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 Ortholog table Other DBs Orthology K13375 transforming growth factor beta-1
K13376 transforming growth factor beta-2
K13377 transforming growth factor beta-3
K04501 mothers against decapentaplegic homolog 4
K23605 mothers against decapentaplegic homolog 3
K07198 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31 ]
K07199 5'-AMP-activated protein kinase, regulatory beta subunit
K07200 5'-AMP-activated protein kinase, regulatory gamma subunit
K03875 F-box and leucine-rich repeat protein 1 (S-phase kinase-associated protein 2)
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:2.7.11.24 ]
K04411 serine/threonine kinase 4
K05459 insulin-like growth factor 1
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:2.7.1.153 ]
K02649 phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04467 inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K07209 inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
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
K17848 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2
K04692 signal transducer and activator of transcription 3
K04357 epidermal growth factor
K04364 growth factor receptor-bound protein 2
K04365 B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04366 RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K08845 A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
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
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
K04402 growth arrest and DNA-damage-inducible protein
K04389 tumor necrosis factor ligand superfamily member 6
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
K04288 sphingosine 1-phosphate receptor 1
K04293 sphingosine 1-phosphate receptor 4
K10988 recombination-activating protein 2
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
LinkDB All DBs
