title: Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells.
abstract: Both the rate of overall translation and the specific acceleration of proinsulin synthesis are known to be glucose-regulated processes in the beta-cell. In this study, we propose that glucose-induced stimulation of overall translation in beta-cells depends on a protein phosphatase-1-mediated decrease in serine-51 phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha), a pivotal translation initiation factor. The decrease was rapid and detectable within 15 min and proportional to the range of glucose concentrations that also stimulate translation. Lowered net eIF2alpha phosphorylation was not associated with a detectable decrease in activity of any eIF2alpha kinase. Moreover, okadaic acid blocked glucose-induced eIF2alpha dephosphorylation, suggesting that the net effect was mediated by a protein phosphatase. Experiments with salubrinal on intact cells and nuclear inhibitor of protein phosphatase-1 (PP1) on cell extracts suggested that this phosphatase was PP1. The net effect contained, however, a component of glucose-induced folding load in the endoplasmic reticulum because coincubation with cycloheximide further amplified the effect of glucose on eIF2alpha dephosphorylation. Thus, the steady-state level of eIF2alpha phosphorylation in beta-cells is the result of a balance between folding-load-induced phosphorylation and PP1-dependent dephosphorylation. Because defects in the pancreatic endoplasmic reticulum kinase-eIF2alpha signaling system lead to beta-cell failure and diabetes, deregulation of the PP1 system could likewise lead to cellular dysfunction and disease.
authors.affiliation: Gene Expression Unit, Department of Molecular Cell Biology, KU-Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Vander Mierde
authors.forename: Donalyn
authors.initials: D
authors.lastname: Scheuner
authors.forename: Roel
authors.initials: R
authors.lastname: Quintens
authors.forename: Rupali
authors.initials: R
authors.lastname: Patel
authors.forename: Benbo
authors.initials: B
authors.lastname: Song
authors.forename: Katsura
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Monique
authors.initials: M
authors.lastname: Beullens
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
authors.forename: Frans C
authors.initials: FC
authors.lastname: Schuit
mesh_terms: D000818:Animals; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006706:Homeostasis / Q000502:physiology; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D017510:Protein Folding; D054645:Protein Phosphatase 1; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors; D011506:Proteins; C073882:phosphoprotein phosphatase inhibitor 1; D003513:Cycloheximide; D019892:eIF-2 Kinase; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D005947:Glucose