Authors: Narasimhan SD; Yen K; Bansal A; Kwon ES; Padmanabhan S; Tissenbaum HA
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-beta signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-beta 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-beta 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.
Keywords: Animals; Animals, Genetically Modified/genetics/growth & development/metabolism; Caenorhabditis elegans/*enzymology/genetics/growth & development; Caenorhabditis elegans Proteins/*metabolism; Gene Expression Regulation, Developmental; Insulin/metabolism; Longevity/*genetics; Mutation; Phenotype; Pyruvate Dehydrogenase (Lipoamide)-Phosphatase/genetics/*metabolism; RNA Interference; Receptor, IGF Type 1/genetics/metabolism; Receptor, Insulin/*metabolism; Receptors, Transforming Growth Factor beta/metabolism; Signal Transduction; Transcription Factors/*metabolism|
Journal: PLoS genetics Volume: 7 Issue: 4 Pages: e1001377 Date: May 3, 2011 PMID: 21533078 |
Narasimhan SD, Yen K, Bansal A, Kwon ES, Padmanabhan S, Tissenbaum HA (2011) PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism. PLoS genetics 7: e1001377.
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