PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism

PLoS Genet. 2011 Apr;7(4):e1001377. doi: 10.1371/journal.pgen.1001377. Epub 2011 Apr 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Insulin
  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • daf-16 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Pyruvate Dehydrogenase (Lipoamide)-Phosphatase