RRC ID 46301
Author Narasimhan SD, Yen K, Bansal A, Kwon ES, Padmanabhan S, Tissenbaum HA.
Title PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.
Journal PLoS Genet
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.
Volume 7(4)
Pages e1001377
Published 2011-4
DOI 10.1371/journal.pgen.1001377
PMID 21533078
PMC PMC3080858
MeSH Animals Animals, Genetically Modified / genetics Animals, Genetically Modified / growth & development Animals, Genetically Modified / metabolism Caenorhabditis elegans / enzymology* Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans Proteins / metabolism* Forkhead Transcription Factors Gene Expression Regulation, Developmental Insulin / metabolism Longevity / genetics* Mutation Phenotype Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / genetics Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / metabolism* RNA Interference Receptor, IGF Type 1 / genetics Receptor, IGF Type 1 / metabolism Receptor, Insulin / metabolism* Receptors, Transforming Growth Factor beta / metabolism Signal Transduction Transcription Factors / metabolism*
IF 5.224
Times Cited 38
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm3734 tm339