title: ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation.
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.
authors: Institute of Molecular and Cell Biology, Singapore 138673.
authors: Wei
authors: W
authors: Zhang
authors: Ville
authors: V
authors: Hietakangas
authors: Sheena
authors: S
authors: Wee
authors: Siew Choo
authors: SC
authors: Lim
authors: Jayantha
authors: J
authors: Gunaratne
authors: Stephen M
authors: SM
authors: Cohen
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D061986:MCF-7 Cells; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D051058:Oncogene Protein v-akt; D019892:eIF-2 Kinase