Research Perspective Volume 3, Issue 9 pp 896—905

Figure 1. EGF signaling regulates protein and calcium homeostasis in adult C. elegans. (A) During larval growth, LIN-3/EGF levels in the epithelium are relatively low. Additionally, extracellular HPA-1 and HPA-2 keep EGF signaling repressed by either antagonizing the receptor or the ligand. In the absence of EGF signaling, protein homeostasis is primarily regulated by sHSP chaperones. Native proteins (green elipse) are kept folded and prevented from aggregating by sHSPs. (B) As animals enter adulthood, LIN-3/EGF is resynthesized and secreted, activating the LET-23/EGFR. Activated LET-23/EGFR recruits PLC-3/PLCγ, which produces IP₃ to activate the ITR-1 IP₃ receptor, resulting in the release of calcium from stores within the ER. How calcium release promotes longevity is not known. Activated LET-23 also recruits the Ras/ERK signaling cascade, which phosphorylates multiple transcription factors, including EOR-1 and SKN-1.SKN-1 activates the transcription of phase 2 antioxidant and detoxification enzymes, which help to minimize protein oxidation. EOR-1 and EOR-2 repress the expression of sHSP genes while activating the expression of multiple F-box proteins and the Cullin1 adaptor SKR-5, promoting global protein turnover. Combined, these changes in the transcriptional profile alter the mechanism for maintaining protein homeostasis from one focused around refolding proteins and preventing aggregation to one focused around preventing the accumulation of oxidized proteins.