KEGG   PATHWAY: pcad04068
Entry
pcad04068                   Pathway                                
Name
FoxO signaling pathway - Physeter catodon (sperm whale)
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
pcad04068  FoxO signaling pathway
pcad04068

Other DBs
GO: 0009267
Organism
Physeter catodon (sperm whale) [GN:pcad]
Gene
102975643  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
102993033  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
102977345  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
102978050  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
102995949  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
102986517  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
102989819  SMAD3; mothers against decapentaplegic homolog 3 isoform X2 [KO:K23605]
102991940  STK11; serine/threonine-protein kinase STK11 isoform X5 [KO:K07298] [EC:2.7.11.1]
102987031  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102991456  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102995296  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
102993617  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102982412  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
102993441  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
102990899  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X5 [KO:K07200]
102989137  NLK; serine/threonine-protein kinase NLK isoform X2 [KO:K04468] [EC:2.7.11.24]
102991021  S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
102973239  S-phase kinase-associated protein 2-like [KO:K03875]
102980125  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
102986025  SETD7; histone-lysine N-methyltransferase SETD7 isoform X3 [KO:K11431] [EC:2.1.1.364]
114485354  CREB-binding protein [KO:K04498] [EC:2.3.1.48]
102983478  EP300; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
102991594  CREBBP; CREB-binding protein [KO:K04498] [EC:2.3.1.48]
102993364  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X3 [KO:K11411] [EC:2.3.1.286]
102996770  USP7; ubiquitin carboxyl-terminal hydrolase 7 [KO:K11838] [EC:3.4.19.12]
102996407  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
102996353  MAPK8; mitogen-activated protein kinase 8 isoform X3 [KO:K04440] [EC:2.7.11.24]
102977417  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102984741  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
102979937  STK4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
102990550  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
102977826  IGF1R; insulin-like growth factor 1 receptor isoform X3 [KO:K05087] [EC:2.7.10.1]
112062628  INS; insulin [KO:K04526]
102992290  IRS1; insulin receptor substrate 1 [KO:K16172]
112064787  IRS2; insulin receptor substrate 2 isoform X2 [KO:K07187]
102982336  LOW QUALITY PROTEIN: insulin receptor substrate 1-like [KO:K17445]
102989579  IRS4; insulin receptor substrate 4 [KO:K17446]
102986098  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102978952  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102977108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102975555  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102991779  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102991192  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102977392  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
102977668  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X2 [KO:K04467] [EC:2.7.11.10]
102976706  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102984551  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X2 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
102981524  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102976971  AKT3; RAC-gamma serine/threonine-protein kinase isoform X3 [KO:K04456] [EC:2.7.11.1]
102990087  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112065033  LOW QUALITY PROTEIN: serine/threonine-protein kinase Sgk1-like [KO:K13302] [EC:2.7.11.1]
102987463  SGK1; serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
102992091  SGK2; serine/threonine-protein kinase Sgk2 [KO:K13303] [EC:2.7.11.1]
102982053  SGK3; serine/threonine-protein kinase Sgk3 isoform X1 [KO:K13304] [EC:2.7.11.1]
102980680  FOXO1; forkhead box protein O1 [KO:K07201]
102980970  FOXO3; forkhead box protein O3 isoform X2 [KO:K09408]
102980189  FOXO4; forkhead box protein O4 [KO:K12358]
102978119  FOXO6; forkhead box protein O6 [KO:K17847]
102978027  GRM1; metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
102990875  HOMER1; homer protein homolog 1 isoform X2 [KO:K15010]
102976543  HOMER3; homer protein homolog 3 [KO:K15010]
102974597  HOMER2; homer protein homolog 2 isoform X2 [KO:K15010]
102986096  AGAP2; arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 isoform X1 [KO:K17848]
102981665  CSNK1E; casein kinase I isoform X1 [KO:K08960] [EC:2.7.11.1]
102980126  IL6; interleukin-6 [KO:K05405]
102973585  IL10; interleukin-10 [KO:K05443]
102976764  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
102977431  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
102975467  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
114483947  growth factor receptor-bound protein 2 [KO:K04364]
102991639  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102981677  LOW QUALITY PROTEIN: son of sevenless homolog 2-like [KO:K03099]
102978925  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
102994715  HRAS; GTPase HRas isoform X2 [KO:K02833]
102977125  KRAS; GTPase KRas isoform X1 [KO:K07827]
102992439  LOW QUALITY PROTEIN: GTPase NRas-like [KO:K07828]
102982641  NRAS; LOW QUALITY PROTEIN: GTPase NRas [KO:K07828]
102986916  BRAF; serine/threonine-protein kinase B-raf isoform X3 [KO:K04365] [EC:2.7.11.1]
102987866  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
102974274  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
102992191  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102994150  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102984305  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102989074  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102977531  MAPK12; mitogen-activated protein kinase 12 isoform X3 [KO:K04441] [EC:2.7.11.24]
102989111  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102990302  MAPK13; mitogen-activated protein kinase 13 isoform X3 [KO:K04441] [EC:2.7.11.24]
102977994  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
102995000  CDK2; cyclin-dependent kinase 2 isoform X1 [KO:K02206] [EC:2.7.11.22]
102987597  PRMT1; protein arginine N-methyltransferase 1 isoform X1 [KO:K11434] [EC:2.1.1.319]
102989144  FOXG1; forkhead box protein G1 [KO:K09385]
102980273  CCNB1; G2/mitotic-specific cyclin-B1 [KO:K05868]
112064309  LOW QUALITY PROTEIN: G2/mitotic-specific cyclin-B1-like [KO:K05868]
102995973  LOW QUALITY PROTEIN: G2/mitotic-specific cyclin-B1-like [KO:K05868]
102975742  CCNB2; G2/mitotic-specific cyclin-B2 isoform X1 [KO:K21770]
102991290  G2/mitotic-specific cyclin-B2-like [KO:K21770]
102993390  G2/mitotic-specific cyclin-B3-like [KO:K21771]
102993935  CCNB3; LOW QUALITY PROTEIN: G2/mitotic-specific cyclin-B3 [KO:K21771]
112062967  LOW QUALITY PROTEIN: G2/mitotic-specific cyclin-B3-like [KO:K21771]
102996914  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
102981679  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
102977430  CCNG2; cyclin-G2 isoform X1 [KO:K10146]
102979656  cyclin-dependent kinase 4 inhibitor B [KO:K04685]
102987488  CDKN2D; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
102995437  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
102981902  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
102976320  RBL2; retinoblastoma-like protein 2 [KO:K16332]
102974840  PLK1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
102992172  PLK2; serine/threonine-protein kinase PLK2 isoform X2 [KO:K08861] [EC:2.7.11.21]
102990542  PLK3; serine/threonine-protein kinase PLK3 [KO:K08862] [EC:2.7.11.21]
102992160  PLK4; serine/threonine-protein kinase PLK4 isoform X1 [KO:K08863] [EC:2.7.11.21]
102974987  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
102993403  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
102986518  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
102979864  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
102976319  BCL2L11; bcl-2-like protein 11 isoform X1 [KO:K16341]
102992913  TNFSF10; tumor necrosis factor ligand superfamily member 10 isoform X1 [KO:K04721]
114483874  B-cell lymphoma 6 protein [KO:K15618]
102975594  BNIP3; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 isoform X1 [KO:K15464]
102980295  ATG12; ubiquitin-like protein ATG12 [KO:K08336]
102996693  GABARAP; gamma-aminobutyric acid receptor-associated protein [KO:K08341]
102994264  GABARAPL2; gamma-aminobutyric acid receptor-associated protein-like 2 isoform X1 [KO:K08341]
102973481  GABARAPL1; gamma-aminobutyric acid receptor-associated protein-like 1 isoform X1 [KO:K08341]
102985917  CAT; catalase isoform X2 [KO:K03781] [EC:1.11.1.6]
102981093  SOD2; superoxide dismutase [Mn], mitochondrial isoform X1 [KO:K04564] [EC:1.15.1.1]
102975752  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
102997033  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
102990592  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X2 [KO:K01596] [EC:4.1.1.32]
102996909  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102976416  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102990138  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
102992873  IL7R; interleukin-7 receptor subunit alpha [KO:K05072]
112067634  KLF2; Krueppel-like factor 2 [KO:K17845]
102996942  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
102995336  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
102992940  RAG1; V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
102991832  RAG2; V(D)J recombination-activating protein 2 [KO:K10988]
102994226  FBXO32; F-box only protein 32 [KO:K10305]
102978928  FBXO25; F-box only protein 25 isoform X3 [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
pcad00010  Glycolysis / Gluconeogenesis
pcad00020  Citrate cycle (TCA cycle)
pcad00190  Oxidative phosphorylation
pcad04010  MAPK signaling pathway
pcad04110  Cell cycle
pcad04120  Ubiquitin mediated proteolysis
pcad04140  Autophagy - animal
pcad04151  PI3K-Akt signaling pathway
pcad04210  Apoptosis
pcad04350  TGF-beta signaling pathway
pcad04630  JAK-STAT signaling pathway
pcad04910  Insulin signaling pathway
KO pathway
ko04068   
LinkDB

DBGET integrated database retrieval system