Recruitment of active glycogen synthase kinase-3 into neuronal lipid rafts.
Glycogen synthase kinase (GSK)-3beta has emerged as a key molecule that regulates neuronal apoptosis. To examine the molecular mechanism(s) through which GSK-3beta regulates this process, we studied the subcellular localization of GSK-3beta following exposure of the cells to well-characterized apoptotic stimuli. Here, we report that the induction of apoptosis by withdrawal of serum and potassium triggers dephosphorylation of GSK-3beta at serine 9 and subsequent translocation of these molecules into neuronal lipid raft microdomains. Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau. Consistent with the notion that the lipid raft domains may serve as a platform for the cellular signaling complexes, disruption of lipid rafts protected neurons from apoptosis induced by withdrawal of serum and potassium as well as by HIV-1 Tat. Our observations reveal novel interaction of GSK-3beta and raft domains, and suggest that such interaction could contribute to neuronal apoptosis.
Sui
Ziye
Z
Interdepartmental Program in Neuroscience, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Kovács
Attila D
AD
Maggirwar
Sanjay B
SB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015696:Gene Products, tat / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016895:Culture Media, Serum-Free; D015696:Gene Products, tat; D007211:Indoles; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D012694:Serine; D007334:Insulin-Like Growth Factor I; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D011188:Potassium; C027185:indirubin