DAF-2 insulin/IGF-1-like signaling to DAF-16/FOXO in Caenorhabditis elegans

In Caenorhabditis elegans a large family of insulin-like peptides, secreted mainly by neurons, acts through a single insulin/IGF-1 receptor tyrosine kinase, DAF-2. Active DAF-2 signals through the class I PI3K catalytic subunit AGE-1 to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which the PTEN lipid phosphatase DAF-18 removes. PIP3 supports activation of the 3-phosphoinositide-dependent kinase PDK-1, which in turn activates a kinase complex of AKT-1, AKT-2 and SGK-1. These kinases phosphorylate the FOXO transcription factor DAF-16, and phosphorylated DAF-16 is bound by the 14-3-3 protein FTT-2 and held in the cytoplasm. When ligand input falls, as in poor food or high pheromone conditions, or when the pathway is genetically reduced, DAF-16 enters the nucleus and regulates a broad transcriptional program that includes stress-resistance genes such as the mitochondrial manganese superoxide dismutase sod-3, as well as antimicrobial and metabolic genes. The pathway controls the dauer diapause decision, adult lifespan, stress resistance and fat storage, and DAF-16 is its major output.

Boundary. A concrete C. elegans signaling module running from insulin-like peptide ligands at DAF-2 to DAF-16-dependent transcription. The root parts are the ligand family, the receptor, the AGE-1 PI3K step, the opposing DAF-18 PTEN step, PDK-1, the AKT-1/AKT-2/SGK-1 kinase step, FTT-2 cytoplasmic retention of DAF-16, DAF-16 transcription, and one representative DAF-16 target (SOD-3). SOD-3 is included as an example of the DAF-16 output program, not as a signaling component. Its causal contribution to the daf-2 longevity phenotype is doubtful (see knowledge_gaps), so it should be read as a well-characterized readout. Relation to generic modules. MODULE:insulin_receptor_signaling models receptor activation, IRS docking and PI3K recruitment, then AKT/FOXO output. MODULE:pi3k_akt_mtor models PI3K, PIP3/PDK1, AKT activation, an mTORC1 branch and PTEN-type negative regulation. This module is a worm instance of the shared trunk. It omits the IRS adaptor step: the worm IRS ortholog IST-1 and the p50/p55 PI3K adaptor AAP-1 potentiate DAF-2 signaling but are not required under most conditions (PMID:12393910), and neither has a gene review yet. AAP-1 is mentioned as the AGE-1 partner in the PI3K complex but is not modeled as a separate part. The module also omits the mTORC1 branch. It adds SGK-1 as a co-equal effector kinase with the AKTs and an explicit 14-3-3 retention step. Modulators kept outside the module. SIR-2.1 (Q21921) binds the 14-3-3 proteins and activates DAF-16 in a stress-dependent route that runs in parallel to insulin-like signaling and is not needed for daf-2 lifespan regulation (PMID:16777605). AAK-2/AMPK (Q95ZQ4) is required for the lifespan extension of reduced insulin signaling (PMID:15574588), but it is an energy-sensing input to longevity, not a step between DAF-2 and DAF-16. Both are cited as context in the top-level evidence and are not modeled as parts. The other known DAF-16 inputs (germline signals, JNK-1, TGF-beta DAF-7 at the dauer decision) and DAF-2 outputs other than DAF-16 (such as SKN-1 inhibition) are also outside this boundary. Ligands. C. elegans encodes about 40 insulin-like peptides with agonist and antagonist activities and extensive redundancy. They are represented as a family role, with INS-6 and DAF-28 as representative agonists implicated in the neuron-to-intestine dauer decision (PMID:24671950). Both representatives have gene reviews with hormone activity (GO:0005179) as their core function. The daf-28(sa191) allele is a dominant-negative processing mutant thought to poison other insulins, so its dauer phenotype reports on agonist ILP signaling as a whole rather than on DAF-28 alone (PMID:12654727). Grounding. Every grounded protein has a C. elegans gene review, and each annoton function matches the core molecular function of that review: INS-6 P56174 and DAF-28 Q9NEK7 (hormone activity; Q9NEK7 is an unreviewed TrEMBL entry), DAF-2 Q968Y9, AGE-1 Q94125, DAF-18 G5EE01, PDK-1 Q9Y1J3, AKT-1 Q17941, AKT-2 Q9XTG7, SGK-1 Q2PJ68, FTT-2 Q20655, DAF-16 O16850 and SOD-3 P41977. The AGE-1 MF is the class I PI3K activity (GO:0046934), as in the age-1 review: p110 homology, the AAP-1 partnership and the near-absence of PIP3 in age-1-null animals (PMID:23543623) support it, while the broader GOA GO:0016303 rows are kept there as non-core. The PDK-1 MF is 3-phosphoinositide-dependent protein kinase activity (GO:0004676), as in the pdk-1 review: UniProt cross-references a PDK1-type PH domain on this entry (InterPro IPR033931, Pfam PF14593, SMART SM00233), and the phospholipid-independent PIAK form is defined by lacking that PH domain (PMID:11274160). GOA carries only the parent GO:0004674. DAF-18 also has protein phosphatase activity toward the VAB-1 Eph receptor (PMID:19853560), and SGK-1 is also the main effector of TORC2, acting through PQM-1 independently of DAF-16 (PMID:27401555). Those roles are outside this module and are recorded in the annoton notes only.