Abstract
The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease.
Highlights
Insulin/IGF-1 signaling (IIS) is a conserved neuroendocrine pathway that regulates longevity, development and energy metabolism across phylogeny [1,2]
The insulin/IGF-1 signaling pathway is an important regulator of longevity, development, and metabolism across phylogeny
The roundworm C. elegans has been an excellent model system to study the role of insulin/IGF-1 signaling in the aging process
Summary
Insulin/IGF-1 signaling (IIS) is a conserved neuroendocrine pathway that regulates longevity, development and energy metabolism across phylogeny [1,2]. In the roundworm Caenorhabditis elegans (C. elegans), activation of the DAF-2 insulin/IGF-1 receptor tyrosine kinase intiates an AAP-1/AGE-1 PI 3-kinase signaling cascade involving the downstream serine/threonine kinases PDK-1, AKT-1, and AKT-2 [3,4,5,6,7]. Mutations in the kinases upstream of DAF-16 such as daf-2, age-1, pdk-1, akt-1 and akt-2 result in an increase in lifespan, dauer formation, fat storage and/or stress resistance, and loss-of-function mutations in daf-16 completely suppress these phenotypes [15,16,17,18]. In addition to the IIS pathway, dauer formation in C. elegans is regulated by the DAF-7/TGF-b-like signaling pathway [19,20,21]. Genetic epistasis studies have suggested that the TGF-b pathway acts in a parallel manner with IIS to modulate dauer formation [31,32,33]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
