daf-2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005009 insulin receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2 is the C. elegans insulin/IGF-1 receptor ortholog. The seminal discovery paper (PMID:9252323) identified daf-2 as encoding "an insulin receptor family member" regulating longevity and dauer diapause. The protein contains characteristic receptor tyrosine kinase domains and functions analogously to mammalian insulin receptors. Reason: This is a well-established core function of DAF-2. The original cloning paper demonstrated sequence homology to insulin receptor family members, and extensive genetic and biochemical studies have confirmed DAF-2 acts as an insulin/IGF-1-like receptor controlling metabolism, development, and lifespan. The IBA annotation reflects conserved phylogenetic function. Supporting Evidence: PMID:9252323 daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member file:worm/daf-2/daf-2-deep-research-falcon.md model: Edison Scientific Literature
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: As a transmembrane receptor tyrosine kinase, DAF-2 localizes to the plasma membrane. This is consistent with its function as a cell surface receptor and has been directly confirmed by IDA evidence (PMID:24120884). Reason: Plasma membrane localization is expected for a transmembrane receptor and is supported by direct experimental evidence showing DAF-2::GFP at the plasma membrane in oocytes and neurons. The IBA annotation is phylogenetically consistent with characterized orthologs. Supporting Evidence: PMID:24120884 DAF-2 insulin-like receptor signals through the RAS-ERK pathway
GO:0008286 insulin receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2 is the core receptor initiating insulin/IGF-1-like signaling in C. elegans. The pathway involves AGE-1 (PI3K), PDK-1, AKT-1/2, and culminates in regulation of the FOXO transcription factor DAF-16. Reason: This is the central biological pathway through which DAF-2 functions. Extensive genetic and biochemical studies demonstrate DAF-2 signals through a conserved PI3K/AKT cascade to regulate DAF-16, controlling longevity, metabolism, and dauer formation. Supporting Evidence: PMID:11381260 The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway
GO:0043410 positive regulation of MAPK cascade	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2 signaling couples to the RAS-ERK/MAPK pathway in specific contexts, particularly in oogenesis where DAF-2 signals through the RAS-ERK pathway to drive meiotic progression. Reason: Direct evidence from PMID:24120884 demonstrates DAF-2 activates RAS-ERK signaling in the germline to couple nutrient sensing to meiotic progression. This represents a genuine signaling output of DAF-2 beyond the canonical PI3K/AKT pathway. Supporting Evidence: PMID:24120884 the DAF-2 insulin-like receptor signals through the RAS-ERK pathway to drive meiotic prophase I progression and oogenesis
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2 activates AGE-1 (PI3K), leading to production of PIP3 and activation of AKT-1/AKT-2, which phosphorylate and inhibit DAF-16. Reason: This is the core downstream signaling mechanism of DAF-2. Extensive genetic epistasis and biochemical studies confirm DAF-2 activates PI3K/AKT signaling, which is essential for its effects on lifespan, dauer formation, and metabolism. Supporting Evidence: PMID:11381260 DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway
GO:0042593 glucose homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2 regulates metabolic processes including carbohydrate metabolism. daf-2 mutants accumulate fat and show altered metabolism consistent with insulin receptor function. Reason: Metabolic regulation is a conserved function of insulin/IGF receptors. The original paper noted DAF-2 induces "metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor." While C. elegans glucose metabolism differs from mammals, DAF-2 clearly regulates carbohydrate and lipid metabolism. Supporting Evidence: PMID:9252323 Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor
GO:0005899 insulin receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2 forms a receptor complex as a tetramer of 2 alpha and 2 beta chains linked by disulfide bonds, analogous to mammalian insulin receptors. Reason: UniProt annotation indicates DAF-2 forms a tetrameric receptor complex by analogy to mammalian insulin receptors. This structure is phylogenetically conserved among insulin receptor family members.
GO:0030424 axon	IBA GO_REF:0000033	ACCEPT	Summary: DAF-2, particularly isoform C, localizes to axons in neurons. This was directly demonstrated by imaging DAF-2 translocation to synaptic regions during learning. Reason: Direct experimental evidence (IDA in PMID:25035490) confirms DAF-2 localizes to axons, particularly in ASER gustatory neurons where isoform c is required for taste avoidance learning. The IBA annotation is consistent with experimental data. Supporting Evidence: PMID:25035490 a newly discovered insulin receptor isoform, DAF-2c, is translocated from the cell body to the synaptic region of the chemosensory neuron
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: DAF-2 contains a protein kinase domain that requires ATP binding for catalytic activity. Reason: While correct that DAF-2 binds nucleotides, the more specific term ATP binding (GO:0005524) is more informative and is already annotated. Nucleotide binding is too general. Proposed replacements: ATP binding
GO:0002376 immune system process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: DAF-2/insulin signaling regulates immune function and pathogen resistance in C. elegans. daf-2 mutants have increased resistance to bacterial pathogens. Reason: While DAF-2 does regulate immunity, this is a downstream consequence of its metabolic/stress response signaling rather than a direct immune function. The more specific annotation to innate immune response (GO:0045087) and defense response to Gram-negative bacterium (GO:0050829) are more appropriate for describing this biology. This broad term is acceptable but not core function.
GO:0004672 protein kinase activity	IEA GO_REF:0000002	MODIFY	Summary: DAF-2 contains a protein kinase domain in its cytoplasmic beta chain that autophosphorylates and phosphorylates substrates on tyrosine residues. Reason: The more specific term protein tyrosine kinase activity (GO:0004713) or transmembrane receptor protein tyrosine kinase activity (GO:0004714) should be used instead, as DAF-2 is specifically a tyrosine kinase. Proposed replacements: transmembrane receptor protein tyrosine kinase activity
GO:0004713 protein tyrosine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: DAF-2 is a receptor tyrosine kinase that phosphorylates itself and downstream substrates on tyrosine residues. Reason: DAF-2 is classified in the tyrosine protein kinase family and catalyzes tyrosine phosphorylation as its enzymatic activity. This is a core molecular function of the protein.
GO:0004714 transmembrane receptor protein tyrosine kinase activity	IEA GO_REF:0000003	ACCEPT	Summary: DAF-2 is a single-pass type I transmembrane receptor with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Reason: This is the most accurate and specific molecular function term for DAF-2. The protein has all the hallmarks of a transmembrane receptor tyrosine kinase: extracellular domain for ligand binding, transmembrane domain, and intracellular kinase domain. This should be the preferred MF annotation.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: The kinase domain of DAF-2 binds ATP as a cofactor for its tyrosine kinase activity. Reason: ATP binding is required for the kinase activity of DAF-2. The protein contains characteristic ATP-binding motifs in its kinase domain.
GO:0007155 cell adhesion	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This annotation is based on UniProt keyword mapping. DAF-2 contains fibronectin type III domains which can mediate cell adhesion in some contexts. Reason: While DAF-2 does contain fibronectin type III domains, there is no evidence that cell adhesion is a significant function of DAF-2. The FN3 domains likely serve structural roles in the receptor or may contribute to ligand binding. Cell adhesion is not a documented function of insulin/IGF-1 family receptors.
GO:0016020 membrane	IEA GO_REF:0000044	MODIFY	Summary: DAF-2 is a membrane-localized receptor. Reason: This is too general. The more specific term plasma membrane (GO:0005886) is already annotated and is more appropriate for a cell surface receptor. Proposed replacements: plasma membrane
GO:0016301 kinase activity	IEA GO_REF:0000043	MODIFY	Summary: DAF-2 has tyrosine kinase activity. Reason: Too general. More specific terms (protein tyrosine kinase activity, transmembrane receptor protein tyrosine kinase activity) are already annotated and should be preferred. Proposed replacements: transmembrane receptor protein tyrosine kinase activity
GO:0016740 transferase activity	IEA GO_REF:0000043	MODIFY	Summary: DAF-2 transfers phosphate groups as a kinase. Reason: Far too general. More specific kinase terms are already annotated and should be used instead. Proposed replacements: transmembrane receptor protein tyrosine kinase activity
GO:0030424 axon	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate annotation for axon localization (also annotated via IBA). Reason: This is a valid localization supported by direct experimental evidence (PMID:25035490). Duplicate annotations with different evidence codes are acceptable in GO.
GO:0045087 innate immune response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: DAF-2/insulin signaling regulates innate immunity. daf-2 mutants show enhanced resistance to bacterial pathogens through HSF-1 and DAF-16-dependent mechanisms. Reason: DAF-2 regulates immune function through its control of stress response pathways and transcription factors. While not a direct immune function, this represents an important downstream effect of DAF-2 signaling on organismal defense. Supporting Evidence: PMID:16916933 HSF-1 is needed for the effects of the DAF-2 insulin-like pathway in defense to pathogens
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: The kinase domain requires divalent cations (Mg2+, Mn2+) as cofactors. Reason: Protein kinases typically require divalent metal ions for catalytic activity. UniProt notes Mg2+ as a cofactor for DAF-2.
GO:0050829 defense response to Gram-negative bacterium	IGI PMID:16916933 Heat-shock transcription factor (HSF)-1 pathway required for...	KEEP AS NON CORE	Summary: daf-2 mutants show enhanced resistance to Gram-negative pathogens including Pseudomonas aeruginosa and Salmonella enterica through HSF-1-dependent mechanisms. Reason: DAF-2 regulates pathogen resistance through its control of stress response pathways (HSF-1, DAF-16). This is a downstream consequence of DAF-2 signaling rather than a direct role in immunity, but is a well-documented phenotype. Supporting Evidence: PMID:16916933 HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis
GO:0006606 protein import into nucleus	IMP PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D...	ACCEPT	Summary: DAF-2 signaling prevents DAF-16 nuclear accumulation. In daf-2 mutants, DAF-16 accumulates in nuclei. Reason: DAF-2 acts upstream to negatively regulate DAF-16 nuclear localization. This annotation captures DAF-2's regulatory role in controlling nuclear import of downstream transcription factors. Supporting Evidence: PMID:11381260 the DAF-2 pathway prevents DAF-16 accumulation in nuclei
GO:0006606 protein import into nucleus	IMP PMID:18358814 Direct inhibition of the longevity-promoting factor SKN-1 by...	ACCEPT	Summary: DAF-2 signaling also prevents SKN-1 nuclear accumulation in the intestine. Reduced DAF-2 signaling leads to constitutive SKN-1 nuclear localization. Reason: This demonstrates DAF-2 regulates nuclear import of multiple transcription factors, not just DAF-16. SKN-1 is another important target of IIS. Supporting Evidence: PMID:18358814 reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine
GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process	IMP PMID:23770237 Insulin/IGF-1 signaling regulates proteasome activity throug...	KEEP AS NON CORE	Summary: DAF-2/insulin signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4. Reason: This is a downstream effect of DAF-2 signaling on protein homeostasis, not a core function. The annotation is valid but represents a pleiotropic effect of insulin signaling. Supporting Evidence: PMID:23770237 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:23770237 Insulin/IGF-1 signaling regulates proteasome activity throug...	KEEP AS NON CORE	Summary: DAF-2 signaling regulates transcription through its effects on DAF-16 and other transcription factors. Reason: This is too general and represents an indirect downstream effect. DAF-2's regulation of transcription occurs through its control of transcription factors like DAF-16 and SKN-1. Supporting Evidence: PMID:23770237 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4.
GO:0008340 determination of adult lifespan	IGI PMID:19167330 Age-dependent deterioration of nuclear pore complexes causes...	ACCEPT	Summary: daf-2 mutants have extended lifespan through regulation of nuclear pore complex integrity and other mechanisms. Reason: Lifespan regulation is one of the most well-established and important functions of DAF-2. This is a core function with extensive experimental support. Supporting Evidence: PMID:9252323 Decreased DAF-2 signaling also causes an increase in life-span PMID:19167330 Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells.
GO:0008340 determination of adult lifespan	IMP PMID:19167330 Age-dependent deterioration of nuclear pore complexes causes...	ACCEPT	Summary: daf-2 mutant phenotype directly demonstrates its role in lifespan determination. Reason: Core function of DAF-2 with extensive experimental validation across many studies. Supporting Evidence: PMID:9790527 Decreasing daf-2 activity causes fertile adults to remain active much longer than normal and to live more than twice as long PMID:19167330 Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells.
GO:0010629 negative regulation of gene expression	IMP PMID:17526726 Specificity and complexity of the Caenorhabditis elegans inn...	ACCEPT	Summary: DAF-2 signaling suppresses expression of stress response and longevity genes by inhibiting DAF-16 and SKN-1. Reason: This accurately reflects DAF-2's role in suppressing DAF-16-dependent gene expression. In daf-2 mutants, many DAF-16 target genes are upregulated. Supporting Evidence: PMID:17526726 May 25. Specificity and complexity of the Caenorhabditis elegans innate immune response.
GO:1902075 cellular response to salt	IMP PMID:24013594 Neuropeptide signaling remodels chemosensory circuit composi...	KEEP AS NON CORE	Summary: DAF-2/insulin signaling is involved in salt chemosensory responses and salt learning behavior. Reason: This is a specific neuronal function of DAF-2 in chemosensory neurons but not a core molecular function. Valid annotation for this specific context. Supporting Evidence: PMID:24013594 Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans.
GO:1902075 cellular response to salt	IGI PMID:24013594 Neuropeptide signaling remodels chemosensory circuit composi...	KEEP AS NON CORE	Summary: Genetic interaction evidence for DAF-2 role in salt response. Reason: Valid annotation supporting DAF-2's role in neuronal salt sensing, which is upstream of dauer/lifespan decisions. Supporting Evidence: PMID:24013594 Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans.
GO:1900181 negative regulation of protein localization to nucleus	IMP PMID:24671950 A Caenorhabditis elegans developmental decision requires ins...	ACCEPT	Summary: DAF-2 negatively regulates DAF-16 nuclear localization through AKT-mediated phosphorylation. Reason: This is a core mechanism of DAF-2 action. Phosphorylation of DAF-16 by AKT downstream of DAF-2 prevents its nuclear accumulation, keeping longevity genes suppressed. Supporting Evidence: PMID:11381260 the DAF-2 pathway prevents DAF-16 accumulation in nuclei PMID:24671950 A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication.
GO:1905909 regulation of dauer entry	IGI PMID:24671950 A Caenorhabditis elegans developmental decision requires ins...	ACCEPT	Summary: DAF-2 signaling regulates the decision to enter dauer diapause through neuron-intestine communication. Reason: Dauer regulation is a core function of DAF-2. The receptor integrates environmental signals to control this developmental decision. Supporting Evidence: PMID:24671950 A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication.
GO:1905910 negative regulation of dauer entry	IMP PMID:24671950 A Caenorhabditis elegans developmental decision requires ins...	ACCEPT	Summary: DAF-2 activity prevents dauer entry under favorable conditions. Reason: This is a core function of DAF-2. Active DAF-2 signaling promotes reproductive development rather than dauer arrest. Supporting Evidence: PMID:9252323 daf-2, a key gene in the genetic pathway that mediates this endocrine signaling PMID:24671950 A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication.
GO:0008340 determination of adult lifespan	IMP PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media...	ACCEPT	Summary: Lifespan determination through insulin signaling pathway. Reason: Core function with multiple lines of experimental evidence. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development.
GO:0040024 dauer larval development	IMP PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media...	ACCEPT	Summary: DAF-2 signaling controls dauer larval development. Reason: Core function of DAF-2. daf-2 mutants constitutively enter dauer at restrictive temperatures. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development.
GO:0045887 positive regulation of synaptic assembly at neuromuscular junction	IGI PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media...	KEEP AS NON CORE	Summary: DAF-2/insulin signaling regulates neuromuscular junction development through interaction with FSN-1. Reason: This represents a specific developmental role of DAF-2 in synaptic development, a pleiotropic effect of insulin signaling in neurons. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development.
GO:1900075 positive regulation of neuromuscular synaptic transmission	IGI PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media...	KEEP AS NON CORE	Summary: DAF-2 signaling contributes to normal synaptic transmission at NMJs. Reason: Downstream effect of DAF-2 signaling on neuronal function, not core function. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development.
GO:0010286 heat acclimation	IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: DAF-2 signaling regulates thermotolerance through DAF-16 and stress response genes. Reason: Stress resistance is a well-documented output of DAF-2 signaling. daf-2 mutants have enhanced thermotolerance through DAF-16-dependent mechanisms. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0010286 heat acclimation	IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: Genetic interaction evidence for heat acclimation function. Reason: Valid annotation supporting DAF-2's role in stress response. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:1905909 regulation of dauer entry	IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: Genetic interactions demonstrate DAF-2 role in dauer regulation. Reason: Core function of DAF-2 with extensive genetic support. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0006979 response to oxidative stress	IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: daf-2 mutants have enhanced oxidative stress resistance through DAF-16-dependent activation of antioxidant genes. Reason: Oxidative stress resistance is a key output of reduced DAF-2 signaling and contributes to extended lifespan. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance
GO:0006979 response to oxidative stress	IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: Genetic interaction evidence for oxidative stress response. Reason: Valid annotation supporting DAF-2's role in stress resistance. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0009411 response to UV	IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: daf-2 mutants have enhanced UV resistance. Reason: UV resistance is part of the general stress resistance phenotype of daf-2 mutants, mediated by DAF-16 target genes. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0009411 response to UV	IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: Genetic interaction evidence for UV response. Reason: Valid supporting evidence for stress response function. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0010468 regulation of gene expression	IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: DAF-2 regulates gene expression through DAF-16 and SKN-1. Reason: Gene expression regulation is a fundamental output of DAF-2 signaling, mediated through control of multiple transcription factors. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0010629 negative regulation of gene expression	IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: DAF-2 suppresses DAF-16-dependent gene expression. Reason: Negative regulation of DAF-16 target genes is a core function of active DAF-2 signaling. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0010883 regulation of lipid storage	IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: DAF-2 regulates fat storage through DAF-16-dependent mechanisms. Reason: Fat storage regulation is a well-documented metabolic function of DAF-2. daf-2 mutants accumulate excess fat. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0010888 negative regulation of lipid storage	IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: DAF-2 activity suppresses lipid accumulation. Reason: Active DAF-2 signaling promotes utilization of stored lipids; loss of daf-2 leads to fat accumulation. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:1905910 negative regulation of dauer entry	IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C....	ACCEPT	Summary: DAF-2 prevents dauer entry under favorable conditions. Reason: Core function of DAF-2 signaling. Supporting Evidence: PMID:21531333 Asymmetric arginine dimethylation determines life span in C.
GO:0008340 determination of adult lifespan	IMP PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorha...	ACCEPT	Summary: DAF-2 signaling interacts with translation machinery (eIF4E) to regulate lifespan. Reason: Core lifespan function with genetic evidence. Supporting Evidence: PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans.
GO:0008340 determination of adult lifespan	IGI PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorha...	ACCEPT	Summary: Genetic interactions demonstrate DAF-2 role in lifespan determination. Reason: Core function with multiple supporting genetic interactions. Supporting Evidence: PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans.
GO:0008340 determination of adult lifespan	IMP PMID:27564576 Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is...	ACCEPT	Summary: DAF-2 signaling contributes to lifespan regulation. Reason: Core function with extensive experimental support. Supporting Evidence: PMID:27564576 eCollection 2016 Aug.
GO:0010628 positive regulation of gene expression	IMP PMID:19489741 Endogenous cGMP regulates adult longevity via the insulin si...	KEEP AS NON CORE	Summary: DAF-2 can positively regulate some genes through its downstream signaling. Reason: While DAF-2 primarily suppresses DAF-16 targets, some genes are positively regulated by insulin signaling. This is context-dependent. Supporting Evidence: PMID:19489741 2009 May 31. Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans.
GO:0030536 larval feeding behavior	IMP PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and...	ACCEPT	Summary: DAF-2 signaling regulates feeding behavior and satiety responses. Reason: Feeding regulation is an important metabolic function of insulin signaling. DAF-2 controls satiety and food intake through integration with TGF-beta and cGMP pathways. Supporting Evidence: PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C.
GO:0030536 larval feeding behavior	IGI PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and...	ACCEPT	Summary: Genetic interaction evidence for feeding behavior regulation. Reason: Valid supporting evidence for metabolic/behavioral function. Supporting Evidence: PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C.
GO:1903998 regulation of eating behavior	IMP PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and...	ACCEPT	Summary: DAF-2 regulates eating behavior as part of its metabolic signaling function. Reason: Feeding regulation is a conserved function of insulin signaling pathways. Supporting Evidence: PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C.
GO:1903998 regulation of eating behavior	IGI PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and...	ACCEPT	Summary: Genetic interaction evidence for eating behavior regulation. Reason: Valid supporting evidence. Supporting Evidence: PMID:18316030 Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C.
GO:0061065 regulation of dauer larval development	IMP PMID:1732156 Genetic analysis of chemosensory control of dauer formation ...	ACCEPT	Summary: Classical genetic analysis established DAF-2 as a key regulator of dauer formation in the dauer regulatory pathway. Reason: Foundational study establishing DAF-2's role in dauer regulation through genetic epistasis analysis. Core function. Supporting Evidence: PMID:1732156 Three other genes, daf-2, daf-3 and daf-5, displayed partial or complex epistasis interactions
GO:0005886 plasma membrane	IDA PMID:24120884 DAF-2 and ERK couple nutrient availability to meiotic progre...	ACCEPT	Summary: Direct observation of DAF-2 localization to plasma membrane in oocytes. Reason: Direct experimental evidence for plasma membrane localization consistent with receptor function. Supporting Evidence: PMID:24120884 2013 Oct 10. DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis.
GO:0040024 dauer larval development	IMP PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid...	ACCEPT	Summary: DAF-2 signaling interacts with beta-catenin and FOXO in dauer regulation. Reason: Dauer development is a core function of DAF-2. Supporting Evidence: PMID:15905404 Functional interaction between beta-catenin and FOXO in oxidative stress signaling.
GO:0042169 SH2 domain binding	IPI PMID:18832074 SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pat...	ACCEPT	Summary: DAF-2 physically interacts with the SH2 domain of the adaptor protein SHC-1, which modulates insulin signaling output. Reason: Direct physical interaction demonstrating SH2 domain binding activity. This is important for signal transduction downstream of the receptor. Supporting Evidence: PMID:18832074 SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2
GO:0051425 PTB domain binding	IPI PMID:18832074 SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pat...	ACCEPT	Summary: DAF-2 interacts with the PTB (phosphotyrosine-binding) domain of SHC-1. Reason: Direct physical interaction evidence. PTB domains bind phosphotyrosine residues on activated receptors. Supporting Evidence: PMID:18832074 SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2
GO:0097730 non-motile cilium	IDA PMID:16968739 IFTA-2 is a conserved cilia protein involved in pathways reg...	ACCEPT	Summary: DAF-2 localizes to sensory cilia where it detects environmental signals for dauer formation and lifespan regulation. Reason: Ciliary localization is important for DAF-2's role in sensing environmental conditions that regulate dauer entry and lifespan. Supporting Evidence: PMID:16968739 phenotypes result from defects in the DAF-2 (insulin-IGF-1-like) receptor signaling pathway in ciliated sensory neurons
GO:0030424 axon	IDA PMID:25035490 Role of synaptic phosphatidylinositol 3-kinase in a behavior...	ACCEPT	Summary: DAF-2 isoform c localizes to axons in ASER neurons for taste avoidance learning. Reason: Direct imaging evidence for axonal localization of DAF-2c isoform, required for learning behavior. Supporting Evidence: PMID:25035490 DAF-2c, is translocated from the cell body to the synaptic region of the chemosensory neuron
GO:0043025 neuronal cell body	IDA PMID:25035490 Role of synaptic phosphatidylinositol 3-kinase in a behavior...	ACCEPT	Summary: DAF-2 localizes to neuronal cell bodies before translocation to synaptic regions during learning. Reason: Direct observation of DAF-2 localization in neuronal cell bodies. Supporting Evidence: PMID:25035490 DAF-2c, is translocated from the cell body to the synaptic region
GO:0005737 cytoplasm	IDA PMID:24120884 DAF-2 and ERK couple nutrient availability to meiotic progre...	ACCEPT	Summary: DAF-2 is detected in cytoplasm in addition to membrane locations. Reason: Receptors can be present in cytoplasmic pools during trafficking and recycling. Supporting Evidence: PMID:24120884 2013 Oct 10. DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis.
GO:0031410 cytoplasmic vesicle	IDA PMID:24120884 DAF-2 and ERK couple nutrient availability to meiotic progre...	ACCEPT	Summary: DAF-2 localizes to cytoplasmic vesicles, likely during receptor trafficking. Reason: Vesicular localization is consistent with receptor endocytosis and recycling. Supporting Evidence: PMID:24120884 2013 Oct 10. DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis.
GO:2000785 regulation of autophagosome assembly	IMP PMID:22560223 TOR signaling and rapamycin influence longevity by regulatin...	ACCEPT	Summary: DAF-2 negatively regulates autophagy. daf-2 RNAi increases LGG-1-positive autophagic vesicles. Reason: Autophagy regulation is an important output of DAF-2 signaling that contributes to longevity and stress resistance. Supporting Evidence: PMID:22560223 when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity
GO:0019901 protein kinase binding	IPI PMID:22672310 Modulation of Caenorhabditis elegans infection sensitivity b...	ACCEPT	Summary: DAF-2 binds protein kinases as part of its signaling mechanism. Reason: DAF-2 interacts with downstream kinases in the insulin signaling cascade. Direct interaction evidence. Supporting Evidence: PMID:22672310 Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.
GO:0040018 positive regulation of multicellular organism growth	IMP PMID:12571101 Cyclic GMP-dependent protein kinase EGL-4 controls body size...	ACCEPT	Summary: DAF-2 promotes organismal growth; daf-2 mutants have reduced body size. Reason: Growth regulation is a conserved function of insulin/IGF signaling. DAF-2 promotes reproductive development and body size. Supporting Evidence: PMID:12571101 Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C elegans.
GO:1901031 regulation of response to reactive oxygen species	IMP PMID:12399591 Timing requirements for insulin/IGF-1 signaling in C. elegan...	ACCEPT	Summary: DAF-2 signaling regulates the response to oxidative stress. Reason: Regulation of ROS response is an important function of DAF-2 that contributes to longevity phenotypes. Supporting Evidence: PMID:12399591 Timing requirements for insulin/IGF-1 signaling in C.
GO:0008340 determination of adult lifespan	IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans...	ACCEPT	Summary: Genetic interaction with RAGA-1 in lifespan determination. Reason: Core function with supporting genetic interaction evidence. Supporting Evidence: PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1.
GO:0040034 regulation of development, heterochronic	IGI PMID:21471153 The zinc-finger protein SEA-2 regulates larval developmental...	KEEP AS NON CORE	Summary: DAF-2 interacts with SEA-2 to regulate developmental timing and seam cell development. Reason: Heterochronic regulation is a specific developmental role, not a core function of DAF-2. Valid annotation for this developmental context. Supporting Evidence: PMID:21471153 The zinc-finger protein SEA-2 regulates larval developmental timing and adult lifespan in C.
GO:0008340 determination of adult lifespan	IMP PMID:9790527 Cell nonautonomy of C. elegans daf-2 function in the regulat...	ACCEPT	Summary: Seminal paper demonstrating daf-2 mutants live more than twice as long as wild-type animals. Reason: Core function with foundational experimental support. Supporting Evidence: PMID:9790527 Decreasing daf-2 activity causes fertile adults to remain active much longer than normal and to live more than twice as long
GO:0040024 dauer larval development	IMP PMID:9790527 Cell nonautonomy of C. elegans daf-2 function in the regulat...	ACCEPT	Summary: daf-2 mutants enter dauer diapause at restrictive temperatures. Reason: Core function of DAF-2 in regulating dauer vs. reproductive development. Supporting Evidence: PMID:9790527 A more severe decrease in daf-2 function causes young larvae to enter a state of diapause rather than progressing to adulthood
GO:0043054 dauer exit	IMP PMID:9790527 Cell nonautonomy of C. elegans daf-2 function in the regulat...	ACCEPT	Summary: DAF-2 signaling promotes exit from dauer diapause. Reason: DAF-2 regulates both entry and exit from dauer state. Core developmental function. Supporting Evidence: PMID:9790527 Cell nonautonomy of C.
GO:0005009 insulin receptor activity	ISS PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevit...	ACCEPT	Summary: Sequence similarity to mammalian insulin receptors supports insulin receptor activity annotation. Reason: Core molecular function based on sequence homology and functional conservation. DAF-2 was identified as an insulin receptor family member. Supporting Evidence: PMID:9252323 daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member
GO:0005524 ATP binding	ISS PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevit...	ACCEPT	Summary: ATP binding inferred by sequence similarity to insulin receptor kinase domain. Reason: The kinase domain of DAF-2 has conserved ATP-binding motifs. Supporting Evidence: PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.
GO:0008286 insulin receptor signaling pathway	ISS PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevit...	ACCEPT	Summary: DAF-2 initiates insulin receptor signaling based on sequence homology and genetic evidence. Reason: Core biological process of DAF-2. The receptor initiates a conserved PI3K/AKT signaling cascade. Supporting Evidence: PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.
GO:0017046 peptide hormone binding	ISS PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevit...	ACCEPT	Summary: DAF-2 binds insulin-like peptide (ILP) ligands encoded by the ins gene family. Reason: The extracellular domain of DAF-2 binds insulin-like peptide ligands that regulate its activity. C. elegans has approximately 40 insulin-like peptides. Supporting Evidence: PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.
GO:0040024 dauer larval development	IMP PMID:10625546 Targets of TGF-beta signaling in Caenorhabditis elegans daue...	ACCEPT	Summary: DAF-2 interacts with TGF-beta signaling in dauer regulation. Reason: Core function with multiple supporting studies. Supporting Evidence: PMID:10625546 Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation.
GO:0040024 dauer larval development	IMP PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D...	ACCEPT	Summary: daf-2 mutants show enhanced dauer formation through DAF-16 regulation. Reason: Core function with extensive experimental support. Supporting Evidence: PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling.
GO:0008340 determination of adult lifespan	IMP PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D...	ACCEPT	Summary: daf-2 mutants have extended lifespan requiring DAF-16. Reason: Core function established in this foundational paper. Supporting Evidence: PMID:11381260 Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long
GO:0040024 dauer larval development	IMP PMID:9252323 daf-2, an insulin receptor-like gene that regulates longevit...	ACCEPT	Summary: Original identification of daf-2 as regulator of dauer diapause. Reason: Core function established in the seminal cloning paper. Supporting Evidence: PMID:9252323 A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage

Gene Description

Existing Annotations Review

Core Functions

DAF-2 functions as a transmembrane receptor tyrosine kinase that autophosphorylates and phosphorylates downstream substrates upon ligand binding. As the C. elegans insulin/IGF-1 receptor ortholog, it binds insulin-like peptide ligands to regulate metabolism and development.

References

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Falcon

📚 Additional Documentation

Bioreason Rl Predictions

Bioreason Rl Review

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