标题：Regulation of Neuronal Cell Death by c-Abl-Hippo/MST2 Signaling Pathway
作者：Liu, Weizhe; Wu, Junbing; Xiao, Lei; Bai, Yujie; Qu, Aiqin; Zheng, Zheng; Yuan, Zengqiang
作者机构：[Wu, Junbing; Xiao, Lei; Bai, Yujie; Yuan, Zengqiang] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100080, Peoples R Chin 更多
通讯作者地址：[Liu, WZ]Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100080, Peoples R China.
摘要：Background: Mammalian Ste20-like kinases (MSTs) are the mammalian homologue of Drosophila hippo and play critical roles in regulation of cell death, organ size control, proliferation and tumorigenesis. MSTs exert pro-apoptotic function through cleavage, autophosphorylation and in turn phosphorylation of downstream targets, such as Histone H2B and FOXO ( Forkhead box O). Previously we reported that protein kinase c-Abl mediates oxidative stress-induced neuronal cell death through phosphorylating MST1 at Y433, which is not conserved among mammalian MST2, Drosophila Hippo and C. elegans cst-1/2.; Methodology/Principal Findings: Using immunoblotting, in vitro kinase and cell death assay, we demonstrate that c-Abl kinase phosphorylates MST2 at an evolutionarily conserved site, Y81, within the kinase domain. We further show that the phosphorylation of MST2 by c-Abl leads to the disruption of the interaction with Raf-1 proteins and the enhancement of homodimerization of MST2 proteins. It thereby enhances the MST2 activation and induces neuronal cell death.; Conclusions/Significance: The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST2 suggests that the conserved c-Abl-MST signaling cascade plays an important role in oxidative stress-induced neuronal cell death.