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This version published online on November 2, 2006
Endocrinology, doi:10.1210/en.2006-1012
A more recent version of this article appeared on February 1, 2007
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Submitted on July 27, 2006
Accepted on October 23, 2006

GLUCOSE ACTIVATES A PP1 MEDIATED SIGNALING PATHWAY TO ENHANCE OVERALL TRANSLATION IN PANCREATIC BETA CELLS

Dirk Vander Mierde, Donalyn Scheuner, Roel Quintens, Rupali Patel, Benbo Song, Katsura Tsukamoto, Monique Beullens, Randal J Kaufman, Mathieu Bollen, and Frans C. Schuit*

Dept of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven, Belgium; Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, 48105

* To whom correspondence should be addressed. E-mail: Frans.Schuit{at}med.kuleuven.be.

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 eIF2{alpha} (eukaryotic translation initiation factor 2 alpha), 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 eIF2{alpha} phosphorylation was not associated with a detectable decrease in activity of any eIF2{alpha} kinase. Moreover, OA (okadaic acid) blocked glucose-induced eIF2{alpha} dephosphorylation suggesting that the net effect was mediated by a protein phosphatase. Experiments with Salubrinal on intact cells and NIPP1 (Nuclear inhibitor of protein phosphatase-1) on cell extracts suggested that this phosphatase was PP1 (protein phosphatase-1). The net effect contained, however, a component of glucose-induced folding load in the ER (endoplasmic reticulum) as coincubation with Chx (cycloheximide) further amplified the effect of glucose on eIF2{alpha} dephosphorylation. Thus, the steady-state level of eIF2{alpha} phosphorylation in beta cells is the result of a balance between folding-load-induced phosphorylation and PP1-dependent dephosphorylation. As defects in the PERK (PKR-like endoplasmic reticulum kinase) -eIF2{alpha} signaling system lead to beta cell failure and diabetes, deregulation of PP1 system could likewise lead to cellular dysfunction and disease.
Key words: PP1 • translational control • beta cells




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