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

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Abstract

Glycogen synthase kinase 3β (GSK-3β) 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-3β in cultured human cells. Exposure to 10 µM Be2+ produced a decrease in GSK-3β 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-3β immunoprecipitated from cells that had been treated with either agent. Lithium inhibited GSK-3β kinase activity directly, and it also caused GSK-3β 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-3β signaling network of treated cells.

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Acknowledgments

We thank Derek Jensen for helpful discussions. This project was supported by grants from the National Institute of General Medical Sciences (P20GM103440), the American Cancer Society (IRG-103719), and a UNLV Faculty Opportunity Award.

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Authors and Affiliations

  1. Department of Chemistry, University of Nevada, Las Vegas, 4505 Maryland Parkway, Las Vegas, NV, 89154-4003, USA

    Swapna R. Mudireddy, Ataur Rahman Mohammed Abdul, Priyatham Gorjala & Ronald K. Gary

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  1. Swapna R. Mudireddy
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  2. Ataur Rahman Mohammed Abdul
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  3. Priyatham Gorjala
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  4. Ronald K. Gary
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Correspondence to Ronald K. Gary.

Additional information

Swapna R. Mudireddy and Ataur Rahman Mohammed Abdul have contributed equally.

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Mudireddy, S.R., Abdul, A.R.M., Gorjala, P. et al. Beryllium is an inhibitor of cellular GSK-3β that is 1,000-fold more potent than lithium. Biometals 27, 1203–1216 (2014). https://doi.org/10.1007/s10534-014-9783-y

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  • DOI: https://doi.org/10.1007/s10534-014-9783-y

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