Hyperosmotic hepatocyte shrinkage sensitizes the cells toward CD95 ligand-induced apoptosis by activating the CD95 system. Figure 8.3 summarizes our current view on the signaling events involved in hyperosmotic activation of the CD95 system in hepatocytes. The hyperosmotically induced cascade of signaling events starts with endosomal acidification triggering an ASM-derived increase in the intracellular ceramide concentration, which leads via PKCZ and p47phox to NADPH oxidase activation and subsequent ROS formation as an important upstream event. ROS generation allows via Yes, JNK, and EGFR activation for CD95 tyrosine phosphorylation as a prerequisite for CD95 oligomerization and targeting to the plasma membrane, DISC formation, and apoptosis induction or sensitization. Other covalent modifications, such as CD95 tyrosine nitration or CD95 serine/threonine phosphorylation, can counteract the CD95 activation process. The findings not only provide a mechanistic explanation for the high susceptibility of dehydrated cells for apoptosis, but also give insight into the early signaling events involved in apoptotic cell death in general.
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