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First published online 31 July 2007
doi: 10.1242/jcs.03473

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GSK-3 acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis

¹ Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 701, Taiwan
² Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan 701, Taiwan
³ Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 701, Taiwan
⁴ Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan 701, Taiwan
⁵ Department of Microbiology and Immunology, Chung-Shan Medical University, Taichung 402, Taiwan
⁶ Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University Medical College, Tainan 701, Taiwan

^* Author for correspondence (e-mail: yslin1{at}mail.ncku.edu.tw)

Accepted 21 May 2007

The signaling of glycogen synthase kinase-3 (GSK-3) has been implicated in stress-induced apoptosis. However, the pro-apoptotic role of GSK-3 is still unclear. Here, we show the involvement of GSK-3 in ceramide-induced mitochondrial apoptosis. Ceramide induced GSK-3 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-3 inhibitors lithium chloride and SB216763, and by GSK-3 knockdown using short interfering RNA. We also found that ceramide-activated protein phosphatase 2A (PP2A) indirectly caused GSK-3 activation, and that the PP2A-regulated PI 3-kinase-Akt pathway was involved in GSK-3 activation. These results indicate a role for GSK-3 in ceramide-induced apoptosis, in which GSK-3 acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 and caspase-8.

Key words: Ceramide, GSK-3, Apoptosis

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