Beryllium is an inhibitor of cellular GSK-3β that is 1,000-fold more potent than lithium

Glycogen synthase kinase 3 beta (GSK-3 beta) is a key regulator in signaling networks that control cell proliferation, metabolism, development, and other processes. Lithium chloride is a GSK-3 family inhibitor that has been a mainstay of in vitro and in vivo studies for many years. Beryllium salt has the potential to act as a lithium-like inhibitor of GSK-3, but it is not known whether this agent is effective under physiologically relevant conditions. Here we show that BeSO4 inhibits endogenous GSK-3 beta in cultured human cells. Exposure to 10 A mu M Be2+ produced a decrease in GSK-3 beta kinase activity that was comparable to that produced by 10 mM Li+, indicating that beryllium is about 1,000-fold more potent than the classical inhibitor when treating intact cells. There was a statistically significant dose-dependent reduction in specific activity of GSK-3 beta immunoprecipitated from cells that had been treated with either agent. Lithium inhibited GSK-3 beta kinase activity directly, and it also caused GSK-3 beta in cells to become phosphorylated at serine-9 (Ser-9), a post-translational modification that occurs as part of a well-known positive feedback loop that suppresses the kinase activity. Beryllium also inhibited the kinase directly, but unlike lithium it had little effect on Ser-9 phosphorylation in the cell types tested, suggesting that alternative modes of feedback inhibition may be elicited by this agent. These results indicate that beryllium, like lithium, can induce perturbations in the GSK-3 beta signaling network of treated cells.