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- Title
Glycogen Synthase Kinase-3β Phosphorylates Bax and Promotes Its Mitochondrial Localization during Neuronal Apoptosis.
- Authors
Linseman, Daniel A.; Butts, Brent D.; Precht, Thomas A.; Phelps, Reid A.; Le, Shoshona S.; Laessig, Tracey A.; Bouchard, Ron J.; Florez-McClure, Maria L.; Heidenreich, Kim A.
- Abstract
Glycogen synthase kinase-3β (GSK-3β) is a critical activator of neuronal apoptosis induced by a diverse array of neurotoxic insults. However, the downstream substrates of GSK-3 β that ultimately induce neuronal death are unknown. Here, we show that GSK-3β phosphorylates and regulates the activity of Bax, a pro-apoptotic Bcl-2 family member that stimulates the intrinsic (mitochondrial) death pathway by eliciting cytochrome c release from mitochondria. In cerebellar granule neurons undergoing apoptosis, inhibition of GSK-3β suppressed both the mitochondrial translocation of an expressed green fluorescent protein (GFP)-Baxα fusion protein and the conformational activation of endogenous Bax. GSK-3β directly phosphorylated Baxα, on Ser163, a residue found within a species-conserved, putative GSK-3β phosphorylation motif. Coexpression of GFP-Baxα with a constitutively active mutant of GSK-3α, GSK-3α(Ser9Ala), enhanced the in vivo phosphorylation of wild-type Baxα, but not a Ser163Ala mutant of Baxα, in transfected human embryonic kidney 293 (HEK293) cells. Moreover, cotransfection with constitutively active GSK-3β promoted the localization of Baxα to mitochondria and induced apoptosis in both transfected HEK293 cells and cerebellar granule neurons. In contrast, neither a Ser163Ala point mutant of Baxα nor a naturally occurring splice variant that lacks 13 amino acids encompassing Ser163 (Baxσ) were driven to mitochondria in HEK293 cells coexpressing constitutively active GSK-3β. In a similar manner, either mutation or deletion of the identified GSK-3β phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis. Our results indicate that GSK-3β exerts some of its pro-apoptotic effects in neurons by regulating the mitochondrial localization of Bax, a key component of the intrinsic...
- Subjects
GLYCOGEN; NEURONS; APOPTOSIS; NEUROTOXICOLOGY; CYTOCHROME c
- Publication
Journal of Neuroscience, 2004, Vol 24, Issue 44, p9993
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2057-04.2004