ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation
- Wei Zhang1,2,
- Ville Hietakangas3,
- Sheena Wee1,
- Siew Choo Lim1,
- Jayantha Gunaratne1 and
- Stephen M. Cohen1,2,4
- 1Institute of Molecular and Cell Biology, Singapore 138673;
- 2Department of Biological Sciences, National University of Singapore, Singapore 119077;
- 3Department of Biosciences, Institute of Biotechnology, 00014 University of Helsinki, Helsinki, Finland
Abstract
Endoplasmic reticulum (ER) stress is emerging as a potential contributor to the onset of type 2 diabetes by making cells insulin-resistant. However, our understanding of the mechanisms by which ER stress affects insulin response remains fragmentary. Here we present evidence that the ER stress pathway acts via a conserved signaling mechanism involving the protein kinase PERK to modulate cellular insulin responsiveness. Insulin signaling via AKT reduces activity of FOXO transcription factors. In some cells, PERK can promote insulin responsiveness. However, we found that PERK also acts oppositely via phosphorylation of FOXO to promote FOXO activity. Inhibition of PERK improves cellular insulin responsiveness at the level of FOXO activity. We suggest that the protein kinase PERK may be a promising pharmacological target for ameliorating insulin resistance.
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Footnotes
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↵4 Corresponding author
E-mail scohen{at}imcb.a-star.edu.sg
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.201731.112.
- Received July 23, 2012.
- Accepted January 14, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.