Entry Name FoxO signaling pathway
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 transductionBRITE hierarchy
Pathway map Other DBs Orthology K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K01596 E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32 ]
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K03875 SKP2, FBXL1; F-box and leucine-rich repeat protein 1 (S-phase kinase-associated protein 2)
K04288 S1PR1, EDG1, CD363; sphingosine 1-phosphate receptor 1
K04293 S1PR4, EDG6; sphingosine 1-phosphate receptor 4
K04357 EGF; epidermal growth factor
K04364 GRB2; growth factor receptor-bound protein 2
K04365 BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04366 RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2 ]
K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2 ]
K04389 TNFSF6, FASL, CD178; tumor necrosis factor ligand superfamily member 6
K04402 GADD45; growth arrest and DNA-damage-inducible protein
K04411 STK4, MST1; serine/threonine kinase 4
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K04501 SMAD4; mothers against decapentaplegic homolog 4
K04503 CCND1; G1/S-specific cyclin-D1
K04603 GRM1; metabotropic glutamate receptor 1
K04685 CDKN2B, P15, INK4B; cyclin-dependent kinase inhibitor 2B
K04692 STAT3; signal transducer and activator of transcription 3
K04721 TNFSF10, TRAIL, CD253; tumor necrosis factor ligand superfamily member 10
K05072 IL7R, CD127; interleukin 7 receptor
K05087 IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1 ]
K05443 IL10, CSIF; interleukin 10
K05459 IGF1; insulin-like growth factor 1
K05868 CCNB1; G2/mitotic-specific cyclin-B1
K06276 PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1 ]
K06623 CDKN2D, P19, INK4D; cyclin-dependent kinase inhibitor 2D
K06624 CDKN1B, P27, KIP1; cyclin-dependent kinase inhibitor 1B
K06625 CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A
K07187 IRS2; insulin receptor substrate 2
K07191 SLC2A4, GLUT4; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31 ]
K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit
K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit
K07201 FOXO1; forkhead box protein O1
K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07827 KRAS, KRAS2; GTPase KRas
K08336 ATG12; ubiquitin-like protein ATG12
K08341 GABARAP, ATG8, LC3; GABA(A) receptor-associated protein
K08845 ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K09385 FOXG; forkhead box protein G
K09408 FOXO3; forkhead box protein O3
K10151 CCND2; G1/S-specific cyclin-D2
K10305 FBXO25_32; F-box protein 25/32
K10988 RAG2; recombination-activating protein 2
K11411 SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286 ]
K12358 FOXO4; forkhead box protein O4
K13375 TGFB1; transforming growth factor beta-1
K13376 TGFB2; transforming growth factor beta-2
K13377 TGFB3; transforming growth factor beta-3
K15464 BNIP3; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3
K15618 BCL6; B-cell lymphoma 6 protein
K16172 IRS1; insulin receptor substrate 1
K16332 RBL2; retinoblastoma-like protein 2
K16341 BCL2L11, BIM; Bcl-2-like protein 11
K17445 IRS3; insulin receptor substrate 3
K17446 IRS4; insulin receptor substrate 4
K17845 KLF2; krueppel-like factor 2
K17847 FOXO6; forkhead box protein O6
K17848 AGAP2; Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2
K21770 CCNB2; G2/mitotic-specific cyclin-B2
K21771 CCNB3; G2/mitotic-specific cyclin-B3
K23605 SMAD3; mothers against decapentaplegic homolog 3
Compound 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 Reference Authors van der Horst A, Burgering BM
Title Stressing the role of FoxO proteins in lifespan and disease.
Journal Reference Authors Zhang X, Tang N, Hadden TJ, Rishi AK
Title Akt, FoxO and regulation of apoptosis.
Journal Reference Authors Eijkelenboom A, Burgering BM
Title FOXOs: signalling integrators for homeostasis maintenance.
Journal Reference Authors Daitoku H, Fukamizu A
Title FOXO transcription factors in the regulatory networks of longevity.
Journal Reference Authors Hedrick SM
Title The cunning little vixen: Foxo and the cycle of life and death.
Journal Reference Authors Coffer PJ, Burgering BM
Title Forkhead-box transcription factors and their role in the immune system.
Journal Reference Authors Ro SH, Liu D, Yeo H, Paik JH
Title FoxOs in neural stem cell fate decision.
Journal Reference Authors Maiese K, Chong ZZ, Shang YC
Title OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins.
Journal Reference Authors Hagenbuchner J, Ausserlechner MJ
Title Mitochondria and FOXO3: breath or die.
Journal Reference Authors Maiese K, Chong ZZ, Shang YC
Title "Sly as a FOXO": new paths with Forkhead signaling in the brain.
Journal 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 Reference Authors Huang H, Tindall DJ
Title Regulation of FOXO protein stability via ubiquitination and proteasome degradation.
Journal Reference Authors Greer EL, Brunet A
Title FOXO transcription factors at the interface between longevity and tumor suppression.
Journal 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 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 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 Reference Authors Zhang Y, Gan B, Liu D, Paik JH
Title FoxO family members in cancer.
Journal 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 Related ko00010 Glycolysis / Gluconeogenesis
ko04120 Ubiquitin mediated proteolysis
