KEGG   PATHWAY: mmu04068Help
Entry
mmu04068                    Pathway                                

Name
FoxO signaling pathway - Mus musculus (mouse)
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
mmu04068  FoxO signaling pathway
mmu04068

Ortholog table
Other DBs
GO: 0009267
Organism
Mus musculus (mouse) [GN:mmu]
Gene
21803  Tgfb1; transforming growth factor, beta 1 [KO:K13375]
21808  Tgfb2; transforming growth factor, beta 2 [KO:K13376]
21809  Tgfb3; transforming growth factor, beta 3 [KO:K13377]
21812  Tgfbr1; transforming growth factor, beta receptor I [KO:K04674] [EC:2.7.11.30]
21813  Tgfbr2; transforming growth factor, beta receptor II [KO:K04388] [EC:2.7.11.30]
17128  Smad4; SMAD family member 4 [KO:K04501]
17127  Smad3; SMAD family member 3 [KO:K23605]
20869  Stk11; serine/threonine kinase 11 [KO:K07298] [EC:2.7.11.1]
105787  Prkaa1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.11]
108079  Prkaa2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.11]
19079  Prkab1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
108097  Prkab2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
19082  Prkag1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
241113  Prkag3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
108099  Prkag2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
18099  Nlk; nemo like kinase [KO:K04468] [EC:2.7.11.24]
27401  Skp2; S-phase kinase-associated protein 2 (p45) [KO:K03875]
17246  Mdm2; transformed mouse 3T3 cell double minute 2 [KO:K06643] [EC:2.3.2.27]
73251  Setd7; SET domain containing (lysine methyltransferase) 7 [KO:K11431] [EC:2.1.1.354]
12914  Crebbp; CREB binding protein [KO:K04498] [EC:2.3.1.48]
328572  Ep300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
93759  Sirt1; sirtuin 1 [KO:K11411] [EC:2.3.1.286]
252870  Usp7; ubiquitin specific peptidase 7 [KO:K11838] [EC:3.4.19.12]
20528  Slc2a4; solute carrier family 2 (facilitated glucose transporter), member 4 [KO:K07191]
26419  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
26420  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
26414  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
58231  Stk4; serine/threonine kinase 4 [KO:K04411]
16000  Igf1; insulin-like growth factor 1 [KO:K05459]
16001  Igf1r; insulin-like growth factor I receptor [KO:K05087] [EC:2.7.10.1]
16334  Ins2; insulin II [KO:K04526]
16333  Ins1; insulin I [KO:K04526]
16337  Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
16367  Irs1; insulin receptor substrate 1 [KO:K16172]
384783  Irs2; insulin receptor substrate 2 [KO:K07187]
16369  Irs3; insulin receptor substrate 3 [KO:K17445]
16370  Irs4; insulin receptor substrate 4 [KO:K17446]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
18607  Pdpk1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
12675  Chuk; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
16150  Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:2.7.11.10]
19211  Pten; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
20393  Sgk1; serum/glucocorticoid regulated kinase 1 [KO:K13302] [EC:2.7.11.1]
27219  Sgk2; serum/glucocorticoid regulated kinase 2 [KO:K13303] [EC:2.7.11.1]
170755  Sgk3; serum/glucocorticoid regulated kinase 3 [KO:K13304] [EC:2.7.11.1]
56458  Foxo1; forkhead box O1 [KO:K07201]
56484  Foxo3; forkhead box O3 [KO:K09408]
54601  Foxo4; forkhead box O4 [KO:K12358]
329934  Foxo6; forkhead box O6 [KO:K17847]
14816  Grm1; glutamate receptor, metabotropic 1 [KO:K04603]
26557  Homer2; homer scaffolding protein 2 [KO:K15010]
26556  Homer1; homer scaffolding protein 1 [KO:K15010]
26558  Homer3; homer scaffolding protein 3 [KO:K15010]
216439  Agap2; ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 [KO:K17848]
27373  Csnk1e; casein kinase 1, epsilon [KO:K08960] [EC:2.7.11.1]
16193  Il6; interleukin 6 [KO:K05405]
16153  Il10; interleukin 10 [KO:K05443]
20848  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
13645  Egf; epidermal growth factor [KO:K04357]
13649  Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
14784  Grb2; growth factor receptor bound protein 2 [KO:K04364]
20662  Sos1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
20663  Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
109880  Braf; Braf transforming gene [KO:K04365] [EC:2.7.11.1]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]
11836  Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
26416  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
19094  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
29857  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
26415  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
12566  Cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
15469  Prmt1; protein arginine N-methyltransferase 1 [KO:K11434] [EC:2.1.1.319]
15228  Foxg1; forkhead box G1 [KO:K09385]
268697  Ccnb1; cyclin B1 [KO:K05868]
12442  Ccnb2; cyclin B2 [KO:K21770]
209091  Ccnb3; cyclin B3 [KO:K21771]
12443  Ccnd1; cyclin D1 [KO:K04503]
12444  Ccnd2; cyclin D2 [KO:K10151]
12452  Ccng2; cyclin G2 [KO:K10146]
12579  Cdkn2b; cyclin dependent kinase inhibitor 2B [KO:K04685]
12581  Cdkn2d; cyclin dependent kinase inhibitor 2D [KO:K06623]
12575  Cdkn1a; cyclin-dependent kinase inhibitor 1A (P21) [KO:K06625]
12576  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
19651  Rbl2; RB transcriptional corepressor like 2 [KO:K16332]
18817  Plk1; polo like kinase 1 [KO:K06631] [EC:2.7.11.21]
20620  Plk2; polo like kinase 2 [KO:K08861] [EC:2.7.11.21]
12795  Plk3; polo like kinase 3 [KO:K08862] [EC:2.7.11.21]
20873  Plk4; polo like kinase 4 [KO:K08863] [EC:2.7.11.21]
13197  Gadd45a; growth arrest and DNA-damage-inducible 45 alpha [KO:K04402]
17873  Gadd45b; growth arrest and DNA-damage-inducible 45 beta [KO:K04402]
23882  Gadd45g; growth arrest and DNA-damage-inducible 45 gamma [KO:K04402]
14103  Fasl; Fas ligand (TNF superfamily, member 6) [KO:K04389]
12125  Bcl2l11; BCL2-like 11 (apoptosis facilitator) [KO:K16341]
22035  Tnfsf10; tumor necrosis factor (ligand) superfamily, member 10 [KO:K04721]
12053  Bcl6; B cell leukemia/lymphoma 6 [KO:K15618]
12176  Bnip3; BCL2/adenovirus E1B interacting protein 3 [KO:K15464]
67526  Atg12; autophagy related 12 [KO:K08336]
57436  Gabarapl1; gamma-aminobutyric acid (GABA) A receptor-associated protein-like 1 [KO:K08341]
56486  Gabarap; gamma-aminobutyric acid receptor associated protein [KO:K08341]
93739  Gabarapl2; gamma-aminobutyric acid (GABA) A receptor-associated protein-like 2 [KO:K08341]
12359  Cat; catalase [KO:K03781] [EC:1.11.1.6]
20656  Sod2; superoxide dismutase 2, mitochondrial [KO:K04564] [EC:1.15.1.1]
11920  Atm; ataxia telangiectasia mutated [KO:K04728] [EC:2.7.11.1]
18534  Pck1; phosphoenolpyruvate carboxykinase 1, cytosolic [KO:K01596] [EC:4.1.1.32]
74551  Pck2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:4.1.1.32]
14377  G6pc; glucose-6-phosphatase, catalytic [KO:K01084] [EC:3.1.3.9]
14378  G6pc2; glucose-6-phosphatase, catalytic, 2 [KO:K01084] [EC:3.1.3.9]
68401  G6pc3; glucose 6 phosphatase, catalytic, 3 [KO:K01084] [EC:3.1.3.9]
16197  Il7r; interleukin 7 receptor [KO:K05072]
16598  Klf2; Kruppel-like factor 2 (lung) [KO:K17845]
13609  S1pr1; sphingosine-1-phosphate receptor 1 [KO:K04288]
13611  S1pr4; sphingosine-1-phosphate receptor 4 [KO:K04293]
19373  Rag1; recombination activating 1 [KO:K10628] [EC:2.3.2.27]
19374  Rag2; recombination activating gene 2 [KO:K10988]
66822  Fbxo25; F-box protein 25 [KO:K10305]
67731  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)
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
mmu00010  Glycolysis / Gluconeogenesis
mmu00020  Citrate cycle (TCA cycle)
mmu00190  Oxidative phosphorylation
mmu04010  MAPK signaling pathway
mmu04110  Cell cycle
mmu04120  Ubiquitin mediated proteolysis
mmu04140  Autophagy - animal
mmu04151  PI3K-Akt signaling pathway
mmu04210  Apoptosis
mmu04350  TGF-beta signaling pathway
mmu04630  JAK-STAT signaling pathway
mmu04910  Insulin signaling pathway
KO pathway
ko04068   

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