The GSK3 Kinase Inhibitor Lithium Produces Unexpected Hyperphosphorylation of beta-Catenin, a GSK3 Substrate, in Human Glioblastoma Cells
Journal Article - Open Access
University of Nevada Las Vegas Las Vegas United States
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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. InNIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhancedphosphorylation of Ser9 ofGSK3 via a positive feedback mechanism, and both salts elicited this enhancement. Another GSK3 substrate is-catenin, which has a central role in Wnt signaling. In A172 human glioblastoma cells, lithium treatment caused a surprising increase in phospho-Ser33Ser37--catenin, which was quantified using an antibody-coupled capillary electrophoresis method. The -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 -catenin destruction complex that has a role in coordinating -catenin ubiquitination and protein turnover. The axin and phospho--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--catenin levels.
- Organic Chemistry