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Apoptosis-Associated Tyrosine Kinase and Neuronal Cell Death

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Abstract

Apoptosis-associated tyrosine kinase (AATYK) is up-regulated by phosphorylation in cultured cerebellar granule neurons (CGN) undergoing apoptosis upon switch to low KCl-containing medium. However, the underlying signaling pathways remain to be fully characterized. When CGN at culture day 7 were switched from 25 mM KCl (K25) to 5 mM (K5) medium, AATYK band migration on SDS–PAGE shifted to a more slowly migrating position expected for the hyperphosphorylated protein. The apoptosis-inducing agent C2-ceramide also caused a mobility shift of the AATYK protein. Exposing CGN (K25) to L-type voltage-dependent Ca2+ channel antagonists shifted the AATYK band to the K5-induced position, while the Ca2+ channel activator FPL-64176 had the contrary effect. FK-506, a calcineurin inhibitor caused AATYK hyperphosphorylation under high KCl conditions. CGN death in K5 medium is linked to inhibition of the PI 3-kinase/Akt survival pathway and concomitant activation of the pro-apoptotic downstream target glycogen synthase kinase-3 (GSK-3). GSK-3 inhibitors blocked the K5-induced mobility shift of AATYK. Moreover, CGN cultured from AATYK-deficient mice remained sensitive to death in K5 medium. Thus, AATYK activation may not be a physiologically relevant principal regulatory target of the GSK-3 death pathway in KCl-deprived CGN.

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Author notes

  1. Jane P. Hughes

    Present address: MedImmune, Granta Park, Cambridge, CB1 6GH, UK

Authors and Affiliations

  1. Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, UK

    Jane P. Hughes, Daniel R. Ward, Laura Facci, Jill C. Richardson & Stephen D. Skaper

  2. Faculty of Medicine, Department of Pharmacology and Anesthesiology, University of Padova, Largo “E. Meneghetti” 2, 35131, Padova, Italy

    Laura Facci & Stephen D. Skaper

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  1. Jane P. Hughes
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  2. Daniel R. Ward
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Correspondence to Stephen D. Skaper.

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Daniel R. Ward and Laura Facci contributed equally to this article.

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Hughes, J.P., Ward, D.R., Facci, L. et al. Apoptosis-Associated Tyrosine Kinase and Neuronal Cell Death. Neurochem Res 35, 588–597 (2010). https://doi.org/10.1007/s11064-009-0103-9

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