KEGG   PATHWAY: mpuf04068
Entry
mpuf04068                   Pathway                                
Name
FoxO signaling pathway - Mustela putorius furo (domestic ferret)
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
mpuf04068  FoxO signaling pathway
mpuf04068

Other DBs
GO: 0009267
Organism
Mustela putorius furo (domestic ferret) [GN:mpuf]
Gene
101670064  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
101670127  TGFB1; transforming growth factor beta-1 isoform X1 [KO:K13375]
101670335  CCNB2; G2/mitotic-specific cyclin-B2 [KO:K21770]
101670573  RBL2; retinoblastoma-like protein 2 isoform X1 [KO:K16332]
101670627  FOXG1; forkhead box protein G1 [KO:K09385]
101670844  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
101671066  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
101671073  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101671091  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
101671232  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
101671264  [KO:K17445]
101671422  CCNB3; G2/mitotic-specific cyclin-B3 isoform X1 [KO:K21771]
101671465  IL6; interleukin-6 [KO:K05405]
101671970  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
101672072  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101672145  IL10; interleukin-10 [KO:K05443]
101672227  AGAP2; arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 isoform X1 [KO:K17848]
101672560  PLK3; serine/threonine-protein kinase PLK3 isoform X2 [KO:K08862] [EC:2.7.11.21]
101672817  ATG12; ubiquitin-like protein ATG12 [KO:K08336]
101672835  CDKN2B; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
101672974  USP7; ubiquitin carboxyl-terminal hydrolase 7 isoform X2 [KO:K11838] [EC:3.4.19.12]
101673428  ATM; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
101673972  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
101674139  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
101674418  PLK1; serine/threonine-protein kinase PLK1 isoform X1 [KO:K06631] [EC:2.7.11.21]
101674804  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101675075  [KO:K13304] [EC:2.7.11.1]
101675099  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
101675328  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
101675498  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
101675535  GABARAP; gamma-aminobutyric acid receptor-associated protein [KO:K08341]
101675563  BCL6; B-cell lymphoma 6 protein [KO:K15618]
101675757  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101675806  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
101675892  CDK2; cyclin-dependent kinase 2 isoform X1 [KO:K02206] [EC:2.7.11.22]
101675924  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
101676423  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101676567  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101676895  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101677072  INSR; insulin receptor isoform X2 [KO:K04527] [EC:2.7.10.1]
101677182  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
101677390  STK11; serine/threonine-protein kinase STK11 [KO:K07298] [EC:2.7.11.1]
101677636  CDKN2D; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
101677713  FBXO32; F-box only protein 32 [KO:K10305]
101677980  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
101678248  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
101678368  FOXO4; forkhead box protein O4 [KO:K12358]
101678400  TGFB3; transforming growth factor beta-3 [KO:K13377]
101678505  SGK1; serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
101678743  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101678830  SOD2; superoxide dismutase [Mn], mitochondrial isoform X1 [KO:K04564] [EC:1.15.1.1]
101679455  BNIP3; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [KO:K15464]
101679748  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101679776  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101679858  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
101680131  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
101680232  SGK2; serine/threonine-protein kinase Sgk2 [KO:K13303] [EC:2.7.11.1]
101680399  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101680658  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
101680922  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
101680975  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
101681230  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
101681333  KRAS; GTPase KRas isoform X3 [KO:K07827]
101681349  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101681355  HRAS; GTPase HRas isoform X1 [KO:K02833]
101681508  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
101681650  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101681761  HOMER1; homer protein homolog 1 [KO:K15010]
101681860  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
101681935  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
101682593  CAT; catalase [KO:K03781] [EC:1.11.1.6]
101682622  SKP2; S-phase kinase-associated protein 2 [KO:K03875]
101682951  EGF; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
101683038  NRAS; GTPase NRas [KO:K07828]
101683116  CCNB1; LOW QUALITY PROTEIN: G2/mitotic-specific cyclin-B1 [KO:K05868]
101683234  BCL2L11; bcl-2-like protein 11 isoform X6 [KO:K16341]
101683594  [KO:K02649]
101683710  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101684009  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101684130  FOXO3; forkhead box protein O3 [KO:K09408]
101684443  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101684525  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
101684695  IRS1; insulin receptor substrate 1 [KO:K16172]
101684727  KLF2; Krueppel-like factor 2 [KO:K17845]
101684873  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
101684928  INS; insulin [KO:K04526]
101685196  SIRT1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
101685370  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101685824  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
101686271  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
101686489  IL7R; interleukin-7 receptor subunit alpha [KO:K05072]
101686721  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
101686803  PLK2; serine/threonine-protein kinase PLK2 [KO:K08861] [EC:2.7.11.21]
101686925  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
101686929  GRM1; metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
101686932  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101687186  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
101687213  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101687324  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101687517  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
101687534  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
101687772  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
101687795  GABARAPL2; gamma-aminobutyric acid receptor-associated protein-like 2 [KO:K08341]
101687799  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
101687962  PLK4; serine/threonine-protein kinase PLK4 isoform X1 [KO:K08863] [EC:2.7.11.21]
101688289  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
101688326  CCNG2; cyclin-G2 [KO:K10146]
101688984  HOMER2; homer protein homolog 2 isoform X1 [KO:K15010]
101689279  IRS2; insulin receptor substrate 2 [KO:K07187]
101689782  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
101689809  GABARAPL1; gamma-aminobutyric acid receptor-associated protein-like 1 [KO:K08341]
101689867  SETD7; histone-lysine N-methyltransferase SETD7 [KO:K11431] [EC:2.1.1.364]
101689972  [KO:K27679]
101690214  [KO:K08960] [EC:2.7.11.1]
101690363  FOXO1; forkhead box protein O1 [KO:K07201]
101690482  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101690678  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
101690716  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
101690761  HOMER3; homer protein homolog 3 [KO:K15010]
101690895  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
101691234  [KO:K05868]
101691455  FOXO6; forkhead box protein O6 [KO:K17847]
101691915  PRMT1; protein arginine N-methyltransferase 1 isoform X1 [KO:K11434] [EC:2.1.1.319]
101691963  RAG1; V(D)J recombination-activating protein 1 [KO:K10628] [EC:2.3.2.27]
101692143  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
101693111  RAG2; V(D)J recombination-activating protein 2 [KO:K10988]
101693231  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101693629  NLK; serine/threonine-protein kinase NLK [KO:K04468] [EC:2.7.11.24]
101693694  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
101693939  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
101694276  STK4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
101694554  FBXO25; F-box only protein 25 isoform X1 [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
mpuf00010  Glycolysis / Gluconeogenesis
mpuf00020  Citrate cycle (TCA cycle)
mpuf00190  Oxidative phosphorylation
mpuf04010  MAPK signaling pathway
mpuf04110  Cell cycle
mpuf04120  Ubiquitin mediated proteolysis
mpuf04140  Autophagy - animal
mpuf04151  PI3K-Akt signaling pathway
mpuf04210  Apoptosis
mpuf04350  TGF-beta signaling pathway
mpuf04630  JAK-STAT signaling pathway
mpuf04910  Insulin signaling pathway
KO pathway
ko04068   

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