title: PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.
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.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Sri Devi
authors.initials: SD
authors.lastname: Narasimhan
authors.forename: Kelvin
authors.initials: K
authors.lastname: Yen
authors.forename: Ankita
authors.initials: A
authors.lastname: Bansal
authors.forename: Eun-Soo
authors.initials: ES
authors.lastname: Kwon
authors.forename: Srivatsan
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Tissenbaum
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C107483:DAF-2 protein, C elegans; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase