Title

The Gsk3 Kinase Inhibitor Lithium Produces Unexpected Hyperphosphorylation Of Β-catenin, A Gsk3 Substrate, In Human Glioblastoma Cells

Document Type

Article

Publication Date

1-1-2018

Publication Title

Biology Open

Publisher

Company of Biologists Ltd

Volume

7

Issue

1

Abstract

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 Ser 9 of GSK3 βviaapositive 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. © 2018. Published by The Company of Biologists Ltd.

Keywords

Axin; Capillary electrophoresis; Glycogen synthase kinase; Phosphorylation; Wnt signaling; β-Catenin

Language

English

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