Genomes and Genes
Gene Symbol: daf-2
Description: Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein
Alias: Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein
Species: Caenorhabditis elegans
- Davies S, Leroi A, Bundy J. Fluorodeoxyuridine affects the identification of metabolic responses to daf-2 status in Caenorhabditis elegans. Mech Ageing Dev. 2012;133:46-9 pubmed publisher..This indicates that FUdR should only be used with caution for C. elegans ageing experiments, and should not be assumed to be independent of other factors being studied. ..
- You Y, Kim J, Raizen D, Avery L. Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety. Cell Metab. 2008;7:249-57 pubmed publisher..The EGL-4 cGMP-dependent protein kinase functions downstream of insulin and TGF-beta in sensory neurons including ASI to control quiescence in response to food intake. ..
- Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001;28:139-45 pubmed..Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging. ..
- Houthoofd K, Braeckman B, Lenaerts I, Brys K, Matthijssens F, De Vreese A, et al. DAF-2 pathway mutations and food restriction in aging Caenorhabditis elegans differentially affect metabolism. Neurobiol Aging. 2005;26:689-96 pubmed..In addition, we provide evidence that DAF-2 signaling controls mitochondrial bioenergetics by adjusting the rate of ATP synthesis to the rate of ATP utilization and by regulating the heat-producing proton leak pathway. ..
- Dillin A, Crawford D, Kenyon C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science. 2002;298:830-4 pubmed..Together our findings show that life-span regulation can be dissociated temporally from phenotypes that might seem to decrease the quality of life. ..
- Kwon E, Narasimhan S, Yen K, Tissenbaum H. A new DAF-16 isoform regulates longevity. Nature. 2010;466:498-502 pubmed publisher..Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism. ..
- Larsen P, Albert P, Riddle D. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics. 1995;139:1567-83 pubmed..This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan. ..
- Kimura K, Tissenbaum H, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997;277:942-6 pubmed..Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity. ..
- Alper S, McBride S, Lackford B, Freedman J, Schwartz D. Specificity and complexity of the Caenorhabditis elegans innate immune response. Mol Cell Biol. 2007;27:5544-53 pubmed..We also propose the existence of an "antimicrobial fingerprint," which will aid in assigning newly identified C. elegans innate immunity genes to known immune signaling pathways. ..
- Wolff S, Ma H, Burch D, Maciel G, Hunter T, Dillin A. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell. 2006;124:1039-53 pubmed..SMK-1 therefore plays a role in longevity by modulating DAF-16 transcriptional specificity without affecting other processes regulated by IIS. ..
- Tullet J, Hertweck M, An J, Baker J, Hwang J, Liu S, et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell. 2008;132:1025-38 pubmed publisher..Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS. ..
- Syntichaki P, Troulinaki K, Tavernarakis N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature. 2007;445:922-6 pubmed..Thus, signalling via eIF4E in the soma is a newly discovered pathway influencing ageing in C. elegans. ..
- Schlotterer A, Kukudov G, Bozorgmehr F, Hutter H, Du X, Oikonomou D, et al. C. elegans as model for the study of high glucose- mediated life span reduction. Diabetes. 2009;58:2450-6 pubmed publisher..Most importantly, glucose toxicity can be prevented by improving glyoxalase-1-dependent methylglyoxal detoxification or preventing mitochondrial dysfunction. ..
- Cornils A, Gloeck M, Chen Z, Zhang Y, Alcedo J. Specific insulin-like peptides encode sensory information to regulate distinct developmental processes. Development. 2011;138:1183-93 pubmed publisher..Together, our data suggest that specific ILPs generate precise responses to dauer-inducing cues, such as pheromones and low food levels, to control development through stimulus-regulated expression in different neurons. ..
- Lee J, Kim K, Lee J, Paik Y. Regulation of Dauer formation by O-GlcNAcylation in Caenorhabditis elegans. J Biol Chem. 2010;285:2930-9 pubmed publisher..Analysis of these candidate O-GlcNAcylated proteins suggests that O-GlcNAcylation may regulate cytoskeleton modifications and protein turnover during dauer formation. ..
- Garsin D, Villanueva J, Begun J, Kim D, Sifri C, Calderwood S, et al. Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science. 2003;300:1921 pubmed
- Robida Stubbs S, Glover Cutter K, Lamming D, Mizunuma M, Narasimhan S, Neumann Haefelin E, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012;15:713-24 pubmed publisher..We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity. ..
- Kauffman A, Ashraf J, Corces Zimmerman M, Landis J, Murphy C. Insulin signaling and dietary restriction differentially influence the decline of learning and memory with age. PLoS Biol. 2010;8:e1000372 pubmed publisher..Our results suggest that specific longevity treatments have acute and long-term effects on cognitive functions that decline with age through their regulation of rate-limiting genes required for learning and memory. ..
- McElwee J, Schuster E, Blanc E, Thomas J, Gems D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem. 2004;279:44533-43 pubmed..By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated. ..
- Vowels J, Thomas J. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics. 1992;130:105-23 pubmed..These results suggest that daf-11 is directly involved in chemosensory transduction essential for dauer formation, while the other Daf-c genes play roles downstream of the chemosensory step. ..
- McElwee J, Schuster E, Blanc E, Thornton J, Gems D. Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans. Mech Ageing Dev. 2006;127:458-72 pubmed..We postulate that this fuels increased somatic maintenance activity, as suggested by the disposable soma theory. ..
- Hung W, Hwang C, Gao S, Liao E, Chitturi J, Wang Y, et al. Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. EMBO J. 2013;32:1745-60 pubmed publisher..We propose that FSN-1 may negatively regulate insulin/IGF signalling, in part, through EGL-3-dependent insulin-like ligand processing. ..
- Mehta R, Steinkraus K, Sutphin G, Ramos F, Shamieh L, Huh A, et al. Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science. 2009;324:1196-8 pubmed publisher..VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway. ..
- Essers M, de Vries Smits L, Barker N, Polderman P, Burgering B, Korswagen H. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005;308:1181-4 pubmed..These results demonstrate a role for beta-catenin in regulating FOXO function that is particularly important under conditions of oxidative stress. ..
- Samuelson A, Carr C, Ruvkun G. Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev. 2007;21:2976-94 pubmed..The activities of these genes may normally decline during aging. ..
- Dong M, Venable J, Au N, Xu T, Park S, Cociorva D, et al. Quantitative mass spectrometry identifies insulin signaling targets in C. elegans. Science. 2007;317:660-3 pubmed..In particular, we discovered a compensatory mechanism activated in response to reduced DAF-2 signaling, which involves the protein phosphatase calcineurin. ..
- Berdichevsky A, Viswanathan M, Horvitz H, Guarente L. C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell. 2006;125:1165-77 pubmed..We propose the existence of a stress-dependent pathway in which SIR-2.1 and 14-3-3 act in parallel to the insulin-like pathway to activate DAF-16 and extend life span. ..
- Murphy C, Lee S, Kenyon C. Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2007;104:19046-50 pubmed..Our findings show that feedback regulation of insulin gene expression coordinates DAF-16 activity among the tissues, and they establish the intestine, which is the animal's entire endoderm, as an important insulin-signaling center. ..
- Apfeld J, Kenyon C. Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span. Cell. 1998;95:199-210 pubmed
- Wang M, O Rourke E, Ruvkun G. Fat metabolism links germline stem cells and longevity in C. elegans. Science. 2008;322:957-60 pubmed publisher..This lipase is a key factor in the lipid hydrolysis and increased longevity that are induced by decreased insulin signaling. These results suggest a link between C. elegans fat metabolism and longevity. ..
- Lopez A, Chen J, Joo H, Drake M, Shidate M, Kseib C, et al. DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis. Dev Cell. 2013;27:227-240 pubmed publisher..elegans, ensuring that oocytes are only produced under conditions favorable for the survival of the resulting zygotes. ..
- Inoue T, Ailion M, Poon S, Kim H, Thomas J, Sternberg P. Genetic analysis of dauer formation in Caenorhabditis briggsae. Genetics. 2007;177:809-18 pubmed..elegans. In contrast, C. briggsae, which is capable of growth at higher temperatures than C. elegans, lacks this response. ..
- Leinwand S, Chalasani S. Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans. Nat Neurosci. 2013;16:1461-7 pubmed publisher..Our results indicate that sensory context and neuropeptide signaling modify neural networks and suggest general mechanisms for generating flexible behavioral outputs by modulating neural circuit composition. ..
- Valentini S, Cabreiro F, Ackerman D, Alam M, Kunze M, Kay C, et al. Manipulation of in vivo iron levels can alter resistance to oxidative stress without affecting ageing in the nematode C. elegans. Mech Ageing Dev. 2012;133:282-90 pubmed publisher..These results show that high levels of iron can increase molecular damage and reduce lifespan, but overall suggest that iron levels within the normal physiological range do not promote ageing in C. elegans. ..
- Arda H, Taubert S, MacNeil L, Conine C, Tsuda B, Van Gilst M, et al. Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network. Mol Syst Biol. 2010;6:367 pubmed publisher..As NHRs are metabolic sensors that are poised to respond to ligands, this suggests that C. elegans GRNs evolved to enable rapid and adaptive responses to different cues by a concurrence of NHR family expansion and modular GRN wiring. ..
- McCarthy A. Elixir Pharmaceuticals: targeting molecular sources of aging. Chem Biol. 2004;11:733-4 pubmed
- Huang X, Zhang H, Zhang H. The zinc-finger protein SEA-2 regulates larval developmental timing and adult lifespan in C. elegans. Development. 2011;138:2059-68 pubmed publisher..Our study provides evidence for intricate interplay between the heterochronic circuit that controls developmental timing in larvae and the timing mechanism that modulates aging in adults. ..
- Hibshman J, Hung A, Baugh L. Maternal Diet and Insulin-Like Signaling Control Intergenerational Plasticity of Progeny Size and Starvation Resistance. PLoS Genet. 2016;12:e1006396 pubmed publisher..This work reveals maternal provisioning as an organismal response to DR, demonstrates potentially adaptive intergenerational phenotypic plasticity, and identifies conserved pathways mediating these effects. ..
- McCulloch D, Gems D. Sex-specific effects of the DAF-12 steroid receptor on aging in Caenorhabditis elegans. Ann N Y Acad Sci. 2007;1119:253-9 pubmed..These results could imply that in C. elegans, as in mammals, sex differences in steroid endocrinology contribute to sex differences in aging. ..
- Arantes Oliveira N, Berman J, Kenyon C. Healthy animals with extreme longevity. Science. 2003;302:611 pubmed
- Hahm J, Kim S, Paik Y. Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans. Aging Cell. 2009;8:473-83 pubmed publisher..Our findings provide not only a new mechanism of cGMP-mediated induction of longevity in adult C. elegans but also a possible therapeutic strategy for neuronal disease, which has been likened to brain diabetes. ..
- Schreiber M, Pierce Shimomura J, Chan S, Parry D, McIntire S. Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1. PLoS Genet. 2010;6:e1000972 pubmed publisher..This work indicates that novel modulators of behavioral function can be identified in screens, with implications for future study of the clinical amelioration of age-related decline. ..
- Ihara A, Uno M, Miyatake K, Honjoh S, Nishida E. Cholesterol regulates DAF-16 nuclear localization and fasting-induced longevity in C. elegans. Exp Gerontol. 2017;87:40-47 pubmed publisher..These findings identify a novel role for cholesterol in the regulation of lifespan. ..
- Nanji M, Hopper N, Gems D. LET-60 RAS modulates effects of insulin/IGF-1 signaling on development and aging in Caenorhabditis elegans. Aging Cell. 2005;4:235-45 pubmed..Thus, Ras pathway signaling appears to act with insulin/IGF-1 signaling during larval development, but against it during aging. ..
- Hirose T, Nakano Y, Nagamatsu Y, Misumi T, Ohta H, Ohshima Y. Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C elegans. Development. 2003;130:1089-99 pubmed..Experiments on genetic interaction suggest that the cGMP-EGL-4 signaling pathway represses body size and lifespan through DBL-1/TGF-beta and insulin pathways, respectively. ..
- Ohno H, Kato S, Naito Y, Kunitomo H, Tomioka M, Iino Y. Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans. Science. 2014;345:313-7 pubmed publisher..Thus, synaptic PI3K is crucial for the behavioral switch caused by learning. ..
- Mabon M, Scott B, Crowder C. Divergent mechanisms controlling hypoxic sensitivity and lifespan by the DAF-2/insulin/IGF-receptor pathway. PLoS ONE. 2009;4:e7937 pubmed publisher..However, RNAi knockdown of these genes did not prolong lifespan. These genes definitively separate the mechanisms of hypoxic sensitivity and lifespan and identify biological strategies to survive hypoxic injury. ..
- Ohta A, Ujisawa T, Sonoda S, Kuhara A. Light and pheromone-sensing neurons regulates cold habituation through insulin signalling in Caenorhabditis elegans. Nat Commun. 2014;5:4412 pubmed publisher..Thus, temperature sensation in a light and pheromone-sensing neuron produces a robust effect on insulin signalling that controls experience-dependent temperature habituation. ..
- Mack H, Zhang P, Fonslow B, Yates J. The protein kinase MBK-1 contributes to lifespan extension in daf-2 mutant and germline-deficient Caenorhabditis elegans. Aging (Albany NY). 2017;9:1414-1432 pubmed publisher..elegans longevity upon both, germline ablation and DAF-2 inhibition, and provide evidence for mbk-1 regulating DAF-16 activity in germline-deficient animals. ..
- Davies S, Bundy J, Leroi A. Metabolic Youth in Middle Age: Predicting Aging in Caenorhabditis elegans Using Metabolomics. J Proteome Res. 2015;14:4603-9 pubmed publisher..Finally, we show that metabolic age predicts the timing and magnitude of differences in age-specific mortality between these strains. Thus, the future mortality of these two genotypes can be predicted long before most of the worms die. ..
- Taylor R, Dillin A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell. 2013;153:1435-47 pubmed publisher..Our findings point toward a secreted ER stress signal (SERSS) that promotes ER stress resistance and longevity. ..
- Kirkwood T. Genes that shape the course of ageing. Trends Endocrinol Metab. 2003;14:345-7 pubmed..An elegant new study of genes acting downstream of these signals in the nematode worm Caenorhabditis elegans reveals a plethora of information about the complex network of mechanisms that modulate the ageing process. ..
- Lehtinen M, Yuan Z, Boag P, Yang Y, Villen J, Becker E, et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006;125:987-1001 pubmed
- McGee M, Day N, Graham J, Melov S. cep-1/p53-dependent dysplastic pathology of the aging C. elegans gonad. Aging (Albany NY). 2012;4:256-69 pubmed
- Spanier B, Rubio Aliaga I, Hu H, Daniel H. Altered signalling from germline to intestine pushes daf-2;pept-1 Caenorhabditis elegans into extreme longevity. Aging Cell. 2010;9:636-46 pubmed publisher..elegans lacking a proper function of the insulin receptor and lacking the intestinal peptide transporter. ..
- Ben Arous J, Laffont S, Chatenay D. Molecular and sensory basis of a food related two-state behavior in C. elegans. PLoS ONE. 2009;4:e7584 pubmed publisher..Biogenic amines signaling could allow the worm to adapt to fast changes in the environment when peptide transcriptional pathways may mediate slower adaptive changes. ..
- Toivonen J, Walker G, Martinez Diaz P, Bjedov I, Driege Y, Jacobs H, et al. No influence of Indy on lifespan in Drosophila after correction for genetic and cytoplasmic background effects. PLoS Genet. 2007;3:e95 pubmed..In addition, we saw no effects on lifespan of expression knockdown of the Indy orthologues nac-2 and nac-3 in the nematode Caenorhabditis elegans. ..
- Inoue T, Thomas J. Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation. Dev Biol. 2000;217:192-204 pubmed..Instead, these experiments suggest the nervous system as a target of DAF-7 signaling and that the nervous system in turn regulates dauer formation by other tissues. ..
- Kimura K, Riddle D, Ruvkun G. The C. elegans DAF-2 insulin-like receptor is abundantly expressed in the nervous system and regulated by nutritional status. Cold Spring Harb Symp Quant Biol. 2011;76:113-20 pubmed publisher..The modulation of DAF-2 protein level by nutritional status may constitute an important component in the irreversible commitment to dauer arrest. ..