Caspase Activation of Mammalian Sterile 20-like Kinase 3 (Mst3)

作者：Chi‐Ying F. Huang, Yi-Mi Wu, Chiung‐Yueh Hsu, Wan-Shu Lee, Ming-Derg Lai, Te‐Jung Lu, Chia-Lin Huang, Tzeng‐Horng Leu, Hsiu-Ming Shih, Hsin-I Fang, Dan R. Robinson, Hsing‐Jien Kung, Chiun-Jye Yuan · 发表于：Journal of Biological Chemistry · 年份：2002 · DOI：10.1074/jbc.m202468200 · 被引用次数：87 · 研究领域：Hippo pathway signaling and YAP/TAZ、Plant Genetic and Mutation Studies、Cell death mechanisms and regulation

Mammalian Sterile 20-like kinase 3 (Mst3), the physiological functions of which are unknown, is a member of the germinal center kinase-III family. It contains a conserved kinase domain at its NH(2) terminus, whereas there is a regulatory domain at its COOH terminus. In this study we demonstrate that endogenous Mst3 is specifically cleaved when Jurkat cells were treated with anti-Fas antibody or staurosporine and that this cleavage is inhibited by the caspase inhibitor, Ac-DEVD-CHO. Using apoptotic Jurkat cell extracts and recombinant caspases, we mapped the caspase cleavage site, AETD(313), which is at the junction of the NH(2)-terminal kinase domain and the COOH-terminal regulatory domain. Caspase-mediated cleavage of Mst3 activates its intrinsic kinase activity, suggesting that the COOH-terminal domain of Mst3 negatively regulates the kinase domain. Furthermore, proteolytic removal of the Mst3 COOH-terminal domain by caspases promotes nuclear translocation. Ectopic expression of either wild-type or COOH-terminal truncated Mst3 in cells results in DNA fragmentation and morphological changes characteristic of apoptosis. By contrast, no such changes were exhibited for catalytically inactive Mst3, implicating the involvement of Mst3 kinase activity for mediation of these effects. Collectively, these results support the notion that caspase-mediated proteolytic activation of Mst3 contributes to apoptosis.