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High glucose exposure promotes activation of protein phosphatase 2A in rodent islets and INS-1 832/13 beta-cells by increasing the posttranslational carboxylmethylation of its catalytic subunit.

Authors: Arora, DK  Machhadieh, B  Matti, A  Wadzinski, BE  Ramanadham, S  Kowluru, A 
Citation: Arora DK, etal., Endocrinology. 2014 Feb;155(2):380-91. doi: 10.1210/en.2013-1773. Epub 2013 Nov 21.
Pubmed: (View Article at PubMed) PMID:24265448
DOI: Full-text: DOI:10.1210/en.2013-1773

Existing evidence implicates regulatory roles for protein phosphatase 2A (PP2A) in a variety of cellular functions, including cytoskeletal remodeling, hormone secretion, and apoptosis. We report here activation of PP2A in normal rat islets and insulin-secreting INS-1 832/13 cells under the duress of hyperglycemic (HG) conditions. Small interfering RNA-mediated knockdown of the catalytic subunit of PP2A (PP2Ac) markedly attenuated glucose-induced activation of PP2A. HG, but not nonmetabolizable 3-O-methyl glucose or mannitol (osmotic control), significantly stimulated the methylation of PP2Ac at its C-terminal Leu-309, suggesting a novel role for this posttranslational modification in glucose-induced activation of PP2A. Moreover, knockdown of the cytosolic leucine carboxymethyl transferase 1 (LCMT1), which carboxymethylates PP2Ac, significantly attenuated PP2A activation under HG conditions. In addition, HG conditions, but not 3-O-methyl glucose or mannitol, markedly increased the expression of LCMT1. Furthermore, HG conditions significantly increased the expression of B55alpha, a regulatory subunit of PP2A, which has been implicated in islet dysfunction under conditions of oxidative stress and diabetes. Thapsigargin, a known inducer of endoplasmic reticulum stress, failed to exert any discernible effects on the carboxymethylation of PP2Ac, expression of LCMT1 and B55alpha, or PP2A activity, suggesting no clear role for endoplasmic reticulum stress in HG-induced activation of PP2A. Based on these findings, we conclude that exposure of the islet beta-cell to HG leads to accelerated PP2A signaling pathway, leading to loss in glucose-induced insulin secretion.


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CRRD Object Information
CRRD ID: 8693600
Created: 2014-07-17
Species: All species
Last Modified: 2014-07-17
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.