DAF-18 is the Caenorhabditis elegans ortholog of the PTEN tumour suppressor, a phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase that also has dual-specificity protein phosphatase activity. By converting PIP3 back to PI(4,5)P2 at the plasma membrane it opposes the AGE-1 class I PI3K and limits recruitment and activation of PDK-1 and the AKT-1/AKT-2/SGK-1 kinases, thereby permitting nuclear entry of the FOXO factor DAF-16. Loss of daf-18 suppresses the dauer-constitutive and long-lived phenotypes of daf-2 and age-1 mutants and shortens lifespan. DAF-18 is found in the cytoplasm, at the plasma membrane and in nuclei, and is expressed in neurons. Beyond insulin-like signalling it promotes developmental neurite outgrowth, embryonic apoptosis and germline quiescence during diapause, antagonises the VAB-1 Eph receptor via protein phosphatase activity, and restrains RAS/MAPK signalling during vulval induction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004722 protein serine/threonine phosphatase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA (EC 3.1.3.16 mapping) protein serine/threonine phosphatase activity. Reason: PTEN-family enzymes are dual-specificity protein phosphatases and DAF-18 has protein phosphatase activity toward VAB-1 (PMID:19853560), but the principal in vivo activity is PIP3 3-phosphatase. Serine/threonine protein dephosphorylation by DAF-18 specifically is by similarity to human PTEN. Non-core. Supporting Evidence: PMID:19853560 We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. |
| GO:0004722 protein serine/threonine phosphatase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from human PTEN (P60484) protein serine/threonine phosphatase activity. Reason: Same reasoning as the IEA row; a plausible conserved dual-specificity activity, secondary to the lipid phosphatase function. Supporting Evidence: PMID:19853560 We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. |
| GO:0004725 protein tyrosine phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA protein tyrosine phosphatase activity (PTEN node PTN000959472, including DAF-18 itself). Reason: DAF-18 carries the HCXXGXGRXG PTP signature motif, and dephosphorylates tyrosine-phosphorylated VAB-1 (PMID:19853560). The target appearing among the IBA sources reflects its own experimental annotation. Valid, secondary to lipid phosphatase activity. Supporting Evidence: PMID:10377431 The PTEN protein contains a sequence motif, HCXXGXGRXG, that is highly conserved among members of the protein tyrosine phosphatase family. PMID:19853560 We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. |
| GO:0004725 protein tyrosine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (EC 3.1.3.48) protein tyrosine phosphatase activity. Reason: Consistent with IBA and IMP rows. Supporting Evidence: PMID:10377431 The PTEN protein contains a sequence motif, HCXXGXGRXG, that is highly conserved among members of the protein tyrosine phosphatase family. |
| GO:0004725 protein tyrosine phosphatase activity | IMP PMID:19853560 A role for C. elegans Eph RTK signaling in PTEN regulation. | ACCEPT | Summary: IMP protein tyrosine phosphatase activity (Brisbin et al. 2009): DAF-18 antagonises VAB-1 Eph RTK via protein phosphatase activity. Reason: Experimental support for a protein phosphatase function of DAF-18 that acts on VAB-1, independent of PI3K signalling in oocyte maturation. Supporting Evidence: PMID:19853560 We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. |
| GO:0005515 protein binding | IPI PMID:19853560 A role for C. elegans Eph RTK signaling in PTEN regulation. | MODIFY | Summary: IPI with VAB-1 (O61460), the C. elegans Eph receptor tyrosine kinase. Reason: Generic protein binding is uninformative. The paper shows the VAB-1 kinase domain physically interacts with DAF-18, which is both a VAB-1 substrate and a VAB-1 phosphatase; ephrin receptor binding captures the partner class. Proposed replacements: ephrin receptor binding Supporting Evidence: PMID:19853560 We show that in C. elegans, the VAB-1 Eph kinase domain physically interacts with and phosphorylates PTEN (DAF-18), diminishing its protein levels and function. |
| GO:0005634 nucleus | EXP PMID:22916028 PTEN negatively regulates MAPK signaling during Caenorhabdit... | ACCEPT | Summary: EXP nucleus: DAF-18::GFP is cytoplasmic and nuclear in early vulval precursor cells (Nakdimon et al. 2012). Reason: Direct observation. Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus (PTEN node). Reason: Nuclear PTEN is conserved and observed for DAF-18::GFP. Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005634 nucleus | IDA PMID:19853560 A role for C. elegans Eph RTK signaling in PTEN regulation. | ACCEPT | Summary: IDA nucleus from Brisbin et al. 2009. Reason: Consistent with DAF-18::GFP nuclear signal in other cells (PMID:22916028). Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA nucleus (UniProt subcellular location). Reason: Consistent with experimental data. Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005737 cytoplasm | EXP PMID:22916028 PTEN negatively regulates MAPK signaling during Caenorhabdit... | ACCEPT | Summary: EXP cytoplasm (DAF-18::GFP in vulval precursor cells). Reason: Direct observation. Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA cytoplasm. Reason: Consistent with experimental data. Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytosol (PTEN node). Reason: PTEN is a cytosolic enzyme that is recruited to the membrane; consistent with cytoplasmic DAF-18::GFP. Supporting Evidence: PMID:22916028 p stage), DAF-18::GFP was predominantly localized in the cytoplasm and the nucleus (Figure 3A, 3B and 3B′). |
| GO:0005886 plasma membrane | EXP PMID:22916028 PTEN negatively regulates MAPK signaling during Caenorhabdit... | ACCEPT | Summary: EXP plasma membrane: DAF-18::GFP becomes increasingly plasma-membrane-localised during vulval induction. Reason: Direct observation; plasma membrane is where PIP3 is hydrolysed. Supporting Evidence: PMID:22916028 pxx stages), DAF-18::GFP became increasingly localized to the plasma membrane of the vulval cells (Figure 2C, 2D and 2D′). |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA plasma membrane (PTEN node). Reason: Site of PIP3 dephosphorylation; experimentally observed for DAF-18. Supporting Evidence: PMID:22916028 pxx stages), DAF-18::GFP became increasingly localized to the plasma membrane of the vulval cells (Figure 2C, 2D and 2D′). PMID:25383666 The PI3K and AKT pathway is negatively regulated by the lipid phosphatase DAF-18 (homologous to human Phosphatase and Tensin Homolog, PTEN), which dephosphorylates and converts PIP3 to PIP2 and blocks recruitment of AKT kinases to the plasma membrane28–31. |
| GO:0005886 plasma membrane | IDA PMID:19853560 A role for C. elegans Eph RTK signaling in PTEN regulation. | ACCEPT | Summary: IDA plasma membrane from Brisbin et al. 2009. Reason: Consistent with independent DAF-18::GFP data. Supporting Evidence: PMID:22916028 pxx stages), DAF-18::GFP became increasingly localized to the plasma membrane of the vulval cells (Figure 2C, 2D and 2D′). |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA plasma membrane. Reason: Consistent with experimental data. Supporting Evidence: PMID:22916028 pxx stages), DAF-18::GFP became increasingly localized to the plasma membrane of the vulval cells (Figure 2C, 2D and 2D′). |
| GO:0006606 protein import into nucleus | IGI PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | KEEP AS NON CORE | Summary: IGI protein import into nucleus (acts upstream of, positive effect) from Lin et al. 2001: DAF-2 pathway activity prevents DAF-16 nuclear accumulation, and DAF-18 opposes the pathway. Reason: DAF-18 does not participate in nuclear import machinery; it acts upstream by lowering PIP3 and AKT activity, thereby permitting DAF-16 nuclear entry. The acts-upstream-of qualifier captures this indirect relationship correctly; non-core. Supporting Evidence: PMID:11381260 Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. PMID:10377431 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. |
| GO:0006935 chemotaxis | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemotaxis (with akt-1). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0006935 chemotaxis | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemotaxis (with age-1). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0006935 chemotaxis | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemotaxis (with daf-2). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0007611 learning or memory | IMP PMID:16950159 The insulin/PI 3-kinase pathway regulates salt chemotaxis le... | KEEP AS NON CORE | Summary: IMP learning or memory (salt chemotaxis learning, Tomioka et al. 2006). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0007635 chemosensory behavior | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemosensory behavior (with egl-30-pathway partner). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0007635 chemosensory behavior | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemosensory behavior (genetic interaction row). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0007635 chemosensory behavior | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemosensory behavior (with akt-1). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0007635 chemosensory behavior | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemosensory behavior (with age-1). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0007635 chemosensory behavior | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI chemosensory behavior (with daf-2). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0007635 chemosensory behavior | IMP PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IMP chemosensory behavior. Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0008340 determination of adult lifespan | IGI PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: IGI determination of adult lifespan (with daf-16; Lin et al. 2001). Reason: daf-18 loss shortens lifespan and suppresses daf-2/age-1 longevity; DAF-18 opposition of PIP3 signalling is required for normal and IIS-mutant longevity. Supporting Evidence: PMID:10377431 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. PMID:8601482 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. |
| GO:0009408 response to heat | IGI PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | KEEP AS NON CORE | Summary: IGI response to heat (Lin et al. 2001; thermotolerance assays with daf-16). Reason: Thermotolerance is a DAF-16-dependent output of reduced IIS; DAF-18 contributes indirectly by antagonising PI3K signalling. Non-core. Supporting Evidence: PMID:11381260 Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:16950159 The insulin/PI 3-kinase pathway regulates salt chemotaxis le... | ACCEPT | Summary: IDA cytoplasmic side of plasma membrane (Tomioka et al. 2006). Reason: This is precisely where PIP3 resides and is hydrolysed by PTEN. The cached record for this paper is abstract-only and the localisation experiment is not described in the abstract; deferring to the curator who read the full text. DAF-18 is broadly expressed including in neurons (it acts cell-autonomously in AIY, PMID:22069193). Supporting Evidence: PMID:25383666 The PI3K and AKT pathway is negatively regulated by the lipid phosphatase DAF-18 (homologous to human Phosphatase and Tensin Homolog, PTEN), which dephosphorylates and converts PIP3 to PIP2 and blocks recruitment of AKT kinases to the plasma membrane28–31. PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA PIP3 3-phosphatase activity (PTEN node seeded by human, mouse, fly, plant and yeast members). Reason: Core catalytic activity of DAF-18; deep, well-supported PTEN family function. Supporting Evidence: PMID:10377431 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. PMID:25383666 The PI3K and AKT pathway is negatively regulated by the lipid phosphatase DAF-18 (homologous to human Phosphatase and Tensin Homolog, PTEN), which dephosphorylates and converts PIP3 to PIP2 and blocks recruitment of AKT kinases to the plasma membrane28–31. |
| GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA PIP3 3-phosphatase (EC 3.1.3.67). Reason: Core activity. Supporting Evidence: PMID:10377431 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. |
| GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity | ISS PMID:10377431 The PTEN tumor suppressor homolog in Caenorhabditis elegans ... | ACCEPT | Summary: ISS PIP3 3-phosphatase from human PTEN (Mihaylova et al. 1999). Reason: Genetic data place DAF-18 as the antagonist of AGE-1 PI3K, consistent with in vivo PIP3 phosphatase activity; core. Supporting Evidence: PMID:10377431 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. |
| GO:0016791 phosphatase activity | IEA GO_REF:0000120 | MODIFY | Summary: IEA phosphatase activity (ARBA/InterPro). Reason: Correct but very general; the specific core activity is PIP3 3-phosphatase. Proposed replacements: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity Supporting Evidence: PMID:10377431 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. |
| GO:0030424 axon | IDA PMID:16950159 The insulin/PI 3-kinase pathway regulates salt chemotaxis le... | ACCEPT | Summary: IDA axon (Tomioka et al. 2006). Reason: The cached record for this paper is abstract-only and the localisation experiment is not described in the abstract; deferring to the curator who read the full text. DAF-18 is broadly expressed including in neurons (it acts cell-autonomously in AIY, PMID:22069193). Supporting Evidence: PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0030424 axon | IEA GO_REF:0000044 | ACCEPT | Summary: IEA axon (UniProt subcellular location). Reason: Consistent with neuronal expression and the IDA row. Supporting Evidence: PMID:22069193 DAF-18/PTEN acts cell-autonomously to control neurite length in the AIY interneurons. |
| GO:0030425 dendrite | IDA PMID:16950159 The insulin/PI 3-kinase pathway regulates salt chemotaxis le... | ACCEPT | Summary: IDA dendrite (Tomioka et al. 2006). Reason: The cached record for this paper is abstract-only and the localisation experiment is not described in the abstract; deferring to the curator who read the full text. DAF-18 is broadly expressed including in neurons (it acts cell-autonomously in AIY, PMID:22069193). Supporting Evidence: PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0030425 dendrite | IEA GO_REF:0000044 | ACCEPT | Summary: IEA dendrite. Reason: Consistent with the IDA row. Supporting Evidence: PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0040024 dauer larval development | IGI PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: IGI dauer larval development (with daf-16). Reason: daf-18 is required for dauer arrest of daf-2/age-1 mutants; DAF-18 promotes dauer formation by opposing PI3K signalling. Supporting Evidence: PMID:10377431 we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1 |
| GO:0043025 neuronal cell body | IDA PMID:16950159 The insulin/PI 3-kinase pathway regulates salt chemotaxis le... | ACCEPT | Summary: IDA neuronal cell body (Tomioka et al. 2006). Reason: The cached record for this paper is abstract-only and the localisation experiment is not described in the abstract; deferring to the curator who read the full text. DAF-18 is broadly expressed including in neurons (it acts cell-autonomously in AIY, PMID:22069193). Supporting Evidence: PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0043204 perikaryon | EXP PMID:22069193 A conserved PTEN/FOXO pathway regulates neuronal morphology ... | ACCEPT | Summary: EXP perikaryon from the AIY neurite outgrowth study (Christensen et al. 2011). Reason: DAF-18 acts cell-autonomously in AIY neurons; perikaryal localisation is plausible and was directly assessed by the curator. Supporting Evidence: PMID:22069193 DAF-18/PTEN acts cell-autonomously to control neurite length in the AIY interneurons. |
| GO:0043204 perikaryon | IEA GO_REF:0000044 | ACCEPT | Summary: IEA perikaryon. Reason: Consistent with the EXP row. Supporting Evidence: PMID:22069193 DAF-18/PTEN acts cell-autonomously to control neurite length in the AIY interneurons. |
| GO:0046628 positive regulation of insulin receptor signaling pathway | NAS PMID:20207731 Arrestin and the multi-PDZ domain-containing protein MPZ-1 i... | MODIFY | Summary: NAS positive regulation of insulin receptor signaling pathway (Palmitessa & Benovic 2010, ARR-1/MPZ-1/DAF-18 complex). Reason: The sign is inverted. The cited abstract itself states DAF-18 normally serves as a suppressor of DAF-2 signaling; it is ARR-1 that positively regulates DAF-2 signalling. All genetic data place DAF-18 as the PIP3 phosphatase that antagonises DAF-2/AGE-1 signalling. The intended process is negative regulation. Proposed replacements: negative regulation of insulin receptor signaling pathway Supporting Evidence: PMID:20207731 Interestingly, ARR-1 and MPZ-1 are found in a complex with the phosphatase and tensin homolog (PTEN) ortholog DAF-18, which normally serves as a suppressor of DAF-2 signaling, suggesting that these three proteins work together to regulate DAF-2 signaling. PMID:10377431 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. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA regulation of developmental process. Reason: True but very broad; DAF-18 regulates dauer development, vulval induction, germline quiescence and neurite outgrowth. Specific terms are better captured elsewhere. Supporting Evidence: PMID:10377431 we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1 |
| GO:0050920 regulation of chemotaxis | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI regulation of chemotaxis (genetic interaction row). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0050920 regulation of chemotaxis | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI regulation of chemotaxis (genetic interaction row). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0050920 regulation of chemotaxis | IMP PMID:16950159 The insulin/PI 3-kinase pathway regulates salt chemotaxis le... | KEEP AS NON CORE | Summary: IMP regulation of chemotaxis (salt chemotaxis learning). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:16950159 daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. |
| GO:0050927 positive regulation of positive chemotaxis | IMP PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IMP positive regulation of positive chemotaxis (salt attraction, Adachi et al. 2010). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:0051726 regulation of cell cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA regulation of cell cycle (PTEN node). Reason: Conserved PTEN function; in C. elegans DAF-18 maintains Z2/Z3 germline precursor G2 arrest during L1 diapause (UniProt summary of PMID:16631584). Non-core. Supporting Evidence: PMID:10377431 The role of PTEN as a tumor suppressor has been attributed to its ability to modulate two important cellular processes: cell cycle progression and apoptosis. |
| GO:0051896 regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: IBA regulation of PI3K/PKB signal transduction (PTEN node). Reason: Correct but sign-neutral; DAF-18 PIP3 phosphatase activity is the canonical negative regulator of the PI3K/AKT cassette. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000959472 · PTN000959472 SUPPORTS TRANSFER PTEN node; the transfer is sound, but the sign-neutral regulation term is less precise than negative regulation, which all PTEN members perform. Proposed replacements: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction Supporting Evidence: PMID:25383666 The PI3K and AKT pathway is negatively regulated by the lipid phosphatase DAF-18 (homologous to human Phosphatase and Tensin Homolog, PTEN), which dephosphorylates and converts PIP3 to PIP2 and blocks recruitment of AKT kinases to the plasma membrane28–31. |
| GO:0061066 positive regulation of dauer larval development | IMP PMID:6583682 A pheromone-induced developmental switch in Caenorhabditis e... | ACCEPT | Summary: IMP positive regulation of dauer larval development (daf-18(e1375), Golden & Riddle 1984). Reason: daf-18 mutants are dauer-defective/suppress Daf-c; DAF-18 promotes dauer formation by limiting PIP3. Consistent with later work (PMID:10377431). Supporting Evidence: PMID:10377431 we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1 PMID:6583682 Dauer-defective mutants fail to respond to added pheromone |
| GO:0062049 protein phosphatase inhibitor complex | NAS PMID:20207731 Arrestin and the multi-PDZ domain-containing protein MPZ-1 i... | MARK AS OVER ANNOTATED | Summary: NAS protein phosphatase inhibitor complex (ARR-1/MPZ-1/DAF-18 complex). Reason: The abstract reports ARR-1, MPZ-1 and DAF-18 in a complex that regulates DAF-2 signalling, but does not show that the complex inhibits phosphatase activity; under the GO definition DAF-18 would be the phosphatase acted upon, not a component of the inhibitor. Over-interpretation of a co-complex observation. Supporting Evidence: PMID:20207731 Interestingly, ARR-1 and MPZ-1 are found in a complex with the phosphatase and tensin homolog (PTEN) ortholog DAF-18, which normally serves as a suppressor of DAF-2 signaling, suggesting that these three proteins work together to regulate DAF-2 signaling. |
| GO:1902074 response to salt | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI response to salt (genetic interaction row). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:1902074 response to salt | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI response to salt (genetic interaction row). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:1902074 response to salt | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI response to salt (with akt-1). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:1902074 response to salt | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI response to salt (with age-1). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:1902074 response to salt | IGI PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IGI response to salt (with daf-2). Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
| GO:1902074 response to salt | IMP PMID:20837997 Reversal of salt preference is directed by the insulin/PI3K ... | KEEP AS NON CORE | Summary: IMP response to salt. Reason: DAF-18 modulates this salt-chemotaxis behaviour by opposing AGE-1 PI3K signalling in sensory neurons (genetic interactions with daf-2/age-1/akt-1 pathway genes). A real but cell-context-specific output of its PIP3 phosphatase activity; non-core. Supporting Evidence: PMID:20837997 This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. |
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Download this section (compressed HTML)Q: Which DAF-18 functions (vulval MAPK inhibition, VAB-1 antagonism, germline quiescence) require protein versus lipid phosphatase activity in vivo?
Q: Does the ARR-1/MPZ-1/DAF-18 complex inhibit DAF-18 activity or its membrane recruitment?
Experiment: Rescue daf-18 null animals with lipid-phosphatase-dead (G-to-E, PTEN G129E equivalent) and protein-phosphatase-dead (Y138L equivalent) transgenes and score dauer, lifespan, vulval and oocyte phenotypes.
Hypothesis: IIS phenotypes depend on lipid phosphatase activity while VAB-1 antagonism needs protein phosphatase activity.
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.
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