Apoptosis-Associated Tyrosine Kinase and Neuronal Cell Death

作者：Hughes Jane P; Ward Daniel R; Facci Laura; Richardson Jill C; Skaper Stephen D^*

来源：Neurochemical Research, 2010, 35(4): 588-597.

DOI：10.1007/s11064-009-0103-9

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

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 C(2)-ceramide also caused a mobility shift of the AATYK protein. Exposing CGN (K25) to L-type voltage-dependent Ca(2+) channel antagonists shifted the AATYK band to the K5-induced position, while the Ca(2+) 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 proapoptotic 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.

• 出版日期2010-4