KEGG   PATHWAY: puc04068
Entry
puc04068                    Pathway                                
Name
FoxO signaling pathway - Panthera uncia (snow leopard)
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
puc04068  FoxO signaling pathway
puc04068

Other DBs
GO: 0009267
Organism
Panthera uncia (snow leopard) [GN:puc]
Gene
125915432  transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
125925521  transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
125908676  transforming growth factor beta-3 proprotein [KO:K13377]
125920171  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
125921386  TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
125914595  mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
125910090  mothers against decapentaplegic homolog 3 [KO:K23605]
125928796  serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
125935020  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
125912556  5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
125914114  5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
125913268  5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
125930500  5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
125919017  5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
125911173  5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
125927481  serine/threonine-protein kinase NLK [KO:K04468] [EC:2.7.11.24]
125934645  S-phase kinase-associated protein 2 [KO:K03875]
125919324  E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
125923703  histone-lysine N-methyltransferase SETD7 [KO:K11431] [EC:2.1.1.364]
125927249  CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
125920347  histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
125932669  NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
125927866  ubiquitin carboxyl-terminal hydrolase 7 isoform X1 [KO:K11838] [EC:3.4.19.12]
125926175  solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
125916877  mitogen-activated protein kinase 10-like [KO:K04440] [EC:2.7.11.24]
125917114  mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
125933328  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
125935352  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
125936555  serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
125919488  insulin-like growth factor I isoform X1 [KO:K05459]
125910252  insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
125911602  insulin [KO:K04526]
125928720  insulin receptor [KO:K04527] [EC:2.7.10.1]
125911117  insulin receptor substrate 1 [KO:K16172]
125933954  insulin receptor substrate 2 [KO:K07187]
125928238  insulin receptor substrate 1-like [KO:K17445]
125931893  insulin receptor substrate 4 isoform X1 [KO:K17446]
125921850  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
125913143  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
125921289  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
125913493  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
125935698  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
125929237  phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
125927192  3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
125932873  inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
125923306  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
125933550  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]
125915806  RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125909102  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
125925091  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125937990  serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
125936586  serine/threonine-protein kinase Sgk2 isoform X1 [KO:K13303] [EC:2.7.11.1]
125924846  serine/threonine-protein kinase Sgk3 isoform X1 [KO:K13304] [EC:2.7.11.1]
125933732  forkhead box protein O1 [KO:K07201]
125938770  forkhead box protein O3 [KO:K09408]
125931752  forkhead box protein O4 [KO:K12358]
125912720  forkhead box protein O6 [KO:K17847]
125938983  metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
125929268  homer protein homolog 3 isoform X1 [KO:K15010]
125910801  homer protein homolog 2 isoform X1 [KO:K15010]
125934940  homer protein homolog 1 [KO:K15010]
125919867  LOW QUALITY PROTEIN: arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2-like [KO:K17848]
125919606  casein kinase I isoform X1 [KO:K08960] [EC:2.7.11.1]
125930836  interleukin-6 [KO:K05405]
125916760  interleukin-10 isoform X1 [KO:K05443]
125916763  interleukin-10 isoform X1 [KO:K05443]
125926571  signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
125923024  pro-epidermal growth factor isoform X1 [KO:K04357]
125929783  epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
125926370  growth factor receptor-bound protein 2 [KO:K04364]
125909520  son of sevenless homolog 2 isoform X1 [KO:K03099]
125917913  son of sevenless homolog 1 [KO:K03099]
125917917  son of sevenless homolog 1 [KO:K03099]
125937753  GTPase HRas isoform X1 [KO:K02833]
125918906  GTPase KRas isoform X1 [KO:K07827]
125912218  GTPase NRas [KO:K07828]
125930477  serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
125930728  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
125931647  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
125910082  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
125918032  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
125918034  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
125914884  mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
125928028  mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
125937867  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
125937868  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
125919741  mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
125919935  mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
125919210  cyclin-dependent kinase 2 isoform X1 [KO:K02206] [EC:2.7.11.22]
125915338  protein arginine N-methyltransferase 1 isoform X1 [KO:K11434] [EC:2.1.1.319]
125909615  forkhead box protein G1 [KO:K09385]
125911501  G2/mitotic-specific cyclin-B1-like [KO:K05868]
125935703  G2/mitotic-specific cyclin-B1 [KO:K05868]
125937565  G2/mitotic-specific cyclin-B2-like [KO:K21770]
125910050  G2/mitotic-specific cyclin-B2 [KO:K21770]
125931684  G2/mitotic-specific cyclin-B3 isoform X1 [KO:K21771]
125930010  G1/S-specific cyclin-D1 [KO:K04503]
125917183  G1/S-specific cyclin-D2 [KO:K10151]
125918030  G1/S-specific cyclin-D2 [KO:K10151]
125922850  cyclin-G2 isoform X1 [KO:K10146]
125915304  cyclin-dependent kinase 4 inhibitor B isoform X1 [KO:K04685]
125930594  cyclin-dependent kinase 4 inhibitor D [KO:K06623]
125938307  cyclin-dependent kinase inhibitor 1 [KO:K06625]
125918841  cyclin-dependent kinase inhibitor 1B [KO:K06624]
125915346  retinoblastoma-like protein 2 isoform X1 [KO:K16332]
125927966  serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
125935658  serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
125913482  serine/threonine-protein kinase PLK3 isoform X1 [KO:K08862] [EC:2.7.11.21]
125923106  serine/threonine-protein kinase PLK4 [KO:K08863] [EC:2.7.11.21]
125929753  growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
125930526  growth arrest and DNA damage-inducible protein GADD45 beta isoform X1 [KO:K04402]
125912521  growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
125925158  tumor necrosis factor ligand superfamily member 6 [KO:K04389]
125937460  bcl-2-like protein 11 isoform X1 [KO:K16341]
125921880  tumor necrosis factor ligand superfamily member 10 [KO:K04721]
125921820  B-cell lymphoma 6 protein [KO:K15618]
125933052  BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [KO:K15464]
125935407  ubiquitin-like protein ATG12 isoform X1 [KO:K08336]
125916343  gamma-aminobutyric acid receptor-associated protein-like 2 [KO:K08341]
125927062  gamma-aminobutyric acid receptor-associated protein [KO:K08341]
125920114  gamma-aminobutyric acid receptor-associated protein-like 1 [KO:K08341]
125934840  catalase [KO:K03781] [EC:1.11.1.6]
125939025  superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
125917066  serine-protein kinase ATM-like [KO:K04728] [EC:2.7.11.1]
125917870  serine-protein kinase ATM-like [KO:K04728] [EC:2.7.11.1]
125909664  phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
125936463  phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
125926590  glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
125926619  glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
125911859  glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
125934650  interleukin-7 receptor subunit alpha [KO:K05072]
125929176  Krueppel-like factor 2 [KO:K17845]
125912336  sphingosine 1-phosphate receptor 1 [KO:K04288]
125930518  sphingosine 1-phosphate receptor 4 [KO:K04293]
125934490  V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
125934496  V(D)J recombination-activating protein 2 [KO:K10988]
125923507  F-box only protein 25 isoform X1 [KO:K10305]
125924424  F-box only protein 32 isoform X1 [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
puc00010  Glycolysis / Gluconeogenesis
puc00020  Citrate cycle (TCA cycle)
puc00190  Oxidative phosphorylation
puc04010  MAPK signaling pathway
puc04110  Cell cycle
puc04120  Ubiquitin mediated proteolysis
puc04140  Autophagy - animal
puc04151  PI3K-Akt signaling pathway
puc04210  Apoptosis
puc04350  TGF-beta signaling pathway
puc04630  JAK-STAT signaling pathway
puc04910  Insulin signaling pathway
KO pathway
ko04068   
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