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Apoptosis-associated tyrosine kinase and neuronal cell death

Jane P Hughes1, Daniel R Ward, Laura Facci

  • 1Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Harlow, UK.

Neurochemical Research
|November 27, 2009
PubMed

Insights

Apoptosis-associated tyrosine kinase (AATYK) phosphorylation is linked to cell death pathways in neurons. However, AATYK activation is not the primary target of the glycogen synthase kinase-3 (GSK-3) death pathway in potassium-deprived cerebellar granule neurons.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Apoptosis-associated tyrosine kinase (AATYK) phosphorylation increases during apoptosis in cultured cerebellar granule neurons (CGN) when switched to low potassium conditions.
  • The specific signaling pathways regulating AATYK phosphorylation and its role in neuronal apoptosis are not fully understood.

Purpose of the Study:

  • To investigate the signaling pathways involved in AATYK phosphorylation during apoptosis in CGN.
  • To determine the role of AATYK in the death pathway induced by low potassium.

Main Methods:

  • CGN were cultured and subjected to low potassium (K5) or high potassium (K25) medium.
  • Apoptosis was induced using C(2)-ceramide.
  • L-type voltage-dependent Ca(2+) channel modulators and calcineurin inhibitor FK-506 were used.
  • PI 3-kinase/Akt and GSK-3 pathways were analyzed.
  • AATYK phosphorylation was assessed by SDS-PAGE mobility shifts.
  • Experiments were conducted using CGN from AATYK-deficient mice.

Main Results:

  • Switching CGN to low KCl medium induced AATYK hyperphosphorylation, indicated by a slower migration on SDS-PAGE.
  • C(2)-ceramide also caused AATYK mobility shift.
  • L-type Ca(2+) channel antagonists mimicked the low KCl effect, while activators had the opposite effect.
  • FK-506 induced AATYK hyperphosphorylation under high KCl.
  • Low KCl-induced CGN death involved inhibition of PI 3-kinase/Akt and activation of GSK-3.
  • GSK-3 inhibitors blocked the low KCl-induced AATYK mobility shift.
  • CGN from AATYK-deficient mice remained sensitive to low KCl-induced death.

Conclusions:

  • AATYK phosphorylation is modulated by calcium channels and calcineurin.
  • While linked to GSK-3 activation, AATYK phosphorylation is not the principal regulatory target of the GSK-3 death pathway in KCl-deprived CGN.
  • AATYK is not essential for KCl-deprivation-induced CGN apoptosis.

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