KEGG   PATHWAY: mthb04068
Entry
mthb04068                   Pathway                                
Name
FoxO signaling pathway - Macaca thibetana thibetana (Pere David's macaque)
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
mthb04068  FoxO signaling pathway
mthb04068

Other DBs
GO: 0009267
Organism
Macaca thibetana thibetana (Pere David's macaque) [GN:mthb]
Gene
126941768  transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
126948495  transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
126959539  transforming growth factor beta-3 proprotein [KO:K13377]
126938052  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
126946646  TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
126941313  mothers against decapentaplegic homolog 4 [KO:K04501]
126957972  mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
126942954  serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
126956450  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
126932625  5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
126930676  5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
126932421  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
126930179  5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
126932994  5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
126951597  5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
126938723  serine/threonine-protein kinase NLK [KO:K04468] [EC:2.7.11.24]
126957088  S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
126931704  E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
126954611  histone-lysine N-methyltransferase SETD7 isoform X1 [KO:K11431] [EC:2.1.1.364]
126963565  histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
126944569  CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
126962950  NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
126944593  ubiquitin carboxyl-terminal hydrolase 7 isoform X1 [KO:K11838] [EC:3.4.19.12]
126939701  solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
126954697  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
126963142  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
126956917  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
126963827  serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
126931779  insulin-like growth factor I isoform X1 [KO:K05459]
126959327  insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
126935873  insulin isoform X1 [KO:K04526]
126942469  insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
126932885  insulin receptor substrate 1 [KO:K16172]
126940155  insulin receptor substrate 2 [KO:K07187]
126945702  insulin receptor substrate 4 [KO:K17446]
126947557  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
126952893  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
126948170  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
126961422  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
126956531  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
126942202  phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
126944637  3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
126944712  LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1-like [KO:K06276] [EC:2.7.11.1]
126963067  inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
126960750  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
126963336  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]
126943096  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
126959416  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126942032  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126952874  serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
126963835  serine/threonine-protein kinase Sgk2 isoform X1 [KO:K13303] [EC:2.7.11.1]
126961505  serine/threonine-protein kinase Sgk3 isoform X1 [KO:K13304] [EC:2.7.11.1]
126940335  forkhead box protein O1 [KO:K07201]
126953626  forkhead box protein O3 [KO:K09408]
126946179  forkhead box protein O4 [KO:K12358]
126959537  forkhead box protein O6 [KO:K17847]
126952576  metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
126957597  homer protein homolog 1 isoform X1 [KO:K15010]
126958069  homer protein homolog 2 isoform X1 [KO:K15010]
126942292  homer protein homolog 3 isoform X1 [KO:K15010]
126930359  arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 isoform X1 [KO:K17848]
126963728  casein kinase I isoform X1 [KO:K08960] [EC:2.7.11.1]
126950025  interleukin-6 isoform X1 [KO:K05405]
126949419  interleukin-10 isoform X1 [KO:K05443]
126938424  signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
126954925  pro-epidermal growth factor isoform X1 [KO:K04357]
126950202  epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
126939255  growth factor receptor-bound protein 2 [KO:K04364]
126933534  son of sevenless homolog 1 isoform X1 [KO:K03099]
126958499  son of sevenless homolog 2 isoform X1 [KO:K03099]
126935869  GTPase HRas isoform X1 [KO:K02833]
126931572  GTPase KRas [KO:K07827]
126930824  GTPase NRas [KO:K07828]
126949633  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
126949054  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
126945567  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
126957976  dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
126942673  dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
126944456  mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
126929669  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
126952773  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
126952775  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
126929437  mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
126929447  mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
126931216  cyclin-dependent kinase 2 isoform X1 [KO:K02206] [EC:2.7.11.22]
126956349  LOW QUALITY PROTEIN: protein arginine N-methyltransferase 1-like [KO:K11434] [EC:2.1.1.319]
126959388  forkhead box protein G1 [KO:K09385]
126956539  G2/mitotic-specific cyclin-B1 [KO:K05868]
126958476  G2/mitotic-specific cyclin-B2 [KO:K21770]
126946478  G2/mitotic-specific cyclin-B3 isoform X1 [KO:K21771]
126935963  G1/S-specific cyclin-D1 [KO:K04503]
126931745  G1/S-specific cyclin-D2 [KO:K10151]
126954867  cyclin-G2 [KO:K10146]
126937616  cyclin-dependent kinase 4 inhibitor B [KO:K04685]
126942828  cyclin-dependent kinase 4 inhibitor D [KO:K06623]
126952813  cyclin-dependent kinase inhibitor 1 [KO:K06625]
126930782  cyclin-dependent kinase inhibitor 1B [KO:K06624]
126944978  retinoblastoma-like protein 2 isoform X1 [KO:K16332]
126944390  serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
126956212  serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
126959449  serine/threonine-protein kinase PLK3 [KO:K08862] [EC:2.7.11.21]
126954362  serine/threonine-protein kinase PLK4 isoform X1 [KO:K08863] [EC:2.7.11.21]
126942832  growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
126937334  growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
126939469  growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
126941397  tumor necrosis factor ligand superfamily member 6 [KO:K04389]
126933423  bcl-2-like protein 11 isoform X1 [KO:K16341]
126948360  tumor necrosis factor ligand superfamily member 10 [KO:K04721]
126948040  B-cell lymphoma 6 protein isoform X1 [KO:K15618]
126963312  BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [KO:K15464]
126956258  ubiquitin-like protein ATG12 [KO:K08336]
126930013  gamma-aminobutyric acid receptor-associated protein-like 1 [KO:K08341]
126943775  gamma-aminobutyric acid receptor-associated protein-like 2 [KO:K08341]
126934131  gamma-aminobutyric acid receptor-associated protein-like [KO:K08341]
126939812  gamma-aminobutyric acid receptor-associated protein [KO:K08341]
126962802  protein DEPP1 isoform X1 [KO:K27679]
126936228  catalase [KO:K03781] [EC:1.11.1.6]
126953664  superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
126936196  serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
126964013  phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
126958803  phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
126932332  glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
126938517  glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
126938691  glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
126956291  interleukin-7 receptor subunit alpha isoform X1 [KO:K05072]
126942293  Krueppel-like factor 2 [KO:K17845]
126929132  sphingosine 1-phosphate receptor 1 [KO:K04288]
126942680  sphingosine 1-phosphate receptor 4 [KO:K04293]
126936613  V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
126936614  V(D)J recombination-activating protein 2 [KO:K10988]
126960548  F-box only protein 25 isoform X1 [KO:K10305]
126960561  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
mthb00010  Glycolysis / Gluconeogenesis
mthb00020  Citrate cycle (TCA cycle)
mthb00190  Oxidative phosphorylation
mthb04010  MAPK signaling pathway
mthb04110  Cell cycle
mthb04120  Ubiquitin mediated proteolysis
mthb04140  Autophagy - animal
mthb04151  PI3K-Akt signaling pathway
mthb04210  Apoptosis
mthb04350  TGF-beta signaling pathway
mthb04630  JAK-STAT signaling pathway
mthb04910  Insulin signaling pathway
KO pathway
ko04068   
LinkDB

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