Caspase activation of mammalian Sterile 20-like kinase 3 (Mst3) - Nuclear translocation and induction of apoptosis

被引:166
作者
Huang, CYF
Wu, YM
Hsu, CY
Lee, WS
Lai, MD
Lu, TJ
Huang, CL
Leu, TH
Shih, HM
Fang, HI
Robinson, DR
Kung, HJ
Yuan, CJ
机构
[1] Natl Chiao Tung Univ, Dept Biol Sci & Technol, Hsinchu 300, Taiwan
[2] Natl Hlth Res Inst, Div Mol & Genom Med, Taipei 115, Taiwan
[3] Natl Cheng Kung Univ, Coll Med, Dept Biochem, Tainan 70101, Taiwan
[4] Natl Cheng Kung Univ, Coll Med, Dept Pharmacol, Tainan 70101, Taiwan
[5] China Jr Coll Med Technol, Dept Med Technol, Tainan 717, Taiwan
[6] Univ Calif Davis, Dept Biol Chem, Sacramento, CA 95817 USA
[7] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA
关键词
D O I
10.1074/jbc.M202468200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 NH2 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 NH2-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.
引用
收藏
页码:34367 / 34374
页数:8
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