KEGG   PATHWAY: pki04068
Entry
pki04068                    Pathway                                
Name
FoxO signaling pathway - Paramormyrops kingsleyae
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
pki04068  FoxO signaling pathway
pki04068

Other DBs
GO: 0009267
Organism
Paramormyrops kingsleyae [GN:pki]
Gene
111832715  rbl2; retinoblastoma-like protein 2 [KO:K16332]
111833308  cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
111833435  [KO:K06276] [EC:2.7.11.1]
111833563  [KO:K04364]
111833605  [KO:K06623]
111833736  [KO:K04468] [EC:2.7.11.24]
111833948  [KO:K08341]
111834215  grb2; growth factor receptor-bound protein 2 [KO:K04364]
111834375  [KO:K05459]
111834606  [KO:K12358]
111834803  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
111834820  [KO:K04389]
111834821  pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
111834824  [KO:K13304] [EC:2.7.11.1]
111835157  [KO:K15010]
111835201  [KO:K13376]
111835223  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
111835495  ccnb1; G2/mitotic-specific cyclin-B1 [KO:K05868]
111835611  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
111835615  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
111835740  [KO:K03099]
111835825  [KO:K04371] [EC:2.7.11.24]
111835993  [KO:K04441] [EC:2.7.11.24]
111836028  irs1; insulin receptor substrate 1 [KO:K16172]
111836359  [KO:K12358]
111836364  [KO:K00922] [EC:2.7.1.153]
111836645  map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
111836657  stk11; serine/threonine-protein kinase STK11 [KO:K07298] [EC:2.7.11.1]
111836679  bcl6; B-cell lymphoma 6 protein isoform X1 [KO:K15618]
111836730  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
111836749  chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
111836806  [KO:K10151]
111836885  [KO:K11434] [EC:2.1.1.319]
111836934  [KO:K03099]
111836956  [KO:K08862] [EC:2.7.11.21]
111837095  [KO:K17848]
111837477  raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
111837545  [KO:K04411]
111837599  [KO:K15618]
111837776  foxg1; forkhead box protein G1 [KO:K09385]
111838013  [KO:K13375]
111838434  [KO:K04501]
111838854  [KO:K04456] [EC:2.7.11.1]
111838972  [KO:K04674] [EC:2.7.11.30]
111839152  [KO:K15464]
111839168  gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
111839186  [KO:K15010]
111839275  [KO:K04402]
111839280  [KO:K04402]
111839282  [KO:K04402]
111839330  plk2; serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
111839331  [KO:K07199]
111839372  [KO:K04440] [EC:2.7.11.24]
111839429  ccng2; cyclin-G2 [KO:K10146]
111839665  [KO:K13302] [EC:2.7.11.1]
111839670  [KO:K17847]
111840297  sgk2; serine/threonine-protein kinase Sgk2 [KO:K13303] [EC:2.7.11.1]
111840300  [KO:K04366] [EC:2.7.11.1]
111840348  [KO:K04441] [EC:2.7.11.24]
111840699  [KO:K02833]
111841036  [KO:K07199]
111841153  sod2; superoxide dismutase [Mn], mitochondrial isoform X1 [KO:K04564] [EC:1.15.1.1]
111841179  sgk1; serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
111841291  fbxo25; F-box only protein 25 isoform X1 [KO:K10305]
111841476  [KO:K13375]
111841535  [KO:K07187]
111841598  [KO:K04361] [EC:2.7.10.1]
111842029  [KO:K07199]
111842105  [KO:K05072]
111842164  skp2; S-phase kinase-associated protein 2 [KO:K03875]
111842404  [KO:K07827]
111842512  stat3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
111843121  [KO:K06625]
111843207  [KO:K04498] [EC:2.3.1.48]
111843667  [KO:K07187]
111844198  plk4; serine/threonine-protein kinase PLK4 isoform X1 [KO:K08863] [EC:2.7.11.21]
111844437  [KO:K13377]
111844555  [KO:K13302] [EC:2.7.11.1]
111844589  s1pr1; sphingosine 1-phosphate receptor 1 [KO:K04288]
111844594  gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
111844683  [KO:K06625]
111844715  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
111844902  atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
111844941  [KO:K15010]
111844972  ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
111845000  igf1r; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
111845136  [KO:K01084] [EC:3.1.3.9]
111845140  g6pc; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
111845232  [KO:K04498] [EC:2.3.1.48]
111845253  [KO:K08960] [EC:2.7.11.1]
111845255  fbxo32; F-box only protein 32 [KO:K10305]
111845541  plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
111845594  smad3; mothers against decapentaplegic homolog 3 [KO:K23605]
111845607  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
111845660  kras; GTPase KRas isoform X1 [KO:K07827]
111845666  [KO:K04441] [EC:2.7.11.24]
111845679  [KO:K04441] [EC:2.7.11.24]
111845734  [KO:K05087] [EC:2.7.10.1]
111845781  atg12; ubiquitin-like protein ATG12 [KO:K08336]
111845832  [KO:K07200]
111845900  [KO:K04361] [EC:2.7.10.1]
111846317  [KO:K07187]
111846388  [KO:K06276] [EC:2.7.11.1]
111846472  gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
111846569  igf1; LOW QUALITY PROTEIN: insulin-like growth factor I [KO:K05459]
111846694  [KO:K21770]
111846761  [KO:K15010]
111846921  il6; interleukin-6 [KO:K05405]
111847325  setd7; histone-lysine N-methyltransferase SETD7 [KO:K11431] [EC:2.1.1.364]
111847562  [KO:K04527] [EC:2.7.10.1]
111847593  [KO:K17845]
111847640  [KO:K02649]
111848076  gabarapl2; gamma-aminobutyric acid receptor-associated protein-like 2 [KO:K08341]
111848368  [KO:K04440] [EC:2.7.11.24]
111848387  bnip3; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [KO:K15464]
111848647  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
111848797  [KO:K17847]
111849137  [KO:K06631] [EC:2.7.11.21]
111849192  usp7; ubiquitin carboxyl-terminal hydrolase 7 isoform X1 [KO:K11838] [EC:3.4.19.12]
111849374  egf; pro-epidermal growth factor isoform X1 [KO:K04357]
111849713  cat; catalase [KO:K03781] [EC:1.11.1.6]
111849875  homer1; homer protein homolog 1 [KO:K15010]
111849957  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
111850356  mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
111850468  [KO:K04721]
111850628  [KO:K08341]
111850633  [KO:K04456] [EC:2.7.11.1]
111850649  [KO:K07201]
111850762  [KO:K04440] [EC:2.7.11.24]
111850821  ins; insulin isoform X1 [KO:K04526]
111851197  mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:2.3.2.27]
111851230  [KO:K10151]
111851322  [KO:K07201]
111851370  [KO:K11434] [EC:2.1.1.319]
111851387  [KO:K04674] [EC:2.7.11.30]
111851414  [KO:K07187]
111851556  tgfb2; transforming growth factor beta-2 [KO:K13376]
111851656  [KO:K07200]
111851863  [KO:K04503]
111851952  [KO:K08341]
111852322  bcl2l11; bcl-2-like protein 11 [KO:K16341]
111852346  [KO:K09385]
111852355  akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111852442  tgfb3; transforming growth factor beta-3 [KO:K13377]
111852585  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
111852751  [KO:K04721]
111852946  [KO:K06625]
111853200  [KO:K08960] [EC:2.7.11.1]
111853235  [KO:K04498] [EC:2.3.1.48]
111853393  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
111853445  [KO:K04721]
111853566  [KO:K00922] [EC:2.7.1.153]
111853698  pten; 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]
111853904  [KO:K04441] [EC:2.7.11.24]
111853914  nras; GTPase NRas [KO:K07828]
111854327  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
111854363  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
111854392  [KO:K04721]
111854443  il10; interleukin-10 [KO:K05443]
111854450  slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
111854483  [KO:K16172]
111854487  [KO:K08341]
111854723  cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
111855069  sirt1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
111855469  [KO:K04440] [EC:2.7.11.24]
111856019  [KO:K04692]
111856186  [KO:K04441] [EC:2.7.11.24]
111856339  [KO:K06623]
111856400  nlk; serine/threonine-protein kinase NLK isoform X1 [KO:K04468] [EC:2.7.11.24]
111856450  foxo3; forkhead box protein O3 [KO:K09408]
111856532  smad4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
111856594  [KO:K02649]
111856891  ccnb3; G2/mitotic-specific cyclin-B3 [KO:K21771]
111857200  [KO:K04388] [EC:2.7.11.30]
111857566  ccnd2; G1/S-specific cyclin-D2 isoform X1 [KO:K10151]
111857802  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
111857846  tgfbr2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
111857894  [KO:K09408]
111857957  [KO:K04603]
111858241  [KO:K10151]
111858357  prkag3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
111858596  [KO:K06624]
111858884  [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
111859259  [KO:K04685]
111859427  rag1; V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
111859495  rag2; V(D)J recombination-activating protein 2 [KO:K10988]
111859528  hras; GTPase HRas [KO:K02833]
111860229  [KO:K15010]
111860235  [KO:K04527] [EC:2.7.10.1]
111860329  s1pr4; sphingosine 1-phosphate receptor 4 [KO:K04293]
111860367  [KO:K04369] [EC:2.7.12.2]
111860386  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
111860418  [KO:K17845]
111860453  pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
111860540  cntd2; cyclin N-terminal domain-containing protein 2 [KO:K21770]
111860551  [KO:K09385]
111860582  [KO:K04498] [EC:2.3.1.48]
111860909  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
111860932  [KO:K16172]
111860965  akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
111861008  [KO:K04456] [EC:2.7.11.1]
111861148  sgk3; serine/threonine-protein kinase Sgk3 isoform X1 [KO:K13304] [EC:2.7.11.1]
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
pki00010  Glycolysis / Gluconeogenesis
pki00020  Citrate cycle (TCA cycle)
pki00190  Oxidative phosphorylation
pki04010  MAPK signaling pathway
pki04110  Cell cycle
pki04120  Ubiquitin mediated proteolysis
pki04140  Autophagy - animal
pki04210  Apoptosis
pki04350  TGF-beta signaling pathway
pki04910  Insulin signaling pathway
KO pathway
ko04068   

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