Glycogen Synthase Kinase-3 and Omi/HtrA2 Induce Annexin A2 Cleavage followed by Cell Cycle Inhibition and Apoptosis

被引:34
作者
Wang, Chi-Yun [1 ,2 ]
Lin, Yee-Shin [1 ,3 ]
Su, Wu-Chou [1 ,2 ]
Chen, Chia-Ling [3 ]
Lin, Chiou-Feng [1 ,2 ,3 ]
机构
[1] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 701, Taiwan
[2] Natl Cheng Kung Univ, Coll Med, Inst Clin Med, Tainan 701, Taiwan
[3] Natl Cheng Kung Univ, Coll Med, Dept Microbiol & Immunol, Tainan 701, Taiwan
关键词
PROTEIN PHOSPHATASE 2A; TYROSINE PHOSPHORYLATION; MITOCHONDRIAL APOPTOSIS; MEMBRANE DYNAMICS; II EXPRESSION; LIPID RAFTS; BAX; CANCER; MCL-1; CYTOSKELETON;
D O I
10.1091/mbc.E09-02-0174
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Annexin A2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of annexin A2 makes cells more sensitive to apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced annexin A2 cleavage, which contributes to cell cycle inhibition and apoptosis. Annexin A2 was persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma cell A549-derived tumors. Knockdown expression of annexin A2 made cells susceptible to either serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Under apoptotic stimuli, annexin A2 was time-dependently cleaved. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated glycogen synthase kinase (GSK)-3 is essential for this process. Therefore, inhibiting GSK-3 reversed serum withdrawal-induced cell cycle inhibition and cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocked apoptotic stimuli-induced annexin A2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, caused annexin A2 cleavage via an Omi/HtrA2-dependent pathway. Taking these results together, we conclude that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis.
引用
收藏
页码:4153 / 4161
页数:9
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