Caspase 在MST3 誘發之細胞凋亡過程中所扮演之角色

Abstract

Mst3隸屬於人類STE20相似蛋白激酵素（human Ste-20 like protein kinase）家族，是一個在細胞凋亡中扮演重要角色的52 kDa蛋白質，它擁有N端的激酵素功能區域以及C端的調控功能區域，之前研究並指出Mst3一般是存在細胞質中而且會被caspases活化。很有趣的是，當Mst3在被切割後會從細胞質轉移至核，前期之研究指出Mst3內含一段細胞內移序列 (nuclear localization signal)，其存在於Mst3可以被caspase切割的位置之前，依據序列比對發現可能有數段細胞核外移序列(nuclear exporting signal)，大量表現刪除特定片段的Mst3證明了Mst3 (335-416)包含兩段細胞核外移序列，其區域在胺基酸336-346與385-395之間。之前的研究指出大量表現Mst3野生株以及截斷株，可以誘發細胞之凋亡，令人感興趣的是，我們發現Mst3引起細胞凋亡可能不是經由caspase所導致。Mst3所導致的細胞凋亡不會被廣效性casapase抑制劑 (zVAN-fmk) 所抑制，而且Mst3和caspase-3共同表現也不會促進細胞凋亡之現象。Mst3引起細胞凋亡的分子機轉仍有待研究。

Mst 3 (Mammalian Ste20-like protein kinase 3), a 52 kDa protein, plays an important role in the process of cell apoptosis. It is a member of human Ste20 like protein kinase family containing a kinase domain at its N-terminus and a regulatory domain at C-terminus. Previous studies have shown that Mst3 is existed in the cytoplasm and can be activated by caspases. Interestingly, the truncation of Mst3 induced a nucleus translocation of itself. Preliminary studies have found that Mst3 contained a NLS (nuclear localization signal) domain located prior to the caspases cleavage site. Upon sequence alignment several NES (nuclear exporting signal) domain were postulated. Overexpression of various deletion mutants of Mst3 demonstrated that Mst3 (335-416) may contain two NES domains at regions between amino acid 336-346 and 385-395. Previous studies have shown that overexpression of Mst3WT and MstWTΔ314 could induce cell apoptosis. Interestingly, we found that Mst3 might mediate cell apoptosis through a caspase-independent manner. Mst3-induced cell aoptosis could not be inhibited by a broad-caspase inhibitor, zVAN-fmk nor facilitated by the coexpression of procaspase-3. The molecular mechanism of Mst3-mediated cell apoptosis remains to be studied.