KEGG   PATHWAY: gfr04068
Entry
gfr04068                    Pathway                                
Name
FoxO signaling pathway - Geospiza fortis (medium ground-finch)
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
gfr04068  FoxO signaling pathway
gfr04068

Other DBs
GO: 0009267
Organism
Geospiza fortis (medium ground-finch) [GN:gfr]
Gene
102037698  TGFB2; transforming growth factor beta 2 [KO:K13376]
102037028  TGFB3; transforming growth factor beta 3 [KO:K13377]
102037879  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
102044945  TGF-beta receptor type-2-like [KO:K04388] [EC:2.7.11.30]
102040558  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
102041942  mothers against decapentaplegic homolog 4-like [KO:K04501]
102043998  SMAD4; SMAD family member 4 [KO:K04501]
102040325  SMAD3; SMAD family member 3 [KO:K23605]
102045531  STK11; serine/threonine kinase 11 [KO:K07298] [EC:2.7.11.1]
102044941  5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
102038682  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.31]
102031783  PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.31]
102045511  PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
102039548  PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
102035320  PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
102042687  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
102033868  PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
102033058  NLK; nemo like kinase [KO:K04468] [EC:2.7.11.24]
102037500  SKP2; S-phase kinase associated protein 2 [KO:K03875]
102041787  MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27]
102040515  SETD7; SET domain containing lysine methyltransferase 7 [KO:K11431] [EC:2.1.1.364]
102038495  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
102043483  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
102038978  SIRT1; sirtuin 1 [KO:K11411] [EC:2.3.1.286]
102042457  USP7; ubiquitin specific peptidase 7 [KO:K11838] [EC:3.4.19.12]
102036009  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
102043776  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
102043222  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
102031383  STK4; serine/threonine kinase 4 [KO:K04411]
102032215  IGF1; insulin like growth factor 1 [KO:K05459]
102036037  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
102044590  INS; insulin [KO:K04526]
102036061  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
102044407  IRS1; insulin receptor substrate 1 [KO:K16172]
102041556  IRS4; insulin receptor substrate 4 [KO:K07187]
102044059  IRS2; insulin receptor substrate 2 [KO:K07187]
102042284  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
102040845  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
102040853  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
102039817  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
102032353  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
102035891  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
102032960  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102042264  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
102035648  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102039901  PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
102036745  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
102036791  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
102037330  SGK1; serum/glucocorticoid regulated kinase 1 [KO:K13302] [EC:2.7.11.1]
102031612  SGK2; SGK2, serine/threonine kinase 2 [KO:K13303] [EC:2.7.11.1]
102036813  SGK3; serine/threonine-protein kinase Sgk3 [KO:K13304] [EC:2.7.11.1]
102039410  FOXO1; forkhead box O1 [KO:K07201]
102034329  FOXO3; forkhead box O3 [KO:K09408]
102043730  FOXO4; forkhead box O4 [KO:K12358]
102031516  forkhead box protein O6-like [KO:K17847]
102038278  GRM1; glutamate metabotropic receptor 1 [KO:K04603]
102039525  HOMER2; homer scaffolding protein 2 [KO:K15010]
102044255  HOMER1; homer scaffolding protein 1 [KO:K15010]
102043767  HOMER3; homer scaffolding protein 3 [KO:K15010]
102035003  CSNK1E; casein kinase I isoform epsilon [KO:K08960] [EC:2.7.11.1]
102040265  IL6; interleukin 6 [KO:K05405]
102044259  IL10; interleukin 10 [KO:K05443]
102036392  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
102034269  EGF; epidermal growth factor [KO:K04357]
102045482  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102038068  GRB2; growth factor receptor bound protein 2 [KO:K04364]
102038427  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
102033314  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
102044012  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
102035876  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
102039955  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
102032961  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
102034977  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
102031727  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102041148  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102043401  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102043521  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
102038787  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
102044158  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
102042160  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
102037592  FOXG1; forkhead box G1 [KO:K09385]
102044449  CCNB2; cyclin B2 [KO:K21770]
102043430  CCNB3; G2/mitotic-specific cyclin-B3 [KO:K21771]
102042858  CCND1; cyclin D1 [KO:K04503]
102034688  CCND2; cyclin D2 [KO:K10151]
102045099  CCNG2; cyclin G2 [KO:K10146]
102041135  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
102045566  CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]
102044028  RBL2; RB transcriptional corepressor like 2 [KO:K16332]
102042745  PLK1; polo like kinase 1 [KO:K06631] [EC:2.7.11.21]
102035739  PLK2; polo like kinase 2 [KO:K08861] [EC:2.7.11.21]
102037104  PLK3; polo like kinase 3 [KO:K08862] [EC:2.7.11.21]
102034868  PLK4; polo like kinase 4 [KO:K08863] [EC:2.7.11.21]
102045588  FASLG; Fas ligand [KO:K04389]
102042782  TNFSF10; tumor necrosis factor superfamily member 10 [KO:K04721]
102041209  BCL6; B-cell CLL/lymphoma 6 [KO:K15618]
102036777  BNIP3; BCL2 interacting protein 3 [KO:K15464]
106632024  BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like [KO:K15464]
102043479  GABARAPL2; GABA type A receptor associated protein like 2 [KO:K08341]
102039558  GABARAPL1; GABA type A receptor associated protein like 1 [KO:K08341]
102031847  CAT; catalase [KO:K03781] [EC:1.11.1.6]
102040279  SOD2; superoxide dismutase 2 [KO:K04564] [EC:1.15.1.1]
102035572  PCK1; phosphoenolpyruvate carboxykinase 1 [KO:K01596] [EC:4.1.1.32]
102043169  G6PC2; glucose-6-phosphatase catalytic subunit 2 [KO:K01084] [EC:3.1.3.9]
102041145  G6PC; glucose-6-phosphatase catalytic subunit [KO:K01084] [EC:3.1.3.9]
102033898  IL7R; interleukin 7 receptor [KO:K05072]
102032912  KLF2; Kruppel like factor 2 [KO:K17845]
102036533  S1PR1; sphingosine-1-phosphate receptor 1 [KO:K04288]
102033804  S1PR4; sphingosine-1-phosphate receptor 4 [KO:K04293]
102041505  RAG1; recombination activating 1 [KO:K10628] [EC:2.3.2.27]
102041336  RAG2; recombination activating 2 [KO:K10988]
102032001  FBXO32; F-box protein 32 [KO:K10305]
102040175  FBXO25; F-box protein 25 [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
gfr00010  Glycolysis / Gluconeogenesis
gfr00020  Citrate cycle (TCA cycle)
gfr00190  Oxidative phosphorylation
gfr04010  MAPK signaling pathway
gfr04110  Cell cycle
gfr04120  Ubiquitin mediated proteolysis
gfr04140  Autophagy - animal
gfr04210  Apoptosis
gfr04350  TGF-beta signaling pathway
gfr04910  Insulin signaling pathway
KO pathway
ko04068   
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