABARAPL1; gamma-aminobutyric acid receptor-associated protein-like 1 [KO:K08341]
116489734  CAT; catalase [KO:K03781] [EC:1.11.1.6]
116488022  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
116490910  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
116495886  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
116501629  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
116498544  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
116490989  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
116500510  IL7R; interleukin-7 receptor subunit alpha [KO:K05072]
116499049  KLF2; Krueppel-like factor 2 [KO:K17845]
116491864  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
116499217  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
116489673  RAG1; V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
116489675  RAG2; V(D)J recombination-activating protein 2 [KO:K10988]
116487847  FBXO25; F-box only protein 25 isoform X1 [KO:K10305]
116485846  FBXO32; F-box only protein 32 [KO:K10305]
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
aful00010  Glycolysis / Gluconeogenesis
aful00020  Citrate cycle (TCA cycle)
aful00190  Oxidative phosphorylation
aful04010  MAPK signaling pathway
aful04110  Cell cycle
aful04120  Ubiquitin mediated proteolysis
aful04140  Autophagy - animal
aful04210  Apoptosis
aful04350  TGF-beta signaling pathway
aful04910  Insulin signaling pathway
KO pathway
ko04068   
LinkDB

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