Narasimhan, Sri DeviYen, KelvinBansal, AnkitaKwon, Eun-SooPadmanabhan, SrivatsanTissenbaum, Heidi A.2022-08-232022-08-232011-04-212011-05-20Narasimhan SD, Yen K, Bansal A, Kwon E-S, Padmanabhan S, et al. (2011) PDP-1 Links the TGF-b and IIS Pathways to Regulate Longevity, Development, and Metabolism. PLoS Genet 7(4): e1001377. doi:10.1371/journal.pgen.1001377. <a href="http://dx.doi.org/10.1371/journal.pgen.1001377">Link to article on publisher's website</a>1553-740410.1371/journal.pgen.100137721533078https://hdl.handle.net/20.500.14038/33198The 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.en-USPDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and MetabolismJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2746&context=gsbs_sp&unstamped=1https://escholarship.umassmed.edu/gsbs_sp/17362023278gsbs_sp/1736