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The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells

Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both sa...

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Autores principales: Abdul, Ata ur Rahman Mohammed, De Silva, Bhagya, Gary, Ronald K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829510/
https://www.ncbi.nlm.nih.gov/pubmed/29212798
http://dx.doi.org/10.1242/bio.030874
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author Abdul, Ata ur Rahman Mohammed
De Silva, Bhagya
Gary, Ronald K.
author_facet Abdul, Ata ur Rahman Mohammed
De Silva, Bhagya
Gary, Ronald K.
author_sort Abdul, Ata ur Rahman Mohammed
collection PubMed
description Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhanced phosphorylation of Ser9 of GSK3β via a positive feedback mechanism, and both salts elicited this enhancement. Another GSK3 substrate is β-catenin, which has a central role in Wnt signaling. In A172 human glioblastoma cells, lithium treatment caused a surprising increase in phospho-Ser33/Ser37-β-catenin, which was quantified using an antibody-coupled capillary electrophoresis method. The β-catenin hyperphosphorylation was unaffected by p53 RNAi knockdown, indicating that p53 is not involved in the mechanism of this response. Lithium caused a decrease in the abundance of axin, a component of the β-catenin destruction complex that has a role in coordinating β-catenin ubiquitination and protein turnover. The axin and phospho-β-catenin results were reproduced in U251 and U87MG glioblastoma cell lines. These observations run contrary to the conventional view of the canonical Wnt signaling pathway, in which a GSK3 inhibitor would be expected to decrease, not increase, phospho-β-catenin levels. This article has an associated First Person interview with the first author of the paper.
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spelling pubmed-58295102018-02-28 The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells Abdul, Ata ur Rahman Mohammed De Silva, Bhagya Gary, Ronald K. Biol Open Research Article Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhanced phosphorylation of Ser9 of GSK3β via a positive feedback mechanism, and both salts elicited this enhancement. Another GSK3 substrate is β-catenin, which has a central role in Wnt signaling. In A172 human glioblastoma cells, lithium treatment caused a surprising increase in phospho-Ser33/Ser37-β-catenin, which was quantified using an antibody-coupled capillary electrophoresis method. The β-catenin hyperphosphorylation was unaffected by p53 RNAi knockdown, indicating that p53 is not involved in the mechanism of this response. Lithium caused a decrease in the abundance of axin, a component of the β-catenin destruction complex that has a role in coordinating β-catenin ubiquitination and protein turnover. The axin and phospho-β-catenin results were reproduced in U251 and U87MG glioblastoma cell lines. These observations run contrary to the conventional view of the canonical Wnt signaling pathway, in which a GSK3 inhibitor would be expected to decrease, not increase, phospho-β-catenin levels. This article has an associated First Person interview with the first author of the paper. The Company of Biologists Ltd 2017-12-06 /pmc/articles/PMC5829510/ /pubmed/29212798 http://dx.doi.org/10.1242/bio.030874 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Abdul, Ata ur Rahman Mohammed
De Silva, Bhagya
Gary, Ronald K.
The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells
title The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells
title_full The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells
title_fullStr The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells
title_full_unstemmed The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells
title_short The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a GSK3 substrate, in human glioblastoma cells
title_sort gsk3 kinase inhibitor lithium produces unexpected hyperphosphorylation of β-catenin, a gsk3 substrate, in human glioblastoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829510/
https://www.ncbi.nlm.nih.gov/pubmed/29212798
http://dx.doi.org/10.1242/bio.030874
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