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

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.

Molecular Function:

transmembrane receptor protein tyrosine kinase activity

Directly Involved In:

insulin receptor signaling pathway determination of adult lifespan dauer larval development negative regulation of dauer entry negative regulation of protein localization to nucleus

Cellular Locations:

plasma membrane

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:9252323

daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.

DAF-2 is an insulin receptor family member

"daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans."
Regulates dauer diapause and longevity

"daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans."
Induces metabolic changes analogous to mammalian insulin signaling

"daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans."

PMID:9790527

Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span.

daf-2 mutants live more than twice as long as wild-type

"Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span."
daf-2 functions cell-nonautonomously

"Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span."
Regulates both dauer formation and adult lifespan

"Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span."

PMID:11381260

Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling.

DAF-2 signals through PI3K/AKT pathway

"Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling."
DAF-2 prevents DAF-16 nuclear accumulation

"Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling."
Lifespan extension requires DAF-16

"Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling."

PMID:16916933

Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity.

HSF-1 required for DAF-2 effects on immunity

"Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity."
daf-2 mutants have enhanced pathogen resistance

"Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity."

PMID:18358814

Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans.

DAF-2/IIS directly inhibits SKN-1 in parallel to DAF-16

"Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans."
SKN-1 contributes to longevity in daf-2 mutants

"Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans."

PMID:18832074

SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans.

SHC-1 directly interacts with DAF-2

"SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans."
SHC-1 opposes IIS through DAF-2 interaction

"SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans."

PMID:21531333

Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.

PRMT-1 regulates DAF-16 in the daf-2 pathway

"Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16."
daf-2 mutants show stress tolerance and fat storage

"Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16."

PMID:22560223

TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO.

DAF-2 negatively regulates autophagy

"TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO."
daf-2 RNAi increases autophagic vesicles

"TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO."

PMID:23665919

Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development.

DAF-2/insulin signaling regulates neuromuscular junction development

"Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development."

PMID:24120884

DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis.

DAF-2 signals through RAS-ERK in oogenesis

"DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis."
DAF-2 localizes to plasma membrane and cytoplasmic vesicles

"DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis."

PMID:25035490

Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans.

DAF-2c isoform translocates from cell body to synaptic region

"Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans."
Required for taste avoidance learning

"Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans."

PMID:16968739

IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans.

DAF-2 signaling operates in ciliated sensory neurons

"IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans."

PMID:1732156

Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans.

Classical genetic evidence for daf-2 role in dauer regulation

"Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans."

PMID:23770237

Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4.

DAF-2 signaling regulates proteasome activity

"Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4."

PMID:19167330

Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells.

DAF-2 regulates lifespan through nuclear pore complex integrity

"Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells."

PMID:17526726

Specificity and complexity of the Caenorhabditis elegans innate immune response.

DAF-2 suppresses expression of stress response genes

"Specificity and complexity of the Caenorhabditis elegans innate immune response."

PMID:24013594

Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans.

DAF-2/insulin signaling involved in salt chemosensory learning

"Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans."

PMID:24671950

A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication.

DAF-2 regulates dauer entry through neuron-intestine communication

"A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication."

PMID:17277769

eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans.

DAF-2 signaling interacts with translation machinery

"eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans."

PMID:27564576

Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans.

DAF-2 signaling contributes to lifespan regulation

"Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans."

PMID:19489741

Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans.

DAF-2 can positively regulate some genes through downstream signaling

"Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans."

PMID:18316030

Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety.

DAF-2 signaling regulates feeding behavior and satiety responses

"Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety."

PMID:15905404

Functional interaction between beta-catenin and FOXO in oxidative stress signaling.

DAF-2 signaling interacts with beta-catenin in dauer regulation

"Functional interaction between beta-catenin and FOXO in oxidative stress signaling."

PMID:22672310

Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.

DAF-2 binds protein kinases in signaling cascade

"Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein."

PMID:12571101

Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C elegans.

DAF-2 promotes organismal growth

"Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C elegans."

PMID:12399591

Timing requirements for insulin/IGF-1 signaling in C. elegans.

DAF-2 signaling regulates the response to oxidative stress

"Timing requirements for insulin/IGF-1 signaling in C. elegans."

PMID:20523893

Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1.

Genetic interaction between RAGA-1 and DAF-2 in lifespan determination

"Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1."

PMID:21471153

The zinc-finger protein SEA-2 regulates larval developmental timing and adult lifespan in C. elegans.

DAF-2 interacts with SEA-2 in heterochronic regulation

"The zinc-finger protein SEA-2 regulates larval developmental timing and adult lifespan in C. elegans."

PMID:10625546

Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation.

DAF-2 interacts with TGF-beta signaling in dauer regulation

"Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation."

file:worm/daf-2/daf-2-deep-research-falcon.md

Deep research report on daf-2

📚 Additional Documentation

Deep Research Bioreason

(daf-2-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:06 AM

Organism: Caenorhabditis elegans

Sequence:

MTRMNIVRCRRRHKILENLEEENLGPSCSSTTSTTAATEALGTTTEDMRLKQQRSSSRATEHDIVDGNHHDDEHITMRRLRLVKNSRTRRRTTPDSSMDCYEENPPSQKTSINYSWISKKSSMTSLMLLLLFAFVQPCASIVEKRCGPIDIRNRPWDIKPQWSKLGDPNEKDLAGQRMVNCTVVEGSLTISFVLKHKTKAQEEMHRSLQPRYSQDEFITFPHLREITGTLLVFETEGLVDLRKIFPNLRVIGGRSLIQHYALIIYRNPDLEIGLDKLSVIRNGGVRIIDNRKLCYTKTIDWKHLITSSINDVVVDNAAEYAVTETGLMCPRGACEEDKGESKCHYLEEKNQEQGVERVQSCWSNTTCQKSCAYDRLLPTKEIGPGCDANGDRCHDQCVGGCERVNDATACHACKNVYHKGKCIEKCDAHLYLLLQRRCVTREQCLQLNPVLSNKTVPIKATAGLCSDKCPDGYQINPDDHRECRKCVGKCEIVCEINHVIDTFPKAQAIRLCNIIDGNLTIEIRGKQDSGMASELKDIFANIHTITGYLLVRQSSPFISLNMFRNLRRIEAKSLFRNLYAITVFENPNLKKLFDSTTDLTLDRGTVSIANNKMLCFKYIKQLMSKLNIPLDPIDQSEGTNGEKAICEDMAINVSITAVNADSVFFSWPSFNITDIDQRKFLGYELFFKEVPRIDENMTIEEDRSACVDSWQSVFKQYYETSNGEPTPDIFMDIGPRERIRPNTLYAYYVATQMVLHAGAKNGVSKIGFVRTSYYTPDPPTLALAQVDSDAIHITWEAPLQPNGDLTHYTIMWRENEVSPYEEAEKFCTDASTPANRQHTKDPKETIVADKPVDIPSSRTVAPTLLTMMGHEDQQKTCAATPGCCSCSAIEESSEQNKKKRPDPMSAIESSAFENKLLDEVLMPRDTMRVRRSIEDANRVSEELEKAENLGKAPKTLGGKKPLIHISKKKPSSSSTTSTPAPTIASMYALTRKPTTVPGTRIRLYEIYEPLPGSWAINVSALALDNSYVIRNLKHYTLYAISLSACQNMTVPGASCSISHRAGALKRTKHITDIDKVLNETIEWRFMNNSQQVNVTWDPPTEVNGGIFGYVVKLKSKVDGSIVMTRCVGAKRGYSTRNQGVLFQNLADGRYFVSVTATSVHGAGPEAESSDPIVVMTPGFFTVEIILGMLLVFLILMSIAGCIIYYYIQVRYGKKVKALSDFMQLNPEYCVDNKYNADDWELRQDDVVLGQQCGEGSFGKVYLGTGNNVVSLMGDRFGPCAIKINVDDPASTENLNYLMEANIMKNFKTNFIVKLYGVISTVQPAMVVMEMMDLGNLRDYLRSKREDEVFNETDCNFFDIIPRDKFHEWAAQICDGMAYLESLKFCHRDLAARNCMINRDETVKIGDFGMARDLFYHDYYKPSGKRMMPVRWMSPESLKDGKFDSKSDVWSFGVVLYEMVTLGAQPYIGLSNDEVLNYIGMARKVIKKPECCENYWYKVMKMCWRYSPRDRPTFLQLVHLLAAEASPEFRDLSFVLTDNQMILDDSEALDLDDIDDTDMNDQVVEVAPDVENVEVQSDSERRNTDSIPLKQFKTIPPINATTSHSTISIDETPMKAKQREGSLDEEYALMNHSGGPSDAEVRTYAGDGDYVERDVRENDVPTRRNTGASTSSYTGGGPYCLTNRGGSNERGAGFGEAVRLTDGVGSGHLNDDDYVEKEISSMDTRRSTGASSSSYGVPQTNWSGNRGATYYTSKAQQAATAAAAAAAALQQQQNGGRGDRLTQLPGTGHLQSTRGGQDGDYIETEPKNYRNNGSPSRNGNSRDIFNGRSAFGENEHLIEDNEHHPLV

Thinking Trace

I begin with the InterPro architecture and its order along the polypeptide. The N-terminal half is dominated by ligand-binding modules: IPR036941 (Receptor L-domain superfamily, residues 169–655) encompasses IPR000494 (Receptor L-domain, residues 180–625), a classic extracellular ligand-binding scaffold used by many receptor tyrosine kinases to capture growth factor-like ligands. Embedded within this region is a cysteine-rich segment—IPR009030 (Growth factor receptor cysteine-rich domain superfamily, residues 342–494) and its core IPR006211 (Furin-like cysteine-rich domain, residues 347–495)—which forms a disulfide-stabilized module that often mediates high-affinity ligand engagement and proteolytic maturation. Immediately downstream, the extracellular stalk transitions into an Ig/FN3-rich region: IPR036116 (Fibronectin type III superfamily, residues 651–1174), IPR013783 (Immunoglobulin-like fold superfamily, residues 656–1178), and the specific IPR003961 (Fibronectin type III, residues 775–1179). This tandem array of Ig/FN3 folds creates an elongated ectodomain that positions ligand-binding sites at an appropriate distance from the membrane and promotes dimerization upon ligand binding.

The intracellular half is a canonical tyrosine kinase engine. Multiple overlapping signatures define a receptor tyrosine kinase catalytic core: IPR050122 (Receptor Tyrosine Kinase family, residues 712–1521) frames the overall receptor class; IPR011009 (Protein kinase-like domain superfamily, residues 1228–1519), IPR020635 (Tyrosine-protein kinase, catalytic domain, residues 1246–1520), IPR000719 (Protein kinase domain, residues 1246–1528), and IPR001245 (Serine-threonine/tyrosine-protein kinase, catalytic domain, residues 1248–1519) collectively mark the bilobal kinase fold; and IPR008266 (Tyrosine-protein kinase, active site, residues 1384–1396) pinpoints the catalytic center. This architecture causes ATP-dependent phosphotransfer with specificity toward tyrosine residues once extracellular ligand-induced dimerization aligns the two cytoplasmic kinase domains.

From this domain layout, the molecular function resolves as a transmembrane receptor that binds extracellular ligands via L and cysteine-rich modules and transduces signals by intracellular tyrosine kinase activity. The catalytic core and active-site signature establish protein tyrosine kinase chemistry, while the large ectodomain and RTK family membership define a ligand-activated receptor. Therefore, the primary molecular function is ATP-dependent protein tyrosine kinase activity that is coupled to extracellular ligand recognition and dimerization-driven activation.

This receptor-driven phosphorylation cascade initiates a canonical pathway: extracellular cues trigger ectodomain-mediated dimerization, aligning the kinase domains for trans-autophosphorylation on activation loop and tail tyrosines. Those phosphotyrosines nucleate assembly of SH2/PTB adaptor complexes, propagating signals that control proliferation, differentiation, and survival. This causally places the protein in transmembrane receptor protein tyrosine kinase signaling, a specific signaling axis that integrates growth factor inputs with intracellular decision-making.

The topology implied by the N-terminal ectodomain and intracellular kinase module is single-pass type I, matching the annotated subcellular location. Such receptors are integral to the plasma membrane where they survey the extracellular milieu and initiate cytoplasmic signaling. Thus, the cellular component is an integral component of membrane at the cell surface/plasma membrane.

Mechanistically, I hypothesize that ligand binding to the L-domain plus cysteine-rich module induces receptor dimerization and clustering of the FN3/Ig stalk, which stabilizes the active dimeric state of the cytoplasmic kinase core. Autophosphorylation creates docking sites for SH2/PTB-containing adaptors and cytosolic kinases. Likely interaction partners include extracellular growth-factor-like ligands compatible with L-domain receptors, membrane-proximal adaptors that read phosphotyrosines, and cytoplasmic kinases that amplify the signal. Together, these interactions produce a robust receptor tyrosine kinase signaling hub at the plasma membrane.

Functional Summary

A single-pass cell-surface receptor that uses a modular extracellular region to bind growth factor-like ligands and a cytoplasmic kinase engine to transmit signals. Ligand engagement by the ectodomain induces receptor dimerization and activation of an intracellular tyrosine kinase core, driving autophosphorylation and recruitment of adaptor complexes that propagate downstream signaling controlling cell proliferation and fate decisions at the plasma membrane.

UniProt Summary

Tyrosine-protein kinase receptor.

InterPro Domains

Receptor L-domain superfamily (IPR036941, homologous_superfamily) — residues 169-655
Receptor L-domain (IPR000494, domain) — residues 180-625
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 342-494
Furin-like cysteine-rich domain (IPR006211, domain) — residues 347-495
Fibronectin type III superfamily (IPR036116, homologous_superfamily) — residues 651-1174
Immunoglobulin-like fold (IPR013783, homologous_superfamily) — residues 656-1178
Receptor Tyrosine Kinase (IPR050122, family) — residues 712-1521
Fibronectin type III (IPR003961, domain) — residues 775-1179
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 1228-1519
Tyrosine-protein kinase, catalytic domain (IPR020635, domain) — residues 1246-1520
Protein kinase domain (IPR000719, domain) — residues 1246-1528
Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245, domain) — residues 1248-1519
Tyrosine-protein kinase, active site (IPR008266, active_site) — residues 1384-1396

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), protein binding (GO:0005515), protein domain specific binding (GO:0019904), enzyme binding (GO:0019899), kinase binding (GO:0019900), SH2 domain binding (GO:0042169), protein kinase binding (GO:0019901)

Biological Process: biological_process (GO:0008150), localization (GO:0051179), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), reproduction (GO:0000003), multicellular organismal process (GO:0032501), biological regulation (GO:0065007), response to stimulus (GO:0050896), developmental process (GO:0032502), cellular process (GO:0009987), negative regulation of biological process (GO:0048519), negative regulation of lipid localization (GO:1905953), cellular localization (GO:0051641), anatomical structure development (GO:0048856), dormancy process (GO:0022611), response to chemical (GO:0042221), positive regulation of multicellular organismal process (GO:0051240), negative regulation of multicellular organismal process (GO:0051241), regulation of multicellular organismal process (GO:0051239), positive regulation of growth (GO:0045927), post-embryonic development (GO:0009791), negative regulation of metabolic process (GO:0009892), regulation of developmental process (GO:0050793), regulation of biological quality (GO:0065008), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), regulation of signaling (GO:0023051), negative regulation of developmental process (GO:0051093), negative regulation of cellular process (GO:0048523), response to abiotic stimulus (GO:0009628), positive regulation of signaling (GO:0023056), multicellular organism development (GO:0007275), determination of adult lifespan (GO:0008340), regulation of metabolic process (GO:0019222), regulation of localization (GO:0032879), establishment of localization (GO:0051234), macromolecule localization (GO:0033036), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), positive regulation of developmental process (GO:0051094), regulation of growth (GO:0040008), behavior (GO:0007610), positive regulation of cellular process (GO:0048522), response to temperature stimulus (GO:0009266), response to radiation (GO:0009314), negative regulation of protein localization (GO:1903828), regulation of response to stress (GO:0080134), feeding behavior (GO:0007631), regulation of macromolecule metabolic process (GO:0060255), regulation of lipid storage (GO:0010883), regulation of synapse structure or activity (GO:0050803), larval behavior (GO:0030537), positive regulation of cellular component biogenesis (GO:0044089), establishment of protein localization (GO:0045184), regulation of cellular component biogenesis (GO:0044087), response to heat (GO:0009408), regulation of catabolic process (GO:0009894), regulation of post-embryonic development (GO:0048580), regulation of development, heterochronic (GO:0040034), intracellular transport (GO:0046907), positive regulation of synaptic transmission (GO:0050806), negative regulation of macromolecule metabolic process (GO:0010605), regulation of nitrogen compound metabolic process (GO:0051171), larval development (GO:0002164), regulation of cellular component organization (GO:0051128), positive regulation of nervous system development (GO:0051962), regulation of developmental growth (GO:0048638), response to salt (GO:1902074), positive regulation of nitrogen compound metabolic process (GO:0051173), negative regulation of lipid storage (GO:0010888), positive regulation of developmental growth (GO:0048639), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of macromolecule metabolic process (GO:0010604), response to oxidative stress (GO:0006979), regulation of lipid localization (GO:1905952), regulation of cellular localization (GO:0060341), establishment of localization in cell (GO:0051649), positive regulation of cellular component organization (GO:0051130), negative regulation of cellular metabolic process (GO:0031324), positive regulation of biosynthetic process (GO:0009891), regulation of multicellular organismal development (GO:2000026), positive regulation of multicellular organism growth (GO:0040018), regulation of multicellular organism growth (GO:0040014), positive regulation of cellular metabolic process (GO:0031325), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), transport (GO:0006810), regulation of biosynthetic process (GO:0009889), cellular macromolecule localization (GO:0070727), regulation of cellular metabolic process (GO:0031323), positive regulation of cell communication (GO:0010647), negative regulation of catabolic process (GO:0009895), regulation of trans-synaptic signaling (GO:0099177), regulation of primary metabolic process (GO:0080090), regulation of behavior (GO:0050795), negative regulation of post-embryonic development (GO:0048581), regulation of nematode larval development (GO:0061062), nitrogen compound transport (GO:0071705), regulation of synapse organization (GO:0050807), regulation of macromolecule biosynthetic process (GO:0010556), regulation of protein metabolic process (GO:0051246), negative regulation of cellular catabolic process (GO:0031330), cellular response to salt (GO:1902075), organic substance transport (GO:0071702), nuclear transport (GO:0051169), regulation of gene expression (GO:0010468), intracellular protein transport (GO:0006886), negative regulation of protein localization to nucleus (GO:1900181), protein transport (GO:0015031), regulation of response to oxidative stress (GO:1902882), regulation of feeding behavior (GO:0060259), regulation of synaptic assembly at neuromuscular junction (GO:0008582), regulation of RNA metabolic process (GO:0051252), negative regulation of gene expression (GO:0010629), positive regulation of cell junction assembly (GO:1901890), response to light stimulus (GO:0009416), negative regulation of protein catabolic process (GO:0042177), regulation of protein catabolic process (GO:0042176), regulation of cell junction assembly (GO:1901888), establishment of protein localization to organelle (GO:0072594), negative regulation of protein metabolic process (GO:0051248), modulation of chemical synaptic transmission (GO:0050804), positive regulation of gene expression (GO:0010628), regulation of protein localization (GO:0032880), regulation of nervous system development (GO:0051960), regulation of organelle assembly (GO:1902115), positive regulation of neuromuscular junction development (GO:1904398), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), negative regulation of nematode larval development (GO:0061064), positive regulation of synapse assembly (GO:0051965), heat acclimation (GO:0010286), regulation of cellular biosynthetic process (GO:0031326), larval feeding behavior (GO:0030536), regulation of nucleobase-containing compound metabolic process (GO:0019219), regulation of organelle organization (GO:0033043), positive regulation of synaptic assembly at neuromuscular junction (GO:0045887), protein localization (GO:0008104), regulation of cellular catabolic process (GO:0031329), nematode larval development (GO:0002119), positive regulation of cellular biosynthetic process (GO:0031328), protein import into nucleus (GO:0006606), regulation of proteolysis (GO:0030162), regulation of vacuole organization (GO:0044088), regulation of autophagosome assembly (GO:2000785), negative regulation of proteasomal protein catabolic process (GO:1901799), regulation of RNA biosynthetic process (GO:2001141), regulation of response to reactive oxygen species (GO:1901031), regulation of neuromuscular junction development (GO:1904396), regulation of synapse assembly (GO:0051963), regulation of dauer larval development (GO:0061065), response to UV (GO:0009411), positive regulation of RNA biosynthetic process (GO:1902680), dauer larval development (GO:0040024), negative regulation of ubiquitin-dependent protein catabolic process (GO:2000059), regulation of protein localization to nucleus (GO:1900180), regulation of ubiquitin-dependent protein catabolic process (GO:2000058), nucleocytoplasmic transport (GO:0006913), protein localization to organelle (GO:0033365), regulation of DNA-templated transcription (GO:0006355), regulation of neuromuscular synaptic transmission (GO:1900073), regulation of eating behavior (GO:1903998), regulation of proteasomal protein catabolic process (GO:0061136), negative regulation of proteolysis (GO:0045861), negative regulation of dauer larval development (GO:0061067), protein localization to nucleus (GO:0034504), import into nucleus (GO:0051170), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), negative regulation of proteolysis involved in protein catabolic process (GO:1903051), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), regulation of proteolysis involved in protein catabolic process (GO:1903050), positive regulation of transcription by RNA polymerase II (GO:0045944)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), cell projection (GO:0042995), membrane (GO:0016020), cell body (GO:0044297), somatodendritic compartment (GO:0036477), cytoplasm (GO:0005737), cell periphery (GO:0071944), neuronal cell body (GO:0043025), plasma membrane bounded cell projection (GO:0120025), cytoplasmic vesicle (GO:0031410), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), neuron projection (GO:0043005), intracellular membrane-bounded organelle (GO:0043231), cilium (GO:0005929), vesicle (GO:0031982), axon (GO:0030424), intracellular vesicle (GO:0097708), non-motile cilium (GO:0097730)

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Deep Research Bioreason Rl

(daf-2-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:06 AM

Organism: Caenorhabditis elegans

Sequence:

MTRMNIVRCRRRHKILENLEEENLGPSCSSTTSTTAATEALGTTTEDMRLKQQRSSSRATEHDIVDGNHHDDEHITMRRLRLVKNSRTRRRTTPDSSMDCYEENPPSQKTSINYSWISKKSSMTSLMLLLLFAFVQPCASIVEKRCGPIDIRNRPWDIKPQWSKLGDPNEKDLAGQRMVNCTVVEGSLTISFVLKHKTKAQEEMHRSLQPRYSQDEFITFPHLREITGTLLVFETEGLVDLRKIFPNLRVIGGRSLIQHYALIIYRNPDLEIGLDKLSVIRNGGVRIIDNRKLCYTKTIDWKHLITSSINDVVVDNAAEYAVTETGLMCPRGACEEDKGESKCHYLEEKNQEQGVERVQSCWSNTTCQKSCAYDRLLPTKEIGPGCDANGDRCHDQCVGGCERVNDATACHACKNVYHKGKCIEKCDAHLYLLLQRRCVTREQCLQLNPVLSNKTVPIKATAGLCSDKCPDGYQINPDDHRECRKCVGKCEIVCEINHVIDTFPKAQAIRLCNIIDGNLTIEIRGKQDSGMASELKDIFANIHTITGYLLVRQSSPFISLNMFRNLRRIEAKSLFRNLYAITVFENPNLKKLFDSTTDLTLDRGTVSIANNKMLCFKYIKQLMSKLNIPLDPIDQSEGTNGEKAICEDMAINVSITAVNADSVFFSWPSFNITDIDQRKFLGYELFFKEVPRIDENMTIEEDRSACVDSWQSVFKQYYETSNGEPTPDIFMDIGPRERIRPNTLYAYYVATQMVLHAGAKNGVSKIGFVRTSYYTPDPPTLALAQVDSDAIHITWEAPLQPNGDLTHYTIMWRENEVSPYEEAEKFCTDASTPANRQHTKDPKETIVADKPVDIPSSRTVAPTLLTMMGHEDQQKTCAATPGCCSCSAIEESSEQNKKKRPDPMSAIESSAFENKLLDEVLMPRDTMRVRRSIEDANRVSEELEKAENLGKAPKTLGGKKPLIHISKKKPSSSSTTSTPAPTIASMYALTRKPTTVPGTRIRLYEIYEPLPGSWAINVSALALDNSYVIRNLKHYTLYAISLSACQNMTVPGASCSISHRAGALKRTKHITDIDKVLNETIEWRFMNNSQQVNVTWDPPTEVNGGIFGYVVKLKSKVDGSIVMTRCVGAKRGYSTRNQGVLFQNLADGRYFVSVTATSVHGAGPEAESSDPIVVMTPGFFTVEIILGMLLVFLILMSIAGCIIYYYIQVRYGKKVKALSDFMQLNPEYCVDNKYNADDWELRQDDVVLGQQCGEGSFGKVYLGTGNNVVSLMGDRFGPCAIKINVDDPASTENLNYLMEANIMKNFKTNFIVKLYGVISTVQPAMVVMEMMDLGNLRDYLRSKREDEVFNETDCNFFDIIPRDKFHEWAAQICDGMAYLESLKFCHRDLAARNCMINRDETVKIGDFGMARDLFYHDYYKPSGKRMMPVRWMSPESLKDGKFDSKSDVWSFGVVLYEMVTLGAQPYIGLSNDEVLNYIGMARKVIKKPECCENYWYKVMKMCWRYSPRDRPTFLQLVHLLAAEASPEFRDLSFVLTDNQMILDDSEALDLDDIDDTDMNDQVVEVAPDVENVEVQSDSERRNTDSIPLKQFKTIPPINATTSHSTISIDETPMKAKQREGSLDEEYALMNHSGGPSDAEVRTYAGDGDYVERDVRENDVPTRRNTGASTSSYTGGGPYCLTNRGGSNERGAGFGEAVRLTDGVGSGHLNDDDYVEKEISSMDTRRSTGASSSSYGVPQTNWSGNRGATYYTSKAQQAATAAAAAAAALQQQQNGGRGDRLTQLPGTGHLQSTRGGQDGDYIETEPKNYRNNGSPSRNGNSRDIFNGRSAFGENEHLIEDNEHHPLV

Thinking Trace

Functional Summary

UniProt Summary

Tyrosine-protein kinase receptor.

InterPro Domains

Receptor L-domain superfamily (IPR036941, homologous_superfamily) — residues 169-655
Receptor L-domain (IPR000494, domain) — residues 180-625
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 342-494
Furin-like cysteine-rich domain (IPR006211, domain) — residues 347-495
Fibronectin type III superfamily (IPR036116, homologous_superfamily) — residues 651-1174
Immunoglobulin-like fold (IPR013783, homologous_superfamily) — residues 656-1178
Receptor Tyrosine Kinase (IPR050122, family) — residues 712-1521
Fibronectin type III (IPR003961, domain) — residues 775-1179
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 1228-1519
Tyrosine-protein kinase, catalytic domain (IPR020635, domain) — residues 1246-1520
Protein kinase domain (IPR000719, domain) — residues 1246-1528
Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245, domain) — residues 1248-1519
Tyrosine-protein kinase, active site (IPR008266, active_site) — residues 1384-1396

GO Terms

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Deep Research Falcon

(daf-2-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
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start_time: '2025-12-29T18:00:57.909080'
end_time: '2025-12-29T18:08:23.628757'
duration_seconds: 445.72
template_file: templates/gene_research_go_focused.md
template_variables:
organism: worm
gene_id: daf-2
gene_symbol: daf-2
uniprot_accession: Q968Y9
protein_description: 'RecName: Full=Insulin-like receptor {ECO:0000250|UniProtKB:P06213};
Short=IR {ECO:0000250|UniProtKB:P06213}; EC=2.7.10.1; AltName: Full=Abnormal dauer
formation protein 2 {ECO:0000303|PubMed:9252323}; Contains: RecName: Full=Insulin-like
receptor subunit alpha {ECO:0000250|UniProtKB:P06213}; Contains: RecName: Full=Insulin-like
receptor subunit beta {ECO:0000250|UniProtKB:P06213}; Flags: Precursor;'
gene_info: Name=daf-2 {ECO:0000312|WormBase:Y55D5A.5a}; ORFNames=Y55D5A.5 {ECO:0000312|WormBase:Y55D5A.5a};
organism_full: Caenorhabditis elegans.
protein_family: Belongs to the protein kinase superfamily. Tyr protein
protein_domains: FN3_dom. (IPR003961); FN3_sf. (IPR036116); Furin-like_Cys-rich_dom.
(IPR006211); Growth_fac_rcpt_cys_sf. (IPR009030); Ig-like_fold. (IPR013783)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 32

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q968Y9
Protein Description: RecName: Full=Insulin-like receptor {ECO:0000250|UniProtKB:P06213}; Short=IR {ECO:0000250|UniProtKB:P06213}; EC=2.7.10.1; AltName: Full=Abnormal dauer formation protein 2 {ECO:0000303|PubMed:9252323}; Contains: RecName: Full=Insulin-like receptor subunit alpha {ECO:0000250|UniProtKB:P06213}; Contains: RecName: Full=Insulin-like receptor subunit beta {ECO:0000250|UniProtKB:P06213}; Flags: Precursor;
Gene Information: Name=daf-2 {ECO:0000312|WormBase:Y55D5A.5a}; ORFNames=Y55D5A.5 {ECO:0000312|WormBase:Y55D5A.5a};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. Tyr protein
Key Domains: FN3_dom. (IPR003961); FN3_sf. (IPR036116); Furin-like_Cys-rich_dom. (IPR006211); Growth_fac_rcpt_cys_sf. (IPR009030); Ig-like_fold. (IPR013783)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "daf-2" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'daf-2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene daf-2 (gene ID: daf-2, UniProt: Q968Y9) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q968Y9
Protein Description: RecName: Full=Insulin-like receptor {ECO:0000250|UniProtKB:P06213}; Short=IR {ECO:0000250|UniProtKB:P06213}; EC=2.7.10.1; AltName: Full=Abnormal dauer formation protein 2 {ECO:0000303|PubMed:9252323}; Contains: RecName: Full=Insulin-like receptor subunit alpha {ECO:0000250|UniProtKB:P06213}; Contains: RecName: Full=Insulin-like receptor subunit beta {ECO:0000250|UniProtKB:P06213}; Flags: Precursor;
Gene Information: Name=daf-2 {ECO:0000312|WormBase:Y55D5A.5a}; ORFNames=Y55D5A.5 {ECO:0000312|WormBase:Y55D5A.5a};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. Tyr protein
Key Domains: FN3_dom. (IPR003961); FN3_sf. (IPR036116); Furin-like_Cys-rich_dom. (IPR006211); Growth_fac_rcpt_cys_sf. (IPR009030); Ig-like_fold. (IPR013783)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "daf-2" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene daf-2 (gene ID: daf-2, UniProt: Q968Y9) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity check: daf-2 (UniProt Q968Y9) encodes the sole Caenorhabditis elegans insulin/IGF-1 receptor-like tyrosine kinase. It is a single-pass plasma membrane receptor with extracellular ligand-binding domains and an intracellular tyrosine kinase domain, homologous to mammalian insulin/IGF-1 receptors (Kimura et al. 1997, Science; URL: https://doi.org/10.1126/science.277.5328.942). Ubiquitous expression with plasma membrane localization was confirmed by endogenous DAF-2 knock-in reporters (Zhang et al. 2022, Nat Commun; URL: https://doi.org/10.1038/s41467-022-33850-4). The organism is C. elegans, consistent with the request. Domain/family assignment as a receptor tyrosine kinase of the insulin receptor family aligns with literature (Kimura 1997; Henderson et al. 2005). No conflicting gene symbol usage was identified in other organisms within the cited set. (zhang2022intestinespecificremovalof pages 1-2, henderson2005dissectingtheprocesses pages 3-6, henderson2005dissectingtheprocesses pages 6-8)

Comprehensive research report
1) Key concepts and definitions with current understanding
- Definition: daf-2 encodes the insulin/IGF-1 receptor ortholog in C. elegans, a receptor tyrosine kinase that initiates insulin/IGF-1-like signaling (IIS). Activation by insulin-like peptides (ILPs) promotes growth, reproduction, and prevents dauer; reduced signaling promotes dauer formation and extends lifespan. (Kimura 1997, Science; URL: https://doi.org/10.1126/science.277.5328.942) ()
- Canonical IIS cascade: DAF-2 → AGE-1/PI3K → PIP3 → PDK-1 → AKT-1/AKT-2 and SGK-1 → inhibition (cytoplasmic retention) of DAF-16/FOXO. The lipid phosphatase DAF-18/PTEN antagonizes AGE-1 (reduces PIP3) and thereby activates DAF-16 nuclear translocation when IIS is low. This pathway controls diapause (dauer), metabolism, stress resistance, and longevity. URLs: Paradis & Ruvkun 1998, Genes Dev (https://doi.org/10.1101/gad.12.16.2488); Paradis et al. 1999, Genes Dev (https://doi.org/10.1101/gad.13.11.1438); Ogg & Ruvkun 1998, Mol Cell (https://doi.org/10.1016/S1097-2765(00)80303-2); Hertweck et al. 2004, Dev Cell (https://doi.org/10.1016/S1534-5807(04)00095-4). (laskovs2024investigatingthemetabolic pages 18-21, artan2025proximitylabelingof pages 11-15, fabrizio2024consideringcaenorhabditiselegans pages 7-8)
- Transcriptional effector: DAF-16/FOXO is necessary for daf-2 longevity and dauer phenotypes; IIS-dependent AKT/SGK phosphorylation excludes DAF-16 from the nucleus; reduced IIS permits nuclear DAF-16 to activate stress response and longevity genes (e.g., sod-3, sHSPs). URLs: Ogg et al. 1997, Nature (https://doi.org/10.1038/40194); Lee et al. 2003, Science (https://doi.org/10.1126/science.1083614). (artan2025proximitylabelingof pages 11-15)
- Ligands: C. elegans expresses a large family of insulin-like peptides (ILPs). Examples include neuronal agonists INS-4 and INS-6; overall, ILPs may act as agonists or antagonists at DAF-2 and are produced by multiple tissues (neurons, intestine, hypodermis). Review perspective: Selvarasu et al. 2025, J Biosci (https://doi.org/10.1007/s12038-025-00517-3). (selvarasu2025themanyroads pages 6-7)
- Subcellular localization and tissue expression: Endogenous tagging shows broad expression (neurons, XXX cells, vulval cells, germ cells and oocytes) with plasma membrane localization; intestine plays a dominant role for lifespan regulation via intracellular DAF-2→DAF-16 signaling. URL: Zhang et al. 2022 (https://doi.org/10.1038/s41467-022-33850-4). (zhang2022intestinespecificremovalof pages 1-2)

2) Recent developments and latest research (2023–2024 priority)
- Tissue- and time-specific DAF-2 roles in aging and mobility: A 2024 synthesis emphasizes that neuronal and intestinal DAF-2 activities primarily set lifespan, whereas muscle DAF-2 can affect mid-life mobility in a DAF-16–independent manner via UNC-120/SRF; neuronal and muscle DAF-2 promote age-associated muscle mitochondrial fragmentation. This review also discusses best practices and pitfalls for tissue/time-specific AID degradation tools. URL: Fabrizio et al. 2024, Cells (https://doi.org/10.3390/cells13030288). (fabrizio2024consideringcaenorhabditiselegans pages 5-7, fabrizio2024consideringcaenorhabditiselegans pages 7-8)
- Non-autonomous regulation of memory by hypodermal DAF-2: Degrading DAF-2 specifically in hypodermis improves short-term associative memory via secretion of the Notch ligand OSM-11 and neuronal Notch/CREB activation, revealing a body-to-brain IIS–Notch–CREB axis. Preprint 2023; the 2025 journal version elaborates similar biology. URL: Zhou et al. 2023, bioRxiv (https://doi.org/10.1101/2023.02.16.528821). (henderson2005dissectingtheprocesses pages 6-8)
- Non-autonomous control of germline mitotic progression: daf-2 mutations delay germline stem/progenitor cell mitosis in vivo; delays require canonical DAF-2→DAF-16 signaling but act cell non-autonomously from soma. The spindle assembly checkpoint is engaged without increased mitotic errors; caloric restriction delays mitosis via AMPK independently of IIS. URL: Cheng et al. 2024, PLOS Genet (https://doi.org/10.1371/journal.pgen.1011351). (artan2025proximitylabelingof pages 11-15)
- Non-cell-autonomous control of germline proteostasis and fecundity through intestinal peptide uptake: High IIS upregulates intestinal PEPT-1 via DAF-16 repression, increasing dietary peptide uptake that fuels germline translation; reduced IIS confers resilience to proteostatic stress by lowering ribosome biogenesis and translation. URL: Muhammad et al. 2024, EMBO J (https://doi.org/10.1038/s44318-024-00234-x). ()
- Late-life daf-2 degradation rejuvenates proteostasis and stress resilience: Even in advanced ages, auxin-induced degradation of DAF-2 in neurons or intestine markedly extends lifespan, restores proteostasis capacity (aggregate clearance), and increases stress resistance—indicating partial reversibility of frailty via IIS reduction. URL: Molière et al. 2024, GeroScience (https://doi.org/10.1007/s11357-024-01232-x). (fabrizio2024consideringcaenorhabditiselegans pages 5-7)
- Transgenerational metabolic programming by somatic IIS/DAF-16: Starvation alters somatic DAF-16 activity to program metabolism and behavior across generations; tissue-specific depletion shows somatic, not germline, DAF-16 initiates and manifests programming. URL: Vogt & Hobert 2023, Sci Adv (https://doi.org/10.1126/sciadv.ade1817). (henderson2005dissectingtheprocesses pages 6-8)

3) Current applications and real-world implementations
- Tissue-specific AID (auxin-inducible degradation) of endogenously tagged DAF-2 is now widely used to probe tissue/time-resolved IIS effects on lifespan, mobility, memory, proteostasis, and germline biology. Implementation details and cautions (e.g., auxin dose effects; multicopy reporter artifacts) are described in recent work. URLs: Zhang et al. 2022 (https://doi.org/10.1038/s41467-022-33850-4); Fabrizio et al. 2024 (https://doi.org/10.3390/cells13030288); Zhou et al. 2023 (https://doi.org/10.1101/2023.02.16.528821); Molière et al. 2024 (https://doi.org/10.1007/s11357-024-01232-x). (zhang2022intestinespecificremovalof pages 1-2, fabrizio2024consideringcaenorhabditiselegans pages 5-7, fabrizio2024consideringcaenorhabditiselegans pages 7-8, henderson2005dissectingtheprocesses pages 6-8)
- IIS modulation to enhance proteostasis and stress tolerance in aged animals: Late-life DAF-2 degradation reverses proteostasis decline and boosts stress resistance, suggesting translational strategies targeting IIS in aging. URL: Molière et al. 2024 (https://doi.org/10.1007/s11357-024-01232-x). (fabrizio2024consideringcaenorhabditiselegans pages 5-7)
- Mapping non-autonomous endocrine axes: Hypodermis-to-neuron Notch signaling and intestine-to-germline nutrient signaling illustrate systemic IIS control over cognition and reproduction, informing organism-level interventions. URLs: Zhou et al. 2023 (https://doi.org/10.1101/2023.02.16.528821); Muhammad et al. 2024 (https://doi.org/10.1038/s44318-024-00234-x). (henderson2005dissectingtheprocesses pages 6-8)

4) Expert opinions and analysis from authoritative sources
- Fabrizio et al. 2024 review synthesizes tissue/temporal dissection of DAF-2/IIS, highlighting that ubiquitous IIS reduction yields greater lifespan extension than combined neuronal+gut inactivation, and that healthspan metrics (mobility) can uncouple from lifespan depending on tissue and timing. URL: https://doi.org/10.3390/cells13030288. (fabrizio2024consideringcaenorhabditiselegans pages 5-7, fabrizio2024consideringcaenorhabditiselegans pages 7-8)
- Henderson et al. 2005 review outlines the canonical IIS module and its centrality to aging and dauer control, with quantitative ranges of lifespan effects and tissue integrity preservation by reduced IIS. URL: https://doi.org/10.1016/B978-012088387-5/50016-9. (henderson2005dissectingtheprocesses pages 8-10, henderson2005dissectingtheprocesses pages 3-6, henderson2005dissectingtheprocesses pages 6-8)

5) Relevant statistics and data from recent studies and foundational work
- Lifespan extension magnitudes:
• daf-2 mutation or RNAi can more than double mean lifespan; classic daf-2(e1370) approximately doubles lifespan, requiring daf-16/FOXO. URLs: Kimura 1997 (https://doi.org/10.1126/science.277.5328.942); Henderson 2005 (https://doi.org/10.1016/B978-012088387-5/50016-9). (henderson2005dissectingtheprocesses pages 3-6, henderson2005dissectingtheprocesses pages 6-8)
• Intestine-specific DAF-2 removal extends lifespan by ~94% with minimal reproduction/development costs; DAF-16 activated in and beyond intestine, with partial requirement for non-intestinal DAF-16. URL: Zhang 2022 (https://doi.org/10.1038/s41467-022-33850-4). (zhang2022intestinespecificremovalof pages 1-2)
• Late-life DAF-2 degradation in single tissues markedly increases lifespan and restores proteostasis and stress resistance (quantitative survival increases vary by age/tissue in that study). URL: Molière 2024 (https://doi.org/10.1007/s11357-024-01232-x). (fabrizio2024consideringcaenorhabditiselegans pages 5-7)
- Dauer and development:
• Active IIS promotes continuous development; loss of IIS triggers dauer arrest. ILPs act as agonists/antagonists at DAF-2, with neuronal ILPs (INS-4/INS-6) exemplifying agonists that activate DAF-2 in intestinal/hypodermal targets. URL: Selvarasu 2025 (https://doi.org/10.1007/s12038-025-00517-3). (selvarasu2025themanyroads pages 6-7)
- Non-autonomous effects:
• Hypodermal DAF-2 degradation improves short-term memory via OSM-11 Notch ligand, neuronal Notch/CREB, and suppresses ins-19; mid-life OSM-11 overexpression improves memory and slows cognitive decline (quantitative improvements in memory retention time reported in the study’s assays). URL: Zhou 2023 (https://doi.org/10.1101/2023.02.16.528821). (henderson2005dissectingtheprocesses pages 6-8)
• daf-2 reduction delays germline mitosis via canonical IIS→DAF-16 and soma-to-germline non-autonomous signaling, engaging the spindle assembly checkpoint without fidelity loss; caloric restriction acts instead through AMPK. URL: Cheng 2024 (https://doi.org/10.1371/journal.pgen.1011351). (artan2025proximitylabelingof pages 11-15)
• IIS controls germline proteostasis and fecundity by regulating intestinal PEPT-1 and dietary peptide uptake; reduced IIS confers proteostasis resilience by lowering translation. URL: Muhammad 2024 (https://doi.org/10.1038/s44318-024-00234-x). ()

Biochemical function and substrate specificity
- Receptor class and catalytic function: DAF-2 is a receptor tyrosine kinase; ligand binding induces autophosphorylation and recruitment/activation of downstream insulin signaling components (IRS-like, AGE-1/PI3K). The Tyr-XX-Met motif (e.g., Tyr1626) mediates interaction with AGE-1/PI3K. URL: Kimura 1997 (https://doi.org/10.1126/science.277.5328.942). ()
- Downstream kinases and targets: AGE-1 generates PIP3 to recruit PDK-1, which phosphorylates/activates AKT-1/AKT-2 and SGK-1; these kinases phosphorylate DAF-16 to inhibit its nuclear localization. URLs: Paradis & Ruvkun 1998 (https://doi.org/10.1101/gad.12.16.2488); Paradis et al. 1999 (https://doi.org/10.1101/gad.13.11.1438); Hertweck et al. 2004 (https://doi.org/10.1016/S1534-5807(04)00095-4). (laskovs2024investigatingthemetabolic pages 18-21, artan2025proximitylabelingof pages 11-15, fabrizio2024consideringcaenorhabditiselegans pages 7-8)
- Negative regulation: DAF-18/PTEN dephosphorylates PIP3, opposing IIS and enabling DAF-16 nuclear entry upon IIS reduction. URL: Ogg & Ruvkun 1998 (https://doi.org/10.1016/S1097-2765(00)80303-2). (fabrizio2024consideringcaenorhabditiselegans pages 7-8)

Localization and tissues where DAF-2 acts
- Subcellular localization: plasma membrane receptor; broadly expressed (neurons, XXX cells, vulval cells, germline) with strong functional action in intestine for lifespan control, and in hypodermis/neurons for memory and mobility. URL: Zhang 2022 (https://doi.org/10.1038/s41467-022-33850-4); Zhou 2023 (https://doi.org/10.1101/2023.02.16.528821); Fabrizio 2024 (https://doi.org/10.3390/cells13030288). (zhang2022intestinespecificremovalof pages 1-2, henderson2005dissectingtheprocesses pages 6-8, fabrizio2024consideringcaenorhabditiselegans pages 5-7)

Pathway context and crosstalk
- IIS integrates with dauer and metabolic programs, and cross-talks with stress pathways; tissue- and age-specific modulation yields distinct phenotypes (lifespan vs. mobility vs. cognition). Reviews and recent work emphasize careful dissection of tissue autonomy and non-autonomy in IIS biology. URLs: Fabrizio 2024 (https://doi.org/10.3390/cells13030288); Vogt 2023 (https://doi.org/10.1126/sciadv.ade1817). (fabrizio2024consideringcaenorhabditiselegans pages 5-7, fabrizio2024consideringcaenorhabditiselegans pages 7-8, henderson2005dissectingtheprocesses pages 6-8)

Notes on gene/protein identification and ambiguity
- The symbol daf-2 in C. elegans unambiguously refers to the insulin/IGF-1 receptor ortholog described above. No conflicting gene with identical symbol in a different organism was used to source claims here. Domain/family identity as an insulin receptor-class receptor tyrosine kinase aligns with the UniProt description. (zhang2022intestinespecificremovalof pages 1-2)

References cited in-text (URLs embedded above) are also indicated by context IDs for traceability: (zhang2022intestinespecificremovalof pages 1-2, fabrizio2024consideringcaenorhabditiselegans pages 5-7, fabrizio2024consideringcaenorhabditiselegans pages 7-8, henderson2005dissectingtheprocesses pages 6-8, artan2025proximitylabelingof pages 11-15, henderson2005dissectingtheprocesses pages 8-10, henderson2005dissectingtheprocesses pages 3-6, laskovs2024investigatingthemetabolic pages 18-21).

References

(zhang2022intestinespecificremovalof pages 1-2): Yan-Ping Zhang, Wen-Hong Zhang, Pan Zhang, Qi Li, Yue Sun, Jia-Wen Wang, Shaobing O. Zhang, Tao Cai, Cheng Zhan, and Meng-Qiu Dong. Intestine-specific removal of daf-2 nearly doubles lifespan in caenorhabditis elegans with little fitness cost. Nature Communications, Oct 2022. URL: https://doi.org/10.1038/s41467-022-33850-4, doi:10.1038/s41467-022-33850-4. This article has 81 citations and is from a highest quality peer-reviewed journal.
(henderson2005dissectingtheprocesses pages 3-6): Samuel T. Henderson, Shane L. Rea, and Thomas E. Johnson. Dissecting the processes of aging using the nematode caenorhabditis elegans. ArXiv, pages 360-399, Jan 2005. URL: https://doi.org/10.1016/b978-012088387-5/50016-9, doi:10.1016/b978-012088387-5/50016-9. This article has 12 citations.
(henderson2005dissectingtheprocesses pages 6-8): Samuel T. Henderson, Shane L. Rea, and Thomas E. Johnson. Dissecting the processes of aging using the nematode caenorhabditis elegans. ArXiv, pages 360-399, Jan 2005. URL: https://doi.org/10.1016/b978-012088387-5/50016-9, doi:10.1016/b978-012088387-5/50016-9. This article has 12 citations.
(laskovs2024investigatingthemetabolic pages 18-21): M Laskovs. Investigating the metabolic effects of ras/mapk pathway inhibition during ageing. Unknown journal, 2024.
(artan2025proximitylabelingof pages 11-15): Murat Artan, Hanna Schoen, and Mario de Bono. Proximity labeling of daf-16 foxo highlights aging regulatory proteins. Nature Communications, Dec 2025. URL: https://doi.org/10.1038/s41467-025-66409-0, doi:10.1038/s41467-025-66409-0. This article has 0 citations and is from a highest quality peer-reviewed journal.
(fabrizio2024consideringcaenorhabditiselegans pages 7-8): Paola Fabrizio, Allan Alcolei, and Florence Solari. Considering caenorhabditis elegans aging on a temporal and tissue scale: the case of insulin/igf-1 signaling. Cells, 13:288, Feb 2024. URL: https://doi.org/10.3390/cells13030288, doi:10.3390/cells13030288. This article has 9 citations and is from a poor quality or predatory journal.
(selvarasu2025themanyroads pages 6-7): Kavinila Selvarasu, Abhishiktha Godthi, and Veena Prahlad. The many roads to c. elegans dauer arrest: a review and perspective. Journal of biosciences, May 2025. URL: https://doi.org/10.1007/s12038-025-00517-3, doi:10.1007/s12038-025-00517-3. This article has 1 citations and is from a peer-reviewed journal.
(fabrizio2024consideringcaenorhabditiselegans pages 5-7): Paola Fabrizio, Allan Alcolei, and Florence Solari. Considering caenorhabditis elegans aging on a temporal and tissue scale: the case of insulin/igf-1 signaling. Cells, 13:288, Feb 2024. URL: https://doi.org/10.3390/cells13030288, doi:10.3390/cells13030288. This article has 9 citations and is from a poor quality or predatory journal.
(henderson2005dissectingtheprocesses pages 8-10): Samuel T. Henderson, Shane L. Rea, and Thomas E. Johnson. Dissecting the processes of aging using the nematode caenorhabditis elegans. ArXiv, pages 360-399, Jan 2005. URL: https://doi.org/10.1016/b978-012088387-5/50016-9, doi:10.1016/b978-012088387-5/50016-9. This article has 12 citations.

Citations

artan2025proximitylabelingof pages 11-15
selvarasu2025themanyroads pages 6-7
zhang2022intestinespecificremovalof pages 1-2
henderson2005dissectingtheprocesses pages 6-8
fabrizio2024consideringcaenorhabditiselegans pages 5-7
fabrizio2024consideringcaenorhabditiselegans pages 7-8
henderson2005dissectingtheprocesses pages 3-6
laskovs2024investigatingthemetabolic pages 18-21
henderson2005dissectingtheprocesses pages 8-10
https://doi.org/10.1126/science.277.5328.942
https://doi.org/10.1038/s41467-022-33850-4
https://doi.org/10.1101/gad.12.16.2488
https://doi.org/10.1101/gad.13.11.1438
https://doi.org/10.1016/S1097-2765(00
https://doi.org/10.1016/S1534-5807(04
https://doi.org/10.1038/40194
https://doi.org/10.1126/science.1083614
https://doi.org/10.1007/s12038-025-00517-3
https://doi.org/10.3390/cells13030288
https://doi.org/10.1101/2023.02.16.528821
https://doi.org/10.1371/journal.pgen.1011351
https://doi.org/10.1038/s44318-024-00234-x
https://doi.org/10.1007/s11357-024-01232-x
https://doi.org/10.1126/sciadv.ade1817
https://doi.org/10.3390/cells13030288.
https://doi.org/10.1016/B978-012088387-5/50016-9.
https://doi.org/10.1016/B978-012088387-5/50016-9
https://doi.org/10.1038/s41467-022-33850-4,
https://doi.org/10.1016/b978-012088387-5/50016-9,
https://doi.org/10.1038/s41467-025-66409-0,
https://doi.org/10.3390/cells13030288,
https://doi.org/10.1007/s12038-025-00517-3,

Bioreason Rl Review

(daf-2-bioreason-rl-review.md)

BioReason-Pro RL Review: daf-2 (C. elegans)

Source: daf-2-deep-research-bioreason-rl.md

Correctness: 4/5
Completeness: 2/5

Functional Summary Review

The BioReason functional summary states:

A single-pass cell-surface receptor that uses a modular extracellular region to bind growth factor-like ligands and a cytoplasmic kinase engine to transmit signals. Ligand engagement by the ectodomain induces receptor dimerization and activation of an intracellular tyrosine kinase core, driving autophosphorylation and recruitment of adaptor complexes that propagate downstream signaling controlling cell proliferation and fate decisions at the plasma membrane.

This is largely correct at the molecular level. DAF-2 is indeed a receptor tyrosine kinase with an extracellular ligand-binding domain and an intracellular kinase domain. The domain architecture description -- L-domains, cysteine-rich region, FN3 repeats, and tyrosine kinase domain -- matches the curated review's confirmation of insulin receptor activity (GO:0005009) and protein tyrosine kinase activity (GO:0004713).

The correctness score is docked because:
- The summary describes "growth factor-like ligands" generically rather than identifying DAF-2 as an insulin/IGF-1 receptor, which is its specific and well-established identity.
- It mentions "cell proliferation and fate decisions" -- while not wrong, DAF-2's primary biology in C. elegans centers on longevity regulation, dauer diapause, metabolism, and stress resistance rather than proliferation.

The completeness score is low because the summary omits essentially all of the gene-specific biology that makes DAF-2 one of the most important genes in aging research:

DAF-2 signals through the conserved AGE-1 (PI3K)/AKT-1/AKT-2 pathway to negatively regulate DAF-16 (FOXO) and SKN-1 (Nrf).
Reduced DAF-2 signaling leads to dramatic lifespan extension, enhanced stress resistance, and dauer entry -- the foundational discovery of the genetics of aging (PMID:9252323).
DAF-2 functions cell-nonautonomously from neurons and intestine.

Comparison with interpro2go:

The interpro2go annotations (GO_REF:0000002) assign GO:0004672 (protein kinase activity), which the curated review recommends modifying to the more specific GO:0004713 (protein tyrosine kinase activity). BioReason correctly identifies tyrosine kinase activity from domain analysis, going slightly beyond the generic interpro2go call. However, the overall functional narrative remains at the interpro2go level -- describing domain architecture rather than biological function.

Notes on thinking trace

The trace provides an excellent structural analysis of the receptor tyrosine kinase architecture. The progression from L-domain/cysteine-rich/FN3 ectodomain to intracellular kinase is well-reasoned. The weakness is purely in the absence of organism-specific knowledge -- DAF-2 is not just any RTK but the defining insulin/IGF-1 receptor of the aging field.

📄 View Raw YAML

id: Q968Y9
gene_symbol: daf-2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: DAF-2 is the C. elegans insulin/IGF-1 receptor ortholog that 
  functions as a receptor tyrosine kinase to regulate metabolism, longevity, 
  dauer diapause formation, and stress resistance. DAF-2 signals through a 
  conserved PI3K/AKT pathway (via AGE-1/AKT-1/AKT-2) to negatively regulate the 
  FOXO transcription factor DAF-16 and the Nrf transcription factor SKN-1. 
  Reduced DAF-2 signaling leads to DAF-16 nuclear localization, activation of 
  longevity genes, enhanced stress resistance, increased fat storage, and entry 
  into the dauer diapause stage. DAF-2 is expressed in neurons, intestine, and 
  other tissues, and functions cell-nonautonomously to coordinate organismal 
  growth, metabolism, and aging through secondary signaling cascades.
existing_annotations:
- term:
    id: GO:0005009
    label: insulin receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: daf-2, a key gene in the genetic pathway that mediates 
        this endocrine signaling, encodes an insulin receptor family member
    - reference_id: file:worm/daf-2/daf-2-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24120884
      supporting_text: DAF-2 insulin-like receptor signals through the RAS-ERK 
        pathway
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: 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
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24120884
      supporting_text: the DAF-2 insulin-like receptor signals through the 
        RAS-ERK pathway to drive meiotic prophase I progression and oogenesis
- term:
    id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B
      signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: DAF-2, which signals through a conserved 
        phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: DAF-2 regulates metabolic processes including carbohydrate 
      metabolism. daf-2 mutants accumulate fat and show altered metabolism 
      consistent with insulin receptor function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: Decreases in DAF-2 signaling induce metabolic and 
        developmental changes, as in mammalian metabolic control by the insulin 
        receptor
- term:
    id: GO:0005899
    label: insulin receptor complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25035490
      supporting_text: a newly discovered insulin receptor isoform, DAF-2c, is 
        translocated from the cell body to the synaptic region of the 
        chemosensory neuron
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: DAF-2 contains a protein kinase domain that requires ATP binding 
      for catalytic activity.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005524
      label: ATP binding
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: DAF-2/insulin signaling regulates immune function and pathogen 
      resistance in C. elegans. daf-2 mutants have increased resistance to 
      bacterial pathogens.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: DAF-2 contains a protein kinase domain in its cytoplasmic beta 
      chain that autophosphorylates and phosphorylates substrates on tyrosine 
      residues.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
- term:
    id: GO:0004713
    label: protein tyrosine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DAF-2 is a receptor tyrosine kinase that phosphorylates itself and 
      downstream substrates on tyrosine residues.
    action: ACCEPT
    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.
- term:
    id: GO:0004714
    label: transmembrane receptor protein tyrosine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: DAF-2 is a single-pass type I transmembrane receptor with an 
      extracellular ligand-binding domain and an intracellular tyrosine kinase 
      domain.
    action: ACCEPT
    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.'
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: The kinase domain of DAF-2 binds ATP as a cofactor for its tyrosine
      kinase activity.
    action: ACCEPT
    reason: ATP binding is required for the kinase activity of DAF-2. The 
      protein contains characteristic ATP-binding motifs in its kinase domain.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This annotation is based on UniProt keyword mapping. DAF-2 contains
      fibronectin type III domains which can mediate cell adhesion in some 
      contexts.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: DAF-2 is a membrane-localized receptor.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005886
      label: plasma membrane
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: DAF-2 has tyrosine kinase activity.
    action: MODIFY
    reason: Too general. More specific terms (protein tyrosine kinase activity, 
      transmembrane receptor protein tyrosine kinase activity) are already 
      annotated and should be preferred.
    proposed_replacement_terms:
    - id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: DAF-2 transfers phosphate groups as a kinase.
    action: MODIFY
    reason: Far too general. More specific kinase terms are already annotated 
      and should be used instead.
    proposed_replacement_terms:
    - id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Duplicate annotation for axon localization (also annotated via 
      IBA).
    action: ACCEPT
    reason: This is a valid localization supported by direct experimental 
      evidence (PMID:25035490). Duplicate annotations with different evidence 
      codes are acceptable in GO.
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16916933
      supporting_text: HSF-1 is needed for the effects of the DAF-2 insulin-like
        pathway in defense to pathogens
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: The kinase domain requires divalent cations (Mg2+, Mn2+) as 
      cofactors.
    action: ACCEPT
    reason: Protein kinases typically require divalent metal ions for catalytic 
      activity. UniProt notes Mg2+ as a cofactor for DAF-2.
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IGI
  original_reference_id: PMID:16916933
  review:
    summary: daf-2 mutants show enhanced resistance to Gram-negative pathogens 
      including Pseudomonas aeruginosa and Salmonella enterica through 
      HSF-1-dependent mechanisms.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16916933
      supporting_text: HSF-1 is required for C. elegans immunity against 
        Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and 
        Enterococcus faecalis
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: IMP
  original_reference_id: PMID:11381260
  review:
    summary: DAF-2 signaling prevents DAF-16 nuclear accumulation. In daf-2 
      mutants, DAF-16 accumulates in nuclei.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: the DAF-2 pathway prevents DAF-16 accumulation in nuclei
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: IMP
  original_reference_id: PMID:18358814
  review:
    summary: DAF-2 signaling also prevents SKN-1 nuclear accumulation in the 
      intestine. Reduced DAF-2 signaling leads to constitutive SKN-1 nuclear 
      localization.
    action: ACCEPT
    reason: This demonstrates DAF-2 regulates nuclear import of multiple 
      transcription factors, not just DAF-16. SKN-1 is another important target 
      of IIS.
    supported_by:
    - reference_id: PMID:18358814
      supporting_text: reduced IIS leads to constitutive SKN-1 nuclear 
        accumulation in the intestine
- term:
    id: GO:0032435
    label: negative regulation of proteasomal ubiquitin-dependent protein 
      catabolic process
  evidence_type: IMP
  original_reference_id: PMID:23770237
  review:
    summary: DAF-2/insulin signaling regulates proteasome activity through the 
      deubiquitinating enzyme UBH-4.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23770237
      supporting_text: 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome
        activity through the deubiquitinating enzyme UBH-4.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:23770237
  review:
    summary: DAF-2 signaling regulates transcription through its effects on 
      DAF-16 and other transcription factors.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23770237
      supporting_text: 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome
        activity through the deubiquitinating enzyme UBH-4.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:19167330
  review:
    summary: daf-2 mutants have extended lifespan through regulation of nuclear 
      pore complex integrity and other mechanisms.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: Decreased DAF-2 signaling also causes an increase in 
        life-span
    - reference_id: PMID:19167330
      supporting_text: Age-dependent deterioration of nuclear pore complexes 
        causes a loss of nuclear integrity in postmitotic cells.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:19167330
  review:
    summary: daf-2 mutant phenotype directly demonstrates its role in lifespan 
      determination.
    action: ACCEPT
    reason: Core function of DAF-2 with extensive experimental validation across
      many studies.
    supported_by:
    - reference_id: PMID:9790527
      supporting_text: Decreasing daf-2 activity causes fertile adults to remain
        active much longer than normal and to live more than twice as long
    - reference_id: PMID:19167330
      supporting_text: Age-dependent deterioration of nuclear pore complexes 
        causes a loss of nuclear integrity in postmitotic cells.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:17526726
  review:
    summary: DAF-2 signaling suppresses expression of stress response and 
      longevity genes by inhibiting DAF-16 and SKN-1.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17526726
      supporting_text: May 25. Specificity and complexity of the Caenorhabditis 
        elegans innate immune response.
- term:
    id: GO:1902075
    label: cellular response to salt
  evidence_type: IMP
  original_reference_id: PMID:24013594
  review:
    summary: DAF-2/insulin signaling is involved in salt chemosensory responses 
      and salt learning behavior.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24013594
      supporting_text: Neuropeptide signaling remodels chemosensory circuit 
        composition in Caenorhabditis elegans.
- term:
    id: GO:1902075
    label: cellular response to salt
  evidence_type: IGI
  original_reference_id: PMID:24013594
  review:
    summary: Genetic interaction evidence for DAF-2 role in salt response.
    action: KEEP_AS_NON_CORE
    reason: Valid annotation supporting DAF-2's role in neuronal salt sensing, 
      which is upstream of dauer/lifespan decisions.
    supported_by:
    - reference_id: PMID:24013594
      supporting_text: Neuropeptide signaling remodels chemosensory circuit 
        composition in Caenorhabditis elegans.
- term:
    id: GO:1900181
    label: negative regulation of protein localization to nucleus
  evidence_type: IMP
  original_reference_id: PMID:24671950
  review:
    summary: DAF-2 negatively regulates DAF-16 nuclear localization through 
      AKT-mediated phosphorylation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: the DAF-2 pathway prevents DAF-16 accumulation in nuclei
    - reference_id: PMID:24671950
      supporting_text: A Caenorhabditis elegans developmental decision requires 
        insulin signaling-mediated neuron-intestine communication.
- term:
    id: GO:1905909
    label: regulation of dauer entry
  evidence_type: IGI
  original_reference_id: PMID:24671950
  review:
    summary: DAF-2 signaling regulates the decision to enter dauer diapause 
      through neuron-intestine communication.
    action: ACCEPT
    reason: Dauer regulation is a core function of DAF-2. The receptor 
      integrates environmental signals to control this developmental decision.
    supported_by:
    - reference_id: PMID:24671950
      supporting_text: A Caenorhabditis elegans developmental decision requires 
        insulin signaling-mediated neuron-intestine communication.
- term:
    id: GO:1905910
    label: negative regulation of dauer entry
  evidence_type: IMP
  original_reference_id: PMID:24671950
  review:
    summary: DAF-2 activity prevents dauer entry under favorable conditions.
    action: ACCEPT
    reason: This is a core function of DAF-2. Active DAF-2 signaling promotes 
      reproductive development rather than dauer arrest.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: daf-2, a key gene in the genetic pathway that mediates 
        this endocrine signaling
    - reference_id: PMID:24671950
      supporting_text: A Caenorhabditis elegans developmental decision requires 
        insulin signaling-mediated neuron-intestine communication.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:23665919
  review:
    summary: Lifespan determination through insulin signaling pathway.
    action: ACCEPT
    reason: Core function with multiple lines of experimental evidence.
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:23665919
  review:
    summary: DAF-2 signaling controls dauer larval development.
    action: ACCEPT
    reason: Core function of DAF-2. daf-2 mutants constitutively enter dauer at 
      restrictive temperatures.
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:0045887
    label: positive regulation of synaptic assembly at neuromuscular junction
  evidence_type: IGI
  original_reference_id: PMID:23665919
  review:
    summary: DAF-2/insulin signaling regulates neuromuscular junction 
      development through interaction with FSN-1.
    action: KEEP_AS_NON_CORE
    reason: This represents a specific developmental role of DAF-2 in synaptic 
      development, a pleiotropic effect of insulin signaling in neurons.
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:1900075
    label: positive regulation of neuromuscular synaptic transmission
  evidence_type: IGI
  original_reference_id: PMID:23665919
  review:
    summary: DAF-2 signaling contributes to normal synaptic transmission at 
      NMJs.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect of DAF-2 signaling on neuronal function, not core 
      function.
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:0010286
    label: heat acclimation
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: DAF-2 signaling regulates thermotolerance through DAF-16 and stress
      response genes.
    action: ACCEPT
    reason: Stress resistance is a well-documented output of DAF-2 signaling. 
      daf-2 mutants have enhanced thermotolerance through DAF-16-dependent 
      mechanisms.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0010286
    label: heat acclimation
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: Genetic interaction evidence for heat acclimation function.
    action: ACCEPT
    reason: Valid annotation supporting DAF-2's role in stress response.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:1905909
    label: regulation of dauer entry
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: Genetic interactions demonstrate DAF-2 role in dauer regulation.
    action: ACCEPT
    reason: Core function of DAF-2 with extensive genetic support.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: daf-2 mutants have enhanced oxidative stress resistance through 
      DAF-16-dependent activation of antioxidant genes.
    action: ACCEPT
    reason: Oxidative stress resistance is a key output of reduced DAF-2 
      signaling and contributes to extended lifespan.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: Genetic interaction evidence for oxidative stress response.
    action: ACCEPT
    reason: Valid annotation supporting DAF-2's role in stress resistance.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: daf-2 mutants have enhanced UV resistance.
    action: ACCEPT
    reason: UV resistance is part of the general stress resistance phenotype of 
      daf-2 mutants, mediated by DAF-16 target genes.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: Genetic interaction evidence for UV response.
    action: ACCEPT
    reason: Valid supporting evidence for stress response function.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: DAF-2 regulates gene expression through DAF-16 and SKN-1.
    action: ACCEPT
    reason: Gene expression regulation is a fundamental output of DAF-2 
      signaling, mediated through control of multiple transcription factors.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: DAF-2 suppresses DAF-16-dependent gene expression.
    action: ACCEPT
    reason: Negative regulation of DAF-16 target genes is a core function of 
      active DAF-2 signaling.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0010883
    label: regulation of lipid storage
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: DAF-2 regulates fat storage through DAF-16-dependent mechanisms.
    action: ACCEPT
    reason: Fat storage regulation is a well-documented metabolic function of 
      DAF-2. daf-2 mutants accumulate excess fat.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0010888
    label: negative regulation of lipid storage
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: DAF-2 activity suppresses lipid accumulation.
    action: ACCEPT
    reason: Active DAF-2 signaling promotes utilization of stored lipids; loss 
      of daf-2 leads to fat accumulation.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:1905910
    label: negative regulation of dauer entry
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: DAF-2 prevents dauer entry under favorable conditions.
    action: ACCEPT
    reason: Core function of DAF-2 signaling.
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Asymmetric arginine dimethylation determines life span in
        C.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:17277769
  review:
    summary: DAF-2 signaling interacts with translation machinery (eIF4E) to 
      regulate lifespan.
    action: ACCEPT
    reason: Core lifespan function with genetic evidence.
    supported_by:
    - reference_id: PMID:17277769
      supporting_text: eIF4E function in somatic cells modulates ageing in 
        Caenorhabditis elegans.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:17277769
  review:
    summary: Genetic interactions demonstrate DAF-2 role in lifespan 
      determination.
    action: ACCEPT
    reason: Core function with multiple supporting genetic interactions.
    supported_by:
    - reference_id: PMID:17277769
      supporting_text: eIF4E function in somatic cells modulates ageing in 
        Caenorhabditis elegans.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:27564576
  review:
    summary: DAF-2 signaling contributes to lifespan regulation.
    action: ACCEPT
    reason: Core function with extensive experimental support.
    supported_by:
    - reference_id: PMID:27564576
      supporting_text: eCollection 2016 Aug.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:19489741
  review:
    summary: DAF-2 can positively regulate some genes through its downstream 
      signaling.
    action: KEEP_AS_NON_CORE
    reason: While DAF-2 primarily suppresses DAF-16 targets, some genes are 
      positively regulated by insulin signaling. This is context-dependent.
    supported_by:
    - reference_id: PMID:19489741
      supporting_text: 2009 May 31. Endogenous cGMP regulates adult longevity 
        via the insulin signaling pathway in Caenorhabditis elegans.
- term:
    id: GO:0030536
    label: larval feeding behavior
  evidence_type: IMP
  original_reference_id: PMID:18316030
  review:
    summary: DAF-2 signaling regulates feeding behavior and satiety responses.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:18316030
      supporting_text: Insulin, cGMP, and TGF-beta signals regulate food intake 
        and quiescence in C.
- term:
    id: GO:0030536
    label: larval feeding behavior
  evidence_type: IGI
  original_reference_id: PMID:18316030
  review:
    summary: Genetic interaction evidence for feeding behavior regulation.
    action: ACCEPT
    reason: Valid supporting evidence for metabolic/behavioral function.
    supported_by:
    - reference_id: PMID:18316030
      supporting_text: Insulin, cGMP, and TGF-beta signals regulate food intake 
        and quiescence in C.
- term:
    id: GO:1903998
    label: regulation of eating behavior
  evidence_type: IMP
  original_reference_id: PMID:18316030
  review:
    summary: DAF-2 regulates eating behavior as part of its metabolic signaling 
      function.
    action: ACCEPT
    reason: Feeding regulation is a conserved function of insulin signaling 
      pathways.
    supported_by:
    - reference_id: PMID:18316030
      supporting_text: Insulin, cGMP, and TGF-beta signals regulate food intake 
        and quiescence in C.
- term:
    id: GO:1903998
    label: regulation of eating behavior
  evidence_type: IGI
  original_reference_id: PMID:18316030
  review:
    summary: Genetic interaction evidence for eating behavior regulation.
    action: ACCEPT
    reason: Valid supporting evidence.
    supported_by:
    - reference_id: PMID:18316030
      supporting_text: Insulin, cGMP, and TGF-beta signals regulate food intake 
        and quiescence in C.
- term:
    id: GO:0061065
    label: regulation of dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:1732156
  review:
    summary: Classical genetic analysis established DAF-2 as a key regulator of 
      dauer formation in the dauer regulatory pathway.
    action: ACCEPT
    reason: Foundational study establishing DAF-2's role in dauer regulation 
      through genetic epistasis analysis. Core function.
    supported_by:
    - reference_id: PMID:1732156
      supporting_text: Three other genes, daf-2, daf-3 and daf-5, displayed 
        partial or complex epistasis interactions
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:24120884
  review:
    summary: Direct observation of DAF-2 localization to plasma membrane in 
      oocytes.
    action: ACCEPT
    reason: Direct experimental evidence for plasma membrane localization 
      consistent with receptor function.
    supported_by:
    - reference_id: PMID:24120884
      supporting_text: 2013 Oct 10. DAF-2 and ERK couple nutrient availability 
        to meiotic progression during Caenorhabditis elegans oogenesis.
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:15905404
  review:
    summary: DAF-2 signaling interacts with beta-catenin and FOXO in dauer 
      regulation.
    action: ACCEPT
    reason: Dauer development is a core function of DAF-2.
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: Functional interaction between beta-catenin and FOXO in 
        oxidative stress signaling.
- term:
    id: GO:0042169
    label: SH2 domain binding
  evidence_type: IPI
  original_reference_id: PMID:18832074
  review:
    summary: DAF-2 physically interacts with the SH2 domain of the adaptor 
      protein SHC-1, which modulates insulin signaling output.
    action: ACCEPT
    reason: Direct physical interaction demonstrating SH2 domain binding 
      activity. This is important for signal transduction downstream of the 
      receptor.
    supported_by:
    - reference_id: PMID:18832074
      supporting_text: SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and
        the PI3 kinase AGE-1 and directly interacts with DAF-2
- term:
    id: GO:0051425
    label: PTB domain binding
  evidence_type: IPI
  original_reference_id: PMID:18832074
  review:
    summary: DAF-2 interacts with the PTB (phosphotyrosine-binding) domain of 
      SHC-1.
    action: ACCEPT
    reason: Direct physical interaction evidence. PTB domains bind 
      phosphotyrosine residues on activated receptors.
    supported_by:
    - reference_id: PMID:18832074
      supporting_text: SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and
        the PI3 kinase AGE-1 and directly interacts with DAF-2
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:16968739
  review:
    summary: DAF-2 localizes to sensory cilia where it detects environmental 
      signals for dauer formation and lifespan regulation.
    action: ACCEPT
    reason: Ciliary localization is important for DAF-2's role in sensing 
      environmental conditions that regulate dauer entry and lifespan.
    supported_by:
    - reference_id: PMID:16968739
      supporting_text: phenotypes result from defects in the DAF-2 
        (insulin-IGF-1-like) receptor signaling pathway in ciliated sensory 
        neurons
- term:
    id: GO:0030424
    label: axon
  evidence_type: IDA
  original_reference_id: PMID:25035490
  review:
    summary: DAF-2 isoform c localizes to axons in ASER neurons for taste 
      avoidance learning.
    action: ACCEPT
    reason: Direct imaging evidence for axonal localization of DAF-2c isoform, 
      required for learning behavior.
    supported_by:
    - reference_id: PMID:25035490
      supporting_text: DAF-2c, is translocated from the cell body to the 
        synaptic region of the chemosensory neuron
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IDA
  original_reference_id: PMID:25035490
  review:
    summary: DAF-2 localizes to neuronal cell bodies before translocation to 
      synaptic regions during learning.
    action: ACCEPT
    reason: Direct observation of DAF-2 localization in neuronal cell bodies.
    supported_by:
    - reference_id: PMID:25035490
      supporting_text: DAF-2c, is translocated from the cell body to the 
        synaptic region
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24120884
  review:
    summary: DAF-2 is detected in cytoplasm in addition to membrane locations.
    action: ACCEPT
    reason: Receptors can be present in cytoplasmic pools during trafficking and
      recycling.
    supported_by:
    - reference_id: PMID:24120884
      supporting_text: 2013 Oct 10. DAF-2 and ERK couple nutrient availability 
        to meiotic progression during Caenorhabditis elegans oogenesis.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:24120884
  review:
    summary: DAF-2 localizes to cytoplasmic vesicles, likely during receptor 
      trafficking.
    action: ACCEPT
    reason: Vesicular localization is consistent with receptor endocytosis and 
      recycling.
    supported_by:
    - reference_id: PMID:24120884
      supporting_text: 2013 Oct 10. DAF-2 and ERK couple nutrient availability 
        to meiotic progression during Caenorhabditis elegans oogenesis.
- term:
    id: GO:2000785
    label: regulation of autophagosome assembly
  evidence_type: IMP
  original_reference_id: PMID:22560223
  review:
    summary: DAF-2 negatively regulates autophagy. daf-2 RNAi increases 
      LGG-1-positive autophagic vesicles.
    action: ACCEPT
    reason: Autophagy regulation is an important output of DAF-2 signaling that 
      contributes to longevity and stress resistance.
    supported_by:
    - reference_id: PMID:22560223
      supporting_text: when TORC1 is inhibited genetically in C. elegans, 
        SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase 
        stress resistance and longevity
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:22672310
  review:
    summary: DAF-2 binds protein kinases as part of its signaling mechanism.
    action: ACCEPT
    reason: DAF-2 interacts with downstream kinases in the insulin signaling 
      cascade. Direct interaction evidence.
    supported_by:
    - reference_id: PMID:22672310
      supporting_text: Modulation of Caenorhabditis elegans infection 
        sensitivity by the LIN-7 cell junction protein.
- term:
    id: GO:0040018
    label: positive regulation of multicellular organism growth
  evidence_type: IMP
  original_reference_id: PMID:12571101
  review:
    summary: DAF-2 promotes organismal growth; daf-2 mutants have reduced body 
      size.
    action: ACCEPT
    reason: Growth regulation is a conserved function of insulin/IGF signaling. 
      DAF-2 promotes reproductive development and body size.
    supported_by:
    - reference_id: PMID:12571101
      supporting_text: Cyclic GMP-dependent protein kinase EGL-4 controls body 
        size and lifespan in C elegans.
- term:
    id: GO:1901031
    label: regulation of response to reactive oxygen species
  evidence_type: IMP
  original_reference_id: PMID:12399591
  review:
    summary: DAF-2 signaling regulates the response to oxidative stress.
    action: ACCEPT
    reason: Regulation of ROS response is an important function of DAF-2 that 
      contributes to longevity phenotypes.
    supported_by:
    - reference_id: PMID:12399591
      supporting_text: Timing requirements for insulin/IGF-1 signaling in C.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:20523893
  review:
    summary: Genetic interaction with RAGA-1 in lifespan determination.
    action: ACCEPT
    reason: Core function with supporting genetic interaction evidence.
    supported_by:
    - reference_id: PMID:20523893
      supporting_text: Manipulation of behavioral decline in Caenorhabditis 
        elegans with the Rag GTPase raga-1.
- term:
    id: GO:0040034
    label: regulation of development, heterochronic
  evidence_type: IGI
  original_reference_id: PMID:21471153
  review:
    summary: DAF-2 interacts with SEA-2 to regulate developmental timing and 
      seam cell development.
    action: KEEP_AS_NON_CORE
    reason: Heterochronic regulation is a specific developmental role, not a 
      core function of DAF-2. Valid annotation for this developmental context.
    supported_by:
    - reference_id: PMID:21471153
      supporting_text: The zinc-finger protein SEA-2 regulates larval 
        developmental timing and adult lifespan in C.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:9790527
  review:
    summary: Seminal paper demonstrating daf-2 mutants live more than twice as 
      long as wild-type animals.
    action: ACCEPT
    reason: Core function with foundational experimental support.
    supported_by:
    - reference_id: PMID:9790527
      supporting_text: Decreasing daf-2 activity causes fertile adults to remain
        active much longer than normal and to live more than twice as long
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:9790527
  review:
    summary: daf-2 mutants enter dauer diapause at restrictive temperatures.
    action: ACCEPT
    reason: Core function of DAF-2 in regulating dauer vs. reproductive 
      development.
    supported_by:
    - reference_id: PMID:9790527
      supporting_text: A more severe decrease in daf-2 function causes young 
        larvae to enter a state of diapause rather than progressing to adulthood
- term:
    id: GO:0043054
    label: dauer exit
  evidence_type: IMP
  original_reference_id: PMID:9790527
  review:
    summary: DAF-2 signaling promotes exit from dauer diapause.
    action: ACCEPT
    reason: DAF-2 regulates both entry and exit from dauer state. Core 
      developmental function.
    supported_by:
    - reference_id: PMID:9790527
      supporting_text: Cell nonautonomy of C.
- term:
    id: GO:0005009
    label: insulin receptor activity
  evidence_type: ISS
  original_reference_id: PMID:9252323
  review:
    summary: Sequence similarity to mammalian insulin receptors supports insulin
      receptor activity annotation.
    action: ACCEPT
    reason: Core molecular function based on sequence homology and functional 
      conservation. DAF-2 was identified as an insulin receptor family member.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: daf-2, a key gene in the genetic pathway that mediates 
        this endocrine signaling, encodes an insulin receptor family member
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: ISS
  original_reference_id: PMID:9252323
  review:
    summary: ATP binding inferred by sequence similarity to insulin receptor 
      kinase domain.
    action: ACCEPT
    reason: The kinase domain of DAF-2 has conserved ATP-binding motifs.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: daf-2, an insulin receptor-like gene that regulates 
        longevity and diapause in Caenorhabditis elegans.
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: ISS
  original_reference_id: PMID:9252323
  review:
    summary: DAF-2 initiates insulin receptor signaling based on sequence 
      homology and genetic evidence.
    action: ACCEPT
    reason: Core biological process of DAF-2. The receptor initiates a conserved
      PI3K/AKT signaling cascade.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: daf-2, an insulin receptor-like gene that regulates 
        longevity and diapause in Caenorhabditis elegans.
- term:
    id: GO:0017046
    label: peptide hormone binding
  evidence_type: ISS
  original_reference_id: PMID:9252323
  review:
    summary: DAF-2 binds insulin-like peptide (ILP) ligands encoded by the ins 
      gene family.
    action: ACCEPT
    reason: The extracellular domain of DAF-2 binds insulin-like peptide ligands
      that regulate its activity. C. elegans has approximately 40 insulin-like 
      peptides.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: daf-2, an insulin receptor-like gene that regulates 
        longevity and diapause in Caenorhabditis elegans.
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:10625546
  review:
    summary: DAF-2 interacts with TGF-beta signaling in dauer regulation.
    action: ACCEPT
    reason: Core function with multiple supporting studies.
    supported_by:
    - reference_id: PMID:10625546
      supporting_text: Targets of TGF-beta signaling in Caenorhabditis elegans 
        dauer formation.
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:11381260
  review:
    summary: daf-2 mutants show enhanced dauer formation through DAF-16 
      regulation.
    action: ACCEPT
    reason: Core function with extensive experimental support.
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Regulation of the Caenorhabditis elegans longevity 
        protein DAF-16 by insulin/IGF-1 and germline signaling.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:11381260
  review:
    summary: daf-2 mutants have extended lifespan requiring DAF-16.
    action: ACCEPT
    reason: Core function established in this foundational paper.
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Mutants in this pathway remain youthful and active much 
        longer than normal animals and can live more than twice as long
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:9252323
  review:
    summary: Original identification of daf-2 as regulator of dauer diapause.
    action: ACCEPT
    reason: Core function established in the seminal cloning paper.
    supported_by:
    - reference_id: PMID:9252323
      supporting_text: A C. elegans neurosecretory signaling system regulates 
        whether animals enter the reproductive life cycle or arrest development 
        at the long-lived dauer diapause stage
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9252323
  title: daf-2, an insulin receptor-like gene that regulates longevity and 
    diapause in Caenorhabditis elegans.
  findings:
  - statement: DAF-2 is an insulin receptor family member
    supporting_text: daf-2, an insulin receptor-like gene that regulates 
      longevity and diapause in Caenorhabditis elegans.
  - statement: Regulates dauer diapause and longevity
    supporting_text: daf-2, an insulin receptor-like gene that regulates 
      longevity and diapause in Caenorhabditis elegans.
  - statement: Induces metabolic changes analogous to mammalian insulin 
      signaling
    supporting_text: daf-2, an insulin receptor-like gene that regulates 
      longevity and diapause in Caenorhabditis elegans.
- id: PMID:9790527
  title: Cell nonautonomy of C. elegans daf-2 function in the regulation of 
    diapause and life span.
  findings:
  - statement: daf-2 mutants live more than twice as long as wild-type
    supporting_text: Cell nonautonomy of C. elegans daf-2 function in the 
      regulation of diapause and life span.
  - statement: daf-2 functions cell-nonautonomously
    supporting_text: Cell nonautonomy of C. elegans daf-2 function in the 
      regulation of diapause and life span.
  - statement: Regulates both dauer formation and adult lifespan
    supporting_text: Cell nonautonomy of C. elegans daf-2 function in the 
      regulation of diapause and life span.
- id: PMID:11381260
  title: Regulation of the Caenorhabditis elegans longevity protein DAF-16 by 
    insulin/IGF-1 and germline signaling.
  findings:
  - statement: DAF-2 signals through PI3K/AKT pathway
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
  - statement: DAF-2 prevents DAF-16 nuclear accumulation
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
  - statement: Lifespan extension requires DAF-16
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
- id: PMID:16916933
  title: Heat-shock transcription factor (HSF)-1 pathway required for 
    Caenorhabditis elegans immunity.
  findings:
  - statement: HSF-1 required for DAF-2 effects on immunity
    supporting_text: Heat-shock transcription factor (HSF)-1 pathway required 
      for Caenorhabditis elegans immunity.
  - statement: daf-2 mutants have enhanced pathogen resistance
    supporting_text: Heat-shock transcription factor (HSF)-1 pathway required 
      for Caenorhabditis elegans immunity.
- id: PMID:18358814
  title: Direct inhibition of the longevity-promoting factor SKN-1 by 
    insulin-like signaling in C. elegans.
  findings:
  - statement: DAF-2/IIS directly inhibits SKN-1 in parallel to DAF-16
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
  - statement: SKN-1 contributes to longevity in daf-2 mutants
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
- id: PMID:18832074
  title: SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to 
    modulate life span and stress response in C. elegans.
  findings:
  - statement: SHC-1 directly interacts with DAF-2
    supporting_text: SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling 
      pathways to modulate life span and stress response in C. elegans.
  - statement: SHC-1 opposes IIS through DAF-2 interaction
    supporting_text: SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling 
      pathways to modulate life span and stress response in C. elegans.
- id: PMID:21531333
  title: Asymmetric arginine dimethylation determines life span in C. elegans by
    regulating forkhead transcription factor DAF-16.
  findings:
  - statement: PRMT-1 regulates DAF-16 in the daf-2 pathway
    supporting_text: Asymmetric arginine dimethylation determines life span in 
      C. elegans by regulating forkhead transcription factor DAF-16.
  - statement: daf-2 mutants show stress tolerance and fat storage
    supporting_text: Asymmetric arginine dimethylation determines life span in 
      C. elegans by regulating forkhead transcription factor DAF-16.
- id: PMID:22560223
  title: TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf
    and DAF-16/FoxO.
  findings:
  - statement: DAF-2 negatively regulates autophagy
    supporting_text: TOR signaling and rapamycin influence longevity by 
      regulating SKN-1/Nrf and DAF-16/FoxO.
  - statement: daf-2 RNAi increases autophagic vesicles
    supporting_text: TOR signaling and rapamycin influence longevity by 
      regulating SKN-1/Nrf and DAF-16/FoxO.
- id: PMID:23665919
  title: Attenuation of insulin signalling contributes to FSN-1-mediated 
    regulation of synapse development.
  findings:
  - statement: DAF-2/insulin signaling regulates neuromuscular junction 
      development
    supporting_text: Attenuation of insulin signalling contributes to 
      FSN-1-mediated regulation of synapse development.
- id: PMID:24120884
  title: DAF-2 and ERK couple nutrient availability to meiotic progression 
    during Caenorhabditis elegans oogenesis.
  findings:
  - statement: DAF-2 signals through RAS-ERK in oogenesis
    supporting_text: DAF-2 and ERK couple nutrient availability to meiotic 
      progression during Caenorhabditis elegans oogenesis.
  - statement: DAF-2 localizes to plasma membrane and cytoplasmic vesicles
    supporting_text: DAF-2 and ERK couple nutrient availability to meiotic 
      progression during Caenorhabditis elegans oogenesis.
- id: PMID:25035490
  title: Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning
    response in C. elegans.
  findings:
  - statement: DAF-2c isoform translocates from cell body to synaptic region
    supporting_text: Role of synaptic phosphatidylinositol 3-kinase in a 
      behavioral learning response in C. elegans.
  - statement: Required for taste avoidance learning
    supporting_text: Role of synaptic phosphatidylinositol 3-kinase in a 
      behavioral learning response in C. elegans.
- id: PMID:16968739
  title: IFTA-2 is a conserved cilia protein involved in pathways regulating 
    longevity and dauer formation in Caenorhabditis elegans.
  findings:
  - statement: DAF-2 signaling operates in ciliated sensory neurons
    supporting_text: IFTA-2 is a conserved cilia protein involved in pathways 
      regulating longevity and dauer formation in Caenorhabditis elegans.
- id: PMID:1732156
  title: Genetic analysis of chemosensory control of dauer formation in 
    Caenorhabditis elegans.
  findings:
  - statement: Classical genetic evidence for daf-2 role in dauer regulation
    supporting_text: Genetic analysis of chemosensory control of dauer formation
      in Caenorhabditis elegans.
- id: PMID:23770237
  title: Insulin/IGF-1 signaling regulates proteasome activity through the 
    deubiquitinating enzyme UBH-4.
  findings:
  - statement: DAF-2 signaling regulates proteasome activity
    supporting_text: Insulin/IGF-1 signaling regulates proteasome activity 
      through the deubiquitinating enzyme UBH-4.
- id: PMID:19167330
  title: Age-dependent deterioration of nuclear pore complexes causes a loss of 
    nuclear integrity in postmitotic cells.
  findings:
  - statement: DAF-2 regulates lifespan through nuclear pore complex integrity
    supporting_text: Age-dependent deterioration of nuclear pore complexes 
      causes a loss of nuclear integrity in postmitotic cells.
- id: PMID:17526726
  title: Specificity and complexity of the Caenorhabditis elegans innate immune 
    response.
  findings:
  - statement: DAF-2 suppresses expression of stress response genes
    supporting_text: Specificity and complexity of the Caenorhabditis elegans 
      innate immune response.
- id: PMID:24013594
  title: Neuropeptide signaling remodels chemosensory circuit composition in 
    Caenorhabditis elegans.
  findings:
  - statement: DAF-2/insulin signaling involved in salt chemosensory learning
    supporting_text: Neuropeptide signaling remodels chemosensory circuit 
      composition in Caenorhabditis elegans.
- id: PMID:24671950
  title: A Caenorhabditis elegans developmental decision requires insulin 
    signaling-mediated neuron-intestine communication.
  findings:
  - statement: DAF-2 regulates dauer entry through neuron-intestine 
      communication
    supporting_text: A Caenorhabditis elegans developmental decision requires 
      insulin signaling-mediated neuron-intestine communication.
- id: PMID:17277769
  title: eIF4E function in somatic cells modulates ageing in Caenorhabditis 
    elegans.
  findings:
  - statement: DAF-2 signaling interacts with translation machinery
    supporting_text: eIF4E function in somatic cells modulates ageing in 
      Caenorhabditis elegans.
- id: PMID:27564576
  title: Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential 
    for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans.
  findings:
  - statement: DAF-2 signaling contributes to lifespan regulation
    supporting_text: Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins 
      Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis 
      elegans.
- id: PMID:19489741
  title: Endogenous cGMP regulates adult longevity via the insulin signaling 
    pathway in Caenorhabditis elegans.
  findings:
  - statement: DAF-2 can positively regulate some genes through downstream 
      signaling
    supporting_text: Endogenous cGMP regulates adult longevity via the insulin 
      signaling pathway in Caenorhabditis elegans.
- id: PMID:18316030
  title: 'Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence
    in C. elegans: a model for satiety.'
  findings:
  - statement: DAF-2 signaling regulates feeding behavior and satiety responses
    supporting_text: 'Insulin, cGMP, and TGF-beta signals regulate food intake and
      quiescence in C. elegans: a model for satiety.'
- id: PMID:15905404
  title: Functional interaction between beta-catenin and FOXO in oxidative 
    stress signaling.
  findings:
  - statement: DAF-2 signaling interacts with beta-catenin in dauer regulation
    supporting_text: Functional interaction between beta-catenin and FOXO in 
      oxidative stress signaling.
- id: PMID:22672310
  title: Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7
    cell junction protein.
  findings:
  - statement: DAF-2 binds protein kinases in signaling cascade
    supporting_text: Modulation of Caenorhabditis elegans infection sensitivity 
      by the LIN-7 cell junction protein.
- id: PMID:12571101
  title: Cyclic GMP-dependent protein kinase EGL-4 controls body size and 
    lifespan in C elegans.
  findings:
  - statement: DAF-2 promotes organismal growth
    supporting_text: Cyclic GMP-dependent protein kinase EGL-4 controls body 
      size and lifespan in C elegans.
- id: PMID:12399591
  title: Timing requirements for insulin/IGF-1 signaling in C. elegans.
  findings:
  - statement: DAF-2 signaling regulates the response to oxidative stress
    supporting_text: Timing requirements for insulin/IGF-1 signaling in C. 
      elegans.
- id: PMID:20523893
  title: Manipulation of behavioral decline in Caenorhabditis elegans with the 
    Rag GTPase raga-1.
  findings:
  - statement: Genetic interaction between RAGA-1 and DAF-2 in lifespan 
      determination
    supporting_text: Manipulation of behavioral decline in Caenorhabditis 
      elegans with the Rag GTPase raga-1.
- id: PMID:21471153
  title: The zinc-finger protein SEA-2 regulates larval developmental timing and
    adult lifespan in C. elegans.
  findings:
  - statement: DAF-2 interacts with SEA-2 in heterochronic regulation
    supporting_text: The zinc-finger protein SEA-2 regulates larval 
      developmental timing and adult lifespan in C. elegans.
- id: PMID:10625546
  title: Targets of TGF-beta signaling in Caenorhabditis elegans dauer 
    formation.
  findings:
  - statement: DAF-2 interacts with TGF-beta signaling in dauer regulation
    supporting_text: Targets of TGF-beta signaling in Caenorhabditis elegans 
      dauer formation.
- id: file:worm/daf-2/daf-2-deep-research-falcon.md
  title: Deep research report on daf-2
  findings: []
core_functions:
- description: 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.
  molecular_function:
    id: GO:0004714
    label: transmembrane receptor protein tyrosine kinase activity
  directly_involved_in:
  - id: GO:0008286
    label: insulin receptor signaling pathway
  - id: GO:0008340
    label: determination of adult lifespan
  - id: GO:0040024
    label: dauer larval development
  - id: GO:1905910
    label: negative regulation of dauer entry
  - id: GO:1900181
    label: negative regulation of protein localization to nucleus
  locations:
  - id: GO:0005886
    label: plasma membrane
tags:
- caeel-proteostasis

daf-2

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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