KEGG   PATHWAY: hsa04068Help
Entry
hsa04068                    Pathway                                

Name
FoxO signaling pathway - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
FoxO signaling pathway
hsa04068

All organismsOrtholog table
Disease
H01385  
Rienhoff syndrome
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
7040  
TGFB1; transforming growth factor, beta 1 [KO:K13375]
7042  
TGFB2; transforming growth factor, beta 2 [KO:K13376]
7043  
TGFB3; transforming growth factor, beta 3 [KO:K13377]
7046  
TGFBR1; transforming growth factor, beta receptor 1 [KO:K04674] [EC:2.7.11.30]
7048  
TGFBR2; transforming growth factor, beta receptor II (70/80kDa) [KO:K04388] [EC:2.7.11.30]
4089  
SMAD4; SMAD family member 4 [KO:K04501]
4087  
SMAD2; SMAD family member 2 [KO:K04500]
4088  
SMAD3; SMAD family member 3 [KO:K04500]
6794  
STK11; serine/threonine kinase 11 [KO:K07298]
5562  
PRKAA1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.11]
5563  
PRKAA2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.11]
5564  
PRKAB1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
5565  
PRKAB2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
5571  
PRKAG1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
53632  
PRKAG3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
51422  
PRKAG2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
51701  
NLK; nemo-like kinase [KO:K04468] [EC:2.7.11.24]
6502  
SKP2; S-phase kinase-associated protein 2, E3 ubiquitin protein ligase [KO:K03875]
4193  
MDM2; MDM2 proto-oncogene, E3 ubiquitin protein ligase [KO:K06643] [EC:6.3.2.19]
80854  
SETD7; SET domain containing (lysine methyltransferase) 7 [KO:K11431] [EC:2.1.1.43]
1387  
CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
2033  
EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
23411  
SIRT1; sirtuin 1 [KO:K11411] [EC:3.5.1.-]
7874  
USP7; ubiquitin specific peptidase 7 (herpes virus-associated) [KO:K11838] [EC:3.4.19.12]
6517  
SLC2A4; solute carrier family 2 (facilitated glucose transporter), member 4 [KO:K07191]
5599  
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
6789  
STK4; serine/threonine kinase 4 [KO:K04411]
3479  
IGF1; insulin-like growth factor 1 (somatomedin C) [KO:K05459]
3480  
IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
3630  
INS; insulin [KO:K04526]
3643  
INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
3667  
IRS1; insulin receptor substrate 1 [KO:K16172]
8660  
IRS2; insulin receptor substrate 2 [KO:K07187]
8471  
IRS4; insulin receptor substrate 4 [KO:K17446]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase, regulatory subunit 1 (alpha) [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
5170  
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
1147  
CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  
IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
5728  
PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.67 3.1.3.48 3.1.3.16]
207  
AKT1; v-akt murine thymoma viral oncogene homolog 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; v-akt murine thymoma viral oncogene homolog 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; v-akt murine thymoma viral oncogene homolog 3 [KO:K04456] [EC:2.7.11.1]
6446  
SGK1; serum/glucocorticoid regulated kinase 1 [KO:K13302] [EC:2.7.11.1]
10110  
SGK2; serum/glucocorticoid regulated kinase 2 [KO:K13303] [EC:2.7.11.1]
23678  
SGK3; serum/glucocorticoid regulated kinase family, member 3 [KO:K13304] [EC:2.7.11.1]
C8orf44-SGK3; C8orf44-SGK3 readthrough [KO:K13304] [EC:2.7.11.1]
2308  
FOXO1; forkhead box O1 [KO:K07201]
2309  
FOXO3; forkhead box O3 [KO:K09408]
4303  
FOXO4; forkhead box O4 [KO:K12358]
FOXO6; forkhead box O6 [KO:K17847]
2911  
GRM1; glutamate receptor, metabotropic 1 [KO:K04603]
9456  
HOMER1; homer homolog 1 (Drosophila) [KO:K15010]
9455  
HOMER2; homer homolog 2 (Drosophila) [KO:K15010]
9454  
HOMER3; homer homolog 3 (Drosophila) [KO:K15010]
116986  
AGAP2; ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 [KO:K17848]
1454  
CSNK1E; casein kinase 1, epsilon [KO:K08960] [EC:2.7.11.1]
CSNK1E; LOC400927-CSNK1E readthrough [KO:K08960] [EC:2.7.11.1]
3569  
IL6; interleukin 6 [KO:K05405]
3586  
IL10; interleukin 10 [KO:K05443]
6774  
STAT3; signal transducer and activator of transcription 3 (acute-phase response factor) [KO:K04692]
1950  
EGF; epidermal growth factor [KO:K04357]
1956  
EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2885  
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
6654  
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655  
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5600  
MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  
MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  
MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  
MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
1017  
CDK2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
3276  
PRMT1; protein arginine methyltransferase 1 [KO:K11434] [EC:2.1.1.-]
2290  
FOXG1; forkhead box G1 [KO:K09385]
891  
CCNB1; cyclin B1 [KO:K05868]
9133  
CCNB2; cyclin B2 [KO:K05868]
85417  
CCNB3; cyclin B3 [KO:K05868]
595  
CCND1; cyclin D1 [KO:K04503]
894  
CCND2; cyclin D2 [KO:K10151]
901  
CCNG2; cyclin G2 [KO:K10146]
1030  
CDKN2B; cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) [KO:K04685]
1032  
CDKN2D; cyclin-dependent kinase inhibitor 2D (p19, inhibits CDK4) [KO:K06623]
1026  
CDKN1A; cyclin-dependent kinase inhibitor 1A (p21, Cip1) [KO:K06625]
1027  
CDKN1B; cyclin-dependent kinase inhibitor 1B (p27, Kip1) [KO:K06624]
5934  
RBL2; retinoblastoma-like 2 [KO:K16332]
5347  
PLK1; polo-like kinase 1 [KO:K06631] [EC:2.7.11.21]
10769  
PLK2; polo-like kinase 2 [KO:K08861] [EC:2.7.11.21]
1263  
PLK3; polo-like kinase 3 [KO:K08862] [EC:2.7.11.21]
10733  
PLK4; polo-like kinase 4 [KO:K08863] [EC:2.7.11.21]
1647  
GADD45A; growth arrest and DNA-damage-inducible, alpha [KO:K04402]
4616  
GADD45B; growth arrest and DNA-damage-inducible, beta [KO:K04402]
10912  
GADD45G; growth arrest and DNA-damage-inducible, gamma [KO:K04402]
356  
FASLG; Fas ligand (TNF superfamily, member 6) [KO:K04389]
10018  
BCL2L11; BCL2-like 11 (apoptosis facilitator) [KO:K16341]
8743  
TNFSF10; tumor necrosis factor (ligand) superfamily, member 10 [KO:K04721]
604  
BCL6; B-cell CLL/lymphoma 6 [KO:K15618]
664  
BNIP3; BCL2/adenovirus E1B 19kDa interacting protein 3 [KO:K15464]
9140  
ATG12; autophagy related 12 [KO:K08336]
11337  
GABARAP; GABA(A) receptor-associated protein [KO:K08341]
23710  
GABARAPL1; GABA(A) receptor-associated protein like 1 [KO:K08341]
11345  
GABARAPL2; GABA(A) receptor-associated protein-like 2 [KO:K08341]
847  
CAT; catalase [KO:K03781] [EC:1.11.1.6]
6648  
SOD2; superoxide dismutase 2, mitochondrial [KO:K04564] [EC:1.15.1.1]
472  
ATM; ATM serine/threonine kinase [KO:K04728] [EC:2.7.11.1]
5105  
PCK1; phosphoenolpyruvate carboxykinase 1 (soluble) [KO:K01596] [EC:4.1.1.32]
5106  
PCK2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:4.1.1.32]
2538  
G6PC; glucose-6-phosphatase, catalytic subunit [KO:K01084] [EC:3.1.3.9]
57818  
G6PC2; glucose-6-phosphatase, catalytic, 2 [KO:K01084] [EC:3.1.3.9]
92579  
G6PC3; glucose 6 phosphatase, catalytic, 3 [KO:K01084] [EC:3.1.3.9]
3575  
IL7R; interleukin 7 receptor [KO:K05072]
10365  
KLF2; Kruppel-like factor 2 [KO:K17845]
1901  
S1PR1; sphingosine-1-phosphate receptor 1 [KO:K04288]
8698  
S1PR4; sphingosine-1-phosphate receptor 4 [KO:K04293]
5896  
RAG1; recombination activating gene 1 [KO:K10628] [EC:6.3.2.19]
5897  
RAG2; recombination activating gene 2 [KO:K10988]
26260  
FBXO25; F-box protein 25 [KO:K10305]
114907  
FBXO32; F-box 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)
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)
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)
Reference
  Authors
Eijkelenboom A, Burgering BM
  Title
FOXOs: signalling integrators for homeostasis maintenance.
  Journal
Nat Rev Mol Cell Biol 14:83-97 (2013)
Reference
  Authors
Daitoku H, Fukamizu A
  Title
FOXO transcription factors in the regulatory networks of longevity.
  Journal
J Biochem 141:769-74 (2007)
Reference
  Authors
Hedrick SM
  Title
The cunning little vixen: Foxo and the cycle of life and death.
  Journal
Nat Immunol 10:1057-63 (2009)
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)
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)
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)
Reference
  Authors
Hagenbuchner J, Ausserlechner MJ
  Title
Mitochondria and FOXO3: breath or die.
  Journal
Front Physiol 4:147 (2013)
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)
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)
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)
Reference
  Authors
Greer EL, Brunet A
  Title
FOXO transcription factors at the interface between longevity and tumor suppression.
  Journal
Oncogene 24:7410-25 (2005)
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)
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)
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)
Reference
  Authors
Zhang Y, Gan B, Liu D, Paik JH
  Title
FoxO family members in cancer.
  Journal
Cancer Biol Ther 12:253-9 (2011)
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)
KO pathway
 

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