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

Chiou Feng Lin, Chia-Ling Chen, Chi-Wu Chiang, Ming-Shiou Jan, Wei-Ching Huang, Yee-Shin Lin

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)2935-2943
Number of pages9
JournalJournal of Cell Science
Volume120
Issue number16
DOIs
Publication statusPublished - Aug 15 2007

Keywords

  • Apoptosis
  • Ceramide
  • GSK-3β

ASJC Scopus subject areas

  • Cell Biology

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