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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal

Daniel A Linseman1, Brent D Butts, Thomas A Precht

  • 1Department of Pharmacology, University of Colorado Health Sciences Center, and Denver Veterans Affairs Medical Center, Denver, Colorado 80262, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|November 5, 2004
PubMed

Insights

Glycogen synthase kinase-3beta (GSK-3beta) activates neuronal apoptosis by phosphorylating Bax, a key protein in the mitochondrial death pathway. This phosphorylation regulates Bax

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Glycogen synthase kinase-3beta (GSK-3beta) is a key regulator of neuronal apoptosis, triggered by various neurotoxic insults.
  • The specific downstream targets of GSK-3beta responsible for inducing neuronal death remained unidentified.
  • Bax, a pro-apoptotic protein of the Bcl-2 family, plays a crucial role in initiating the intrinsic mitochondrial death pathway.

Purpose of the Study:

  • To identify the downstream substrates of GSK-3beta involved in neurotoxicity-induced neuronal apoptosis.
  • To elucidate the regulatory mechanism by which GSK-3beta influences the activity and localization of Bax.
  • To investigate the role of GSK-3beta-mediated Bax phosphorylation in the intrinsic apoptotic cascade.

Main Methods:

  • Utilized cerebellar granule neurons and human embryonic kidney 293 (HEK293) cells for experimental models.
  • Employed green fluorescent protein (GFP)-Bax fusion proteins and point mutants to study Bax translocation and phosphorylation.
  • Investigated the effects of GSK-3beta inhibition and constitutively active GSK-3beta mutants on Bax activity and localization.

Main Results:

  • Demonstrated that GSK-3beta directly phosphorylates Bax at Serine 163 (Ser163), within a conserved motif.
  • GSK-3beta inhibition suppressed Bax mitochondrial translocation and conformational activation in apoptotic neurons.
  • Constitutively active GSK-3beta promoted Bax mitochondrial localization and induced apoptosis, which was prevented by mutating or deleting the Ser163 phosphorylation site.

Conclusions:

  • GSK-3beta regulates neuronal apoptosis by directly phosphorylating Bax at Ser163.
  • This phosphorylation event is critical for Bax's mitochondrial translocation, a key step in initiating apoptosis.
  • GSK-3beta's regulation of Bax represents a significant mechanism within the intrinsic apoptotic pathway in neurons.

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