KEGG   PATHWAY: ko04068Help
ko04068                     Pathway                                

FoxO signaling pathway
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.
Environmental Information Processing; Signal transduction
BRITE hierarchy
Pathway map
ko04068  FoxO signaling pathway

Ortholog table
M00676  PI3K-Akt signaling [PATH:ko04068]
H01385  Rienhoff syndrome
H01456  Diabetic nephropathy
Other DBs
BSID: 924184
GO: 0009267
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04674  TGF-beta receptor type-1 [EC:]
K04388  TGF-beta receptor type-2 [EC:]
K04501  mothers against decapentaplegic homolog 4
K04500  mothers against decapentaplegic homolog 2/3
K07298  serine/threonine-protein kinase 11 [EC:]
K07198  5'-AMP-activated protein kinase, catalytic alpha subunit [EC:]
K07199  5'-AMP-activated protein kinase, regulatory beta subunit
K07200  5'-AMP-activated protein kinase, regulatory gamma subunit
K04468  nemo like kinase [EC:]
K03875  F-box and leucine-rich repeat protein 1 (S-phase kinase-associated protein 2)
K06643  E3 ubiquitin-protein ligase Mdm2 [EC:]
K11431  histone-lysine N-methyltransferase SETD7 [EC:]
K04498  E1A/CREB-binding protein [EC:]
K11411  NAD-dependent deacetylase sirtuin 1 [EC:3.5.1.-]
K11838  ubiquitin carboxyl-terminal hydrolase 7 [EC:]
K07191  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K04411  serine/threonine kinase 4
K05459  insulin-like growth factor 1
K05087  insulin-like growth factor 1 receptor [EC:]
K04526  insulin
K04527  insulin receptor [EC:]
K16172  insulin receptor substrate 1
K07187  insulin receptor substrate 2
K17445  insulin receptor substrate 3
K17446  insulin receptor substrate 4
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K06276  3-phosphoinositide dependent protein kinase-1 [EC:]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:]
K01110  phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:]
K04456  RAC serine/threonine-protein kinase [EC:]
K13302  serum/glucocorticoid-regulated kinase 1 [EC:]
K13303  serum/glucocorticoid-regulated kinase 2 [EC:]
K13304  serum/glucocorticoid-regulated kinase 3 [EC:]
K07201  forkhead box protein O1
K09408  forkhead box protein O3
K12358  forkhead box protein O4
K17847  forkhead box protein O6
K04603  metabotropic glutamate receptor 1
K15010  homer
K17848  Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2
K08960  casein kinase 1, epsilon [EC:]
K05405  interleukin 6
K05443  interleukin 10
K04692  signal transducer and activator of transcription 3
K04357  epidermal growth factor
K04361  epidermal growth factor receptor [EC:]
K04364  growth factor receptor-binding protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:]
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K04441  p38 MAP kinase [EC:]
K02206  cyclin-dependent kinase 2 [EC:]
K11434  type I protein arginine methyltransferase [EC:]
K09385  forkhead box protein G
K05868  G2/mitotic-specific cyclin-B1
K21770  G2/mitotic-specific cyclin-B2
K21771  G2/mitotic-specific cyclin-B3
K04503  G1/S-specific cyclin-D1
K10151  G1/S-specific cyclin-D2
K10146  cyclin G2
K04685  cyclin-dependent kinase inhibitor 2B
K06623  cyclin-dependent kinase inhibitor 2D
K06625  cyclin-dependent kinase inhibitor 1A
K06624  cyclin-dependent kinase inhibitor 1B
K16332  retinoblastoma-like protein 2
K06631  polo-like kinase 1 [EC:]
K08861  polo-like kinase 2 [EC:]
K08862  polo-like kinase 3 [EC:]
K08863  polo-like kinase 4 [EC:]
K04402  growth arrest and DNA-damage-inducible protein
K04389  tumor necrosis factor ligand superfamily member 6
K16341  Bcl-2-like protein 11
K04721  tumor necrosis factor ligand superfamily member 10
K15618  B-cell lymphoma 6 protein
K15464  BCL2/adenovirus E1B 19 kDa protein-interacting protein 3
K08336  ubiquitin-like protein ATG12
K08341  GABA(A) receptor-associated protein
K03781  catalase [EC:]
K04564  superoxide dismutase, Fe-Mn family [EC:]
K04728  serine-protein kinase ATM [EC:]
K01596  phosphoenolpyruvate carboxykinase (GTP) [EC:]
K01084  glucose-6-phosphatase [EC:]
K05072  interleukin 7 receptor
K17845  krueppel-like factor 2
K04288  sphingosine 1-phosphate receptor 1
K04293  sphingosine 1-phosphate receptor 4
K10628  V(D)J recombination-activating protein 1 [EC:]
K10988  recombination-activating protein 2
K10305  F-box protein 25/32
C00008  ADP
C00020  AMP
C00025  L-Glutamate
C00031  D-Glucose
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Glauser DA, Schlegel W
The emerging role of FOXO transcription factors in pancreatic beta cells.
J Endocrinol 193:195-207 (2007)
van der Horst A, Burgering BM
Stressing the role of FoxO proteins in lifespan and disease.
Nat Rev Mol Cell Biol 8:440-50 (2007)
Zhang X, Tang N, Hadden TJ, Rishi AK
Akt, FoxO and regulation of apoptosis.
Biochim Biophys Acta 1813:1978-86 (2011)
Eijkelenboom A, Burgering BM
FOXOs: signalling integrators for homeostasis maintenance.
Nat Rev Mol Cell Biol 14:83-97 (2013)
Daitoku H, Fukamizu A
FOXO transcription factors in the regulatory networks of longevity.
J Biochem 141:769-74 (2007)
Hedrick SM
The cunning little vixen: Foxo and the cycle of life and death.
Nat Immunol 10:1057-63 (2009)
Coffer PJ, Burgering BM
Forkhead-box transcription factors and their role in the immune system.
Nat Rev Immunol 4:889-99 (2004)
Ro SH, Liu D, Yeo H, Paik JH
FoxOs in neural stem cell fate decision.
Arch Biochem Biophys 534:55-63 (2013)
Maiese K, Chong ZZ, Shang YC
OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins.
Trends Mol Med 14:219-27 (2008)
Hagenbuchner J, Ausserlechner MJ
Mitochondria and FOXO3: breath or die.
Front Physiol 4:147 (2013)
Maiese K, Chong ZZ, Shang YC
"Sly as a FOXO": new paths with Forkhead signaling in the brain.
Curr Neurovasc Res 4:295-302 (2007)
Oh HM, Yu CR, Dambuza I, Marrero B, Egwuagu CE
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.
J Biol Chem 287:30436-43 (2012)
Huang H, Tindall DJ
Regulation of FOXO protein stability via ubiquitination and proteasome degradation.
Biochim Biophys Acta 1813:1961-4 (2011)
Greer EL, Brunet A
FOXO transcription factors at the interface between longevity and tumor suppression.
Oncogene 24:7410-25 (2005)
Seoane J, Le HV, Shen L, Anderson SA, Massague J
Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.
Cell 117:211-23 (2004)
Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y, Fukamizu A
Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.
Mol Cell 32:221-31 (2008)
van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM
FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP.
Nat Cell Biol 8:1064-73 (2006)
Zhang Y, Gan B, Liu D, Paik JH
FoxO family members in cancer.
Cancer Biol Ther 12:253-9 (2011)
Van Der Heide LP, Hoekman MF, Smidt MP
The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.
Biochem J 380:297-309 (2004)
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