daf-18;daf-2

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Genetic mutants with daf-18, daf-2 alterations

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

Temperature °C
15
Diet
OP50
Lifespan (days)
24.5
Lifespan change (compared to wild type)
2.94%
Lifespan comparisons
Double mutant daf-18(RNAi);daf-2(e1370) has a lifespan of 24.5 days, while single mutant daf-2(e1370) has a lifespan of 38.9 days, single mutant daf-18(RNAi) has a lifespan of 19.5 days and wild type has a lifespan of 23.8 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Padmanabhan S et al., 2009, A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell. 136(5):939-51 19249087 Click here to select all mutants from this PubMed ID in the graph
Abstract
The C. elegans insulin/IGF-1 signaling (IIS) cascade plays a central role in regulating life span, dauer, metabolism, and stress. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine-specific protein kinases. An RNAi screen for serine/threonine protein phosphatases that counterbalance the effect of the kinases in the IIS pathway identified pptr-1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr-1 affects IIS pathway-associated phenotypes including life span, dauer, stress resistance, and fat storage. We show that PPTR-1 functions by regulating worm AKT-1 phosphorylation at Thr 350. With striking conservation, mammalian B56beta regulates Akt phosphorylation at Thr 308 in 3T3-L1 adipocytes. In C. elegans, this ultimately leads to changes in subcellular localization and transcriptional activity of the forkhead transcription factor DAF-16. This study reveals a conserved role for the B56 regulatory subunit in regulating insulin signaling through AKT dephosphorylation, thereby having widespread implications in cancer and diabetes research.

Temperature °C
15
Diet
OP50
Lifespan (days)
22.5
Lifespan change (compared to wild type)
-5.06%
Lifespan comparisons
Double mutant daf-18(RNAi);daf-2(e1370) has a lifespan of 22.5 days, while single mutant daf-2(e1370) has a lifespan of 35.9 days, single mutant daf-18(RNAi) has a lifespan of 18.4 days and wild type has a lifespan of 23.7 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Padmanabhan S et al., 2009, A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell. 136(5):939-51 19249087 Click here to select all mutants from this PubMed ID in the graph
Abstract
The C. elegans insulin/IGF-1 signaling (IIS) cascade plays a central role in regulating life span, dauer, metabolism, and stress. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine-specific protein kinases. An RNAi screen for serine/threonine protein phosphatases that counterbalance the effect of the kinases in the IIS pathway identified pptr-1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr-1 affects IIS pathway-associated phenotypes including life span, dauer, stress resistance, and fat storage. We show that PPTR-1 functions by regulating worm AKT-1 phosphorylation at Thr 350. With striking conservation, mammalian B56beta regulates Akt phosphorylation at Thr 308 in 3T3-L1 adipocytes. In C. elegans, this ultimately leads to changes in subcellular localization and transcriptional activity of the forkhead transcription factor DAF-16. This study reveals a conserved role for the B56 regulatory subunit in regulating insulin signaling through AKT dephosphorylation, thereby having widespread implications in cancer and diabetes research.

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

Temperature °C
20
Lifespan (days)
16.9
Phenotype
The daf-18 mutation partially suppressed the life span extension of daf-2( e1370). The life span of the double mutant is intermediate between those of daf-18 and daf-2( e1370), but closer to that of daf-18
Lifespan comparisons
Double mutant daf-18(e1375);daf-2(e1370) has a lifespan of 16.9 days, while single mutant daf-2(e1370) has a lifespan of 26.7 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Larsen PL et al., 1995, Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics. 139(4):1567-83 7789761 Click here to select all mutants from this PubMed ID in the graph
Abstract
The nematode Caenorhabditis elegans responds to conditions of overcrowding and limited food by arresting development as a dauer larva. Genetic analysis of mutations that alter dauer larva formation (daf mutations) is presented along with an updated genetic pathway for dauer vs. nondauer development. Mutations in the daf-2 and daf-23 genes double adult life span, whereas mutations in four other dauer-constitutive genes positioned in a separate branch of this pathway (daf-1, daf-4, daf-7 and daf-8) do not. The increased life spans are suppressed completely by a daf-16 mutation and partially in a daf-2; daf-18 double mutant. A genetic pathway for determination of adult life span is presented based on the same strains and growth conditions used to characterize Daf phenotypes. Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner. Mutations in daf-12 do not extend adult life span, but certain combinations of daf-2 and daf-12 mutant alleles nearly quadruple it. This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan.

Temperature °C
25
Diet
OP50
Lifespan (days)
13.0
Lifespan change (compared to wild type)
8.33%
Phenotype
The daf-18(e1375) mutation suppresses the lifespan extension of daf-2(e1370) mutant.
Lifespan comparisons
Double mutant daf-18(e1375);daf-2(e1370) has a lifespan of 13.0 days, while single mutant daf-18(e1375) has a lifespan of 10.0 days, single mutant daf-2(e1370) has a lifespan of 29.0 days and wild type has a lifespan of 12.0 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Dorman JB et al., 1995, The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics. 141(4):1399-406 8601482 Click here to select all mutants from this PubMed ID in the graph
Abstract
Recessive mutations in two genes, daf-2 and age-1, extend the lifespan of Caenorhabditis elegans significantly. The daf-2 gene also regulates formation of an alternative developmental state called the dauer. Here we asked whether these two genes function in the same or different lifespan pathways. We found that the longevity of both age-1 and daf-2 mutants requires the activities of the same two genes, daf-16 and daf-18. In addition, the daf-2(e1370); age-1(hx546) double mutant did not live significantly longer than the daf-2 single mutant. We also found that, like daf-2 mutations, the age-1(hx546) mutation affects certain aspects of dauer formation. These findings suggest that age-1 and daf-2 mutations do act in the same lifespan pathway and extend lifespan by triggering similar if not identical processes.

Temperature °C
20
Diet
OP50
Lifespan (days)
16.0
Lifespan change (compared to wild type)
-15.79%
Lifespan comparisons
Double mutant daf-18(e1375);daf-2(e1370) has a lifespan of 16.0 days, while single mutant daf-2(e1370) has a lifespan of 39.0 days and wild type has a lifespan of 19.0 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Dorman JB et al., 1995, The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics. 141(4):1399-406 8601482 Click here to select all mutants from this PubMed ID in the graph
Abstract
Recessive mutations in two genes, daf-2 and age-1, extend the lifespan of Caenorhabditis elegans significantly. The daf-2 gene also regulates formation of an alternative developmental state called the dauer. Here we asked whether these two genes function in the same or different lifespan pathways. We found that the longevity of both age-1 and daf-2 mutants requires the activities of the same two genes, daf-16 and daf-18. In addition, the daf-2(e1370); age-1(hx546) double mutant did not live significantly longer than the daf-2 single mutant. We also found that, like daf-2 mutations, the age-1(hx546) mutation affects certain aspects of dauer formation. These findings suggest that age-1 and daf-2 mutations do act in the same lifespan pathway and extend lifespan by triggering similar if not identical processes.

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

Temperature °C
25
Diet
NGM; OP50
Lifespan (days)
8.3
Lifespan change (compared to wild type)
-2.35%
Phenotype
The daf-2(e1370) mutation extended the lifespan of daf-18(nr2037) animals at 25°C and restored lifespan to that found for wild type. These observations suggest that the lifespan-shortening phenotype caused by daf-18(nr2037) depends on the positive signal input from daf-2 gene activity. In addition, daf-18(nr2037) also completely suppressed the long-lived phenotype of daf-2(e1370).
Lifespan comparisons
Double mutant daf-18(nr2037);daf-2(e1370) has a lifespan of 8.3 days, while single mutant daf-2(e1370) has a lifespan of 18.8 days, single mutant daf-18(nr2037) has a lifespan of 6.2 days and wild type has a lifespan of 8.5 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Mihaylova VT et al., 1999, The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci U S A. 96(13):7427-32 10377431 Click here to select all mutants from this PubMed ID in the graph
Abstract
Inactivation of the tumor suppressor PTEN gene is found in a variety of human cancers and in cancer predisposition syndromes. Recently, PTEN protein has been shown to possess phosphatase activity on phosphatidylinositol 3,4,5-trisphosphate, a product of phosphatidylinositol 3-kinase. We have identified a homolog of PTEN in Caenorhabditis elegans and have found that it corresponds to the daf-18 gene, which had been defined by a single, phenotypically weak allele, daf-18(e1375). By analyzing an allele, daf-18(nr2037), which bears a deletion of the catalytic portion of CePTEN/DAF-18, we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1, which encode an insulin receptor-like molecule and the catalytic subunit of phosphatidylinositol 3-kinase, respectively. In addition, daf-18(nr2037) dramatically shortens lifespan, both in a wild-type background and in a daf-2 mutant background that normally prolongs lifespan. The lifespan in a daf-18(nr2037) mutant can be restored to essentially that of wild type when combined with a daf-2 mutation. Our studies provide genetic evidence that, in C. elegans, the PTEN homolog DAF-18 functions as a negative regulator of the DAF-2 and AGE-1 signaling pathway, consistent with the notion that DAF-18 acts a phosphatidylinositol 3,4,5-trisphosphate phosphatase in vivo. Furthermore, our studies have uncovered a longevity-promoting activity of the PTEN homolog in C. elegans.

Temperature °C
20
Diet
NGM; OP50
Lifespan (days)
11.1
Lifespan change (compared to wild type)
-12.60%
Phenotype
The daf-2(e1370) mutation extended the lifespan of daf-18(nr2037) animals at 20°C and restored lifespan to that found for wild type. These observations suggest that the lifespan-shortening phenotype caused by daf-18(nr2037) depends on the positive signal input from daf-2 gene activity. In addition, daf-18(nr2037) also completely suppressed the long-lived phenotype of daf-2(e1370).
Lifespan comparisons
Double mutant daf-18(nr2037);daf-2(e1370) has a lifespan of 11.1 days, while single mutant daf-2(e1370) has a lifespan of 25.3 days, single mutant daf-18(nr2037) has a lifespan of 5.8 days and wild type has a lifespan of 12.7 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Mihaylova VT et al., 1999, The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci U S A. 96(13):7427-32 10377431 Click here to select all mutants from this PubMed ID in the graph
Abstract
Inactivation of the tumor suppressor PTEN gene is found in a variety of human cancers and in cancer predisposition syndromes. Recently, PTEN protein has been shown to possess phosphatase activity on phosphatidylinositol 3,4,5-trisphosphate, a product of phosphatidylinositol 3-kinase. We have identified a homolog of PTEN in Caenorhabditis elegans and have found that it corresponds to the daf-18 gene, which had been defined by a single, phenotypically weak allele, daf-18(e1375). By analyzing an allele, daf-18(nr2037), which bears a deletion of the catalytic portion of CePTEN/DAF-18, we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1, which encode an insulin receptor-like molecule and the catalytic subunit of phosphatidylinositol 3-kinase, respectively. In addition, daf-18(nr2037) dramatically shortens lifespan, both in a wild-type background and in a daf-2 mutant background that normally prolongs lifespan. The lifespan in a daf-18(nr2037) mutant can be restored to essentially that of wild type when combined with a daf-2 mutation. Our studies provide genetic evidence that, in C. elegans, the PTEN homolog DAF-18 functions as a negative regulator of the DAF-2 and AGE-1 signaling pathway, consistent with the notion that DAF-18 acts a phosphatidylinositol 3,4,5-trisphosphate phosphatase in vivo. Furthermore, our studies have uncovered a longevity-promoting activity of the PTEN homolog in C. elegans.

Search genes: daf-18 daf-2

Entrez ID
Symbol
GenAge
Wormbase ID

176869
daf-18
View on GenAge (daf-18)
WBGene00000913

Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase daf-18

Locus: CELE_T07A9.6

Wormbase description: daf-18 encodes a lipid phosphatase homologous to the human PTEN tumor suppresor (OMIM:601728, mutated in Cowden disease and several cancers); DAF-18 negatively regulates insulin-like signaling mediated by DAF-2/IR and AGE-1/PI3K and thus plays a role in metabolism, development, and longevity; based on sequence and genetic analysis, DAF-18 is predicted to dephosphorylate AGE-1-generated PIP3 in order to limit activation of the downstream AKT-1 and AKT-2 kinases that negatively regulate DAF-16.

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.

Orthologs of daf-18;daf-2 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene

Orthologs of daf-18 in SynergyAge

Show in SynergyAge
Species	Gene

Orthologs of daf-2 in SynergyAge

Show in SynergyAge
Species	Gene
Drosophila melanogaster	InR

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