GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis.
The signaling of glycogen synthase kinase-3beta (GSK-3beta) has been implicated in stress-induced apoptosis. However, the pro-apoptotic role of GSK-3beta is still unclear. Here, we show the involvement of GSK-3beta in ceramide-induced mitochondrial apoptosis. Ceramide induced GSK-3beta activation via protein dephosphorylation at serine 9. We previously reported that ceramide induced caspase-2 and caspase-8 activation, Bid cleavage, mitochondrial damage, and apoptosis. In this study, we found that caspase-2 activation and the subsequent apoptotic events were abolished by the GSK-3beta inhibitors lithium chloride and SB216763, and by GSK-3beta knockdown using short interfering RNA. We also found that ceramide-activated protein phosphatase 2A (PP2A) indirectly caused GSK-3beta activation, and that the PP2A-regulated PI 3-kinase-Akt pathway was involved in GSK-3beta activation. These results indicate a role for GSK-3beta in ceramide-induced apoptosis, in which GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 and caspase-8.
Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 701, Taiwan.
Chiou-Feng
CF
Lin
Chia-Ling
CL
Chen
Chi-Wu
CW
Chiang
Ming-Shiou
MS
Jan
Wei-Ching
WC
Huang
Yee-Shin
YS
Lin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D051023:BH3 Interacting Domain Death Agonist Protein; D002518:Ceramides; D004791:Enzyme Inhibitors; C086766:Ppp2r1b protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D053143:Caspase 2; D053181:Caspase 8