Neurochemical Research

, Volume 35, Issue 4, pp 588–597 | Cite as

Apoptosis-Associated Tyrosine Kinase and Neuronal Cell Death

  • Jane P. Hughes
  • Daniel R. Ward
  • Laura Facci
  • Jill C. Richardson
  • Stephen D. Skaper
Original Paper


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.


Cerebellar granule neurons Apoptosis Calcium signaling Protein kinase B Glycogen synthase kinase-3 Cortical neurons Amyloid β-peptide 


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jane P. Hughes
    • 1
    • 3
  • Daniel R. Ward
    • 1
  • Laura Facci
    • 1
    • 2
  • Jill C. Richardson
    • 1
  • Stephen D. Skaper
    • 1
    • 2
  1. 1.Neurosciences Centre of Excellence for Drug DiscoveryGlaxoSmithKline Research and Development LimitedHarlowUK
  2. 2.Faculty of Medicine, Department of Pharmacology and AnesthesiologyUniversity of PadovaPadovaItaly
  3. 3.MedImmuneCambridgeUK

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