I

DISC formation

Figure 8.3 Hyperosmolarity-induced CD95 activation in hepatocytes. Our current view is summarized with respect to hyperosmolarity-induced activation of the CD95 system. Hyperosmotic exposure leads to acidification of an endosomal compartment, which activates ASM.The subsequent ceramide formation then activates PKCZ.The latter leads to an activating serine phosphorylation ofthe NADPH oxidase regulatory subunit p47phox, which is followed by the generation of reactive oxygen species (ROS). ROS formation triggers activation of the Src family kinase Yes, which then associates with and activates the epidermal growth factor receptor (EGFR). EGFR then dissociates from Yes and associates with CD95 in a c-Jun-N-terminal kinase (JNK)-dependent way, which leads to EGFR-tyrosine kinase-mediated CD95 tyrosine phosphorylation, which is a prerequisite for CD95 oligomerization and microtubule-dependent translocation of CD95 to the plasma membrane, which allows for subsequent FADD and cas-pase 8 recruitment to the CD95, that is, DISC formation.

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