MST1-JNK promotes apoptosis via caspase-dependent and independent pathways

Background: MST1 is an upstream kinase of the JNK and p38 MAPK pathways who se expression induces apoptotic morphological changes such as nuclear conde nsation. During apoptosis, caspase cleavage of MST1 removes a C-terminal re gulatory domain, increasing the kinase activity of the MST1 N-terminal doma in. Downstream pathways of MST1 in the induction of apoptosis remain to be clarified. Results: In this study, we found that the expression of MST1 resulted in ca spase-3 activation. Therefore, MST1 is not only a target of caspases but al so an activator of caspases. This caspase activation and apoptotic changes occur through JNK, since the coexpression of a dominant-negative mutant of JNK inhibited MST1-induced morphological changes as well as caspase activat ion. In contrast, neither dominant-negative p38 nor the p38 inhibitor SB203 580 inhibited them. MST1 induced nucleosomal DNA fragmentation, which was s uppressed by caspase inhibitors or ICAD (Inhibitor of Caspase-Activated DNa se), Surprisingly, however, other changes such as membrane blebbing and chr omatin condensation were not inhibited by caspase inhibitors. Conclusion: These results suggest that MST1 most Likely promotes two events through JNK activation; first, MST1 induces the activation of caspases, re sulting in CAD-mediated DNA fragmentation, and second, MST1 induces chromat in condensation and membrane blebbing without utilizing downstream caspases .