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

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 Ser9 of GSK3? 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-Ser33/Ser37-?-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.This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Abdul AURM

PROVIDER: S-EPMC5829510 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Abdul Ata Ur Rahman Mohammed AURM De Silva Bhagya B Gary Ronald K RK

Biology open 20180126 1

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 thi ...[more]

PMID: 29212798

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Project description:BACKGROUND:Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer's disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. METHODS:To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. RESULTS:We demonstrate for the first time that tau hyperphosphorylation via GSK3? activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3? reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3?-dependent manner. CONCLUSIONS:Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities.

Dataset Information

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

Publications

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

Similar Datasets

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