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A new phosphatase that modulates the C. elegans Insulin/IGF‐1 signaling pathway
Author(s) -
Tissenbaum Heidi A,
Padmanabhan Srivatsan,
Mukhopadhyay Arnab,
Narasimhan Sridevi
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.93.3
Subject(s) - biology , insulin receptor , phosphorylation , protein phosphatase 2 , transcription factor , signal transduction , protein kinase b , kinase , microbiology and biotechnology , protein subunit , rna interference , phosphatase , insulin , genetics , gene , endocrinology , insulin resistance , rna
The prevalence of Type II diabetes is rapidly expanding in the US. Two factors that contribute to this are the incidence of obese individuals (strong correlation between obesity and Type II diabetes) as well as the increased average age of the population. As individuals age, they become more likely to develop Type II diabetes. The overall goal of our studies is to uncover the molecular mechanism that explains the connection between Insulin/IGF‐1 signaling, the aging process and fat storage, so that Type II diabetes and can be better controlled in humans. We use the nematode, C. elegans, as our model system since mutations in the genes in the Insulin/IGF‐1 signaling pathway lead to changes in both fat storage and longevity and the pathway is highly conserved between humans and C. elegans. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine‐specific protein kinases. In an RNAi screen for serine/threonine protein phosphatases that counter‐balance the effect of the kinases in the IIS pathway, we identified pptr‐1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr‐1 affects phenotypes associated with the IIS pathway including life span and fat storage. We show that PPTR‐1 functions by regulating worm AKT‐1 phosphorylation. In C. elegans, this modulation ultimately leads to changes in sub‐cellular localization and the transcriptional activity of the forkhead transcription factor DAF‐16. This study reveals a c role for the B56 regulatory subunit in modulating Insulin/IGF‐1 signaling through the dephosphorylation of AKT and thereby has widespread implications in diabetes research and cancer.