daf-2;eak-3

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Genetic mutants with daf-2, eak-3 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Lifespan (days)
50.85
Lifespan change (compared to wild type)
300.39%
Phenotype
eak-3 daf-2 double mutants exhibited extended longevity compared to daf-2 single mutants.
Lifespan comparisons
Double mutant daf-2(e1370);eak-3(mg344) has a lifespan of 50.85 days, while single mutant daf-2(e1370) has a lifespan of 45.82 days and wild type has a lifespan of 12.7 days.
Type of interaction
See methods
Partially known monotony. Positive epistasis
Citation
View abstract
Zhang Y et al., 2008, Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity. Dev Biol. 315(2):290-302 18241854 Click here to select all mutants from this PubMed ID in the graph
Abstract
Insulin regulates development, metabolism, and lifespan via a conserved PI3K/Akt pathway that promotes cytoplasmic sequestration of FoxO transcription factors. The regulation of nuclear FoxO is poorly understood. In the nematode Caenorhabditis elegans, insulin-like signaling functions in larvae to inhibit dauer arrest and acts during adulthood to regulate lifespan. In a screen for genes that modulate C. elegans insulin-like signaling, we identified eak-3, which encodes a novel protein that is specifically expressed in the two endocrine XXX cells. The dauer arrest phenotype of eak-3 mutants is fully suppressed by mutations in daf-16/FoxO, which encodes the major target of C. elegans insulin-like signaling, and daf-12, which encodes a nuclear receptor regulated by steroid hormones known as dafachronic acids. eak-3 mutation does not affect DAF-16/FoxO subcellular localization but enhances expression of the direct DAF-16/FoxO target sod-3 in a daf-16/FoxO- and daf-12-dependent manner. eak-3 mutants have normal lifespans, suggesting that EAK-3 decouples insulin-like regulation of development and longevity. We propose that EAK-3 activity in the XXX cells promotes the synthesis and/or secretion of a hormone that acts in parallel to AKT-1 to inhibit the expression of DAF-16/FoxO target genes. Similar hormonal pathways may regulate FoxO target gene expression in mammals.

Search genes: daf-2 eak-3

Entrez ID
Symbol
GenAge
Wormbase ID

175410
daf-2
View on GenAge (daf-2)
WBGene00000898

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.

Entrez ID
Symbol
GenAge
Wormbase ID

190782
eak-3
View on GenAge (eak-3)
WBGene00022356

Enhancer of AKt-1 null

Locus: CELE_Y92C3A.3

Wormbase description: eak-3 encodes a protein required for the subset of DAF-16 functions controlling dauer development, but not for lifespan regulation; EAK-3 is expressed in XXX cells, and localizes to the plasma membrane, probably by N-terminal myristoylation; EAK-3 acts in a genetic pathway parallel to that of AKT-1, which may include AKT-2, EAK-4, EAK-6, or SDF-9; EAK-3 has no homologs outside of C. elegans itself, has 20% leucine-like residues, and has a single predicted coiled-coil domain; eak-3 mutants have a very weak dauer arrest phenotype at 25 deg. C., but strongly enhance the dauer arrest phenotype of akt-1(mg306), and enhances expression of the DAF-16 target sod-3; eak-3's dauer arrest and sod-3 overexpression phenotypes require DAF-12 and DAF-16; however, EAK-3 has no effect on lifespan.

Orthologs of daf-2;eak-3 in SynergyAge

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Species	Gene

Not in SynergyAge
Species	Gene

Orthologs of daf-2 in SynergyAge

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Species	Gene
Drosophila melanogaster	InR

Not in SynergyAge
Species	Gene
Mus musculus	Insr
Mus musculus	Igf1r
Mus musculus	Insrr

Orthologs of eak-3 in SynergyAge

Show in SynergyAge
Species	Gene