哺乳动物Ste20样激酶(MSTs)是果蝇hippo的同源物,在调节细胞死亡,控制器官大小,细胞增殖及肿瘤发生过程中有着至关重要的作用。
研究发现,MSTs通过剪切,自身磷酸化,并磷酸化下游靶点(如组蛋白H2B及FOXO),促进了凋亡的发生。
近日,中国科学院生物物理研究所的袁增强课题组发现,c-Abl-Hippo/MST2信号通路调节了神经元细胞的死亡。相关论文发表在5月9日的PLoS ONE。
之前他们就已经发现,通过磷酸化位于Y433的MST1,蛋白激酶c-Abl介导了氧化应激诱导的神经元细胞的死亡。
使用免疫印记及细胞死亡相关实验,他们发现c-Abl激酶磷酸化了MST2上的一个保守的位点,即位于激酶结构域内的Y81。
进一步研究表明,c-Abl通过磷酸化MST2,干扰了与Raf-1蛋白的相互作用,促进了MST2蛋白的二聚化,因此增强了MST2的激活作用,并诱导神经元细胞的死亡。
c-Abl络氨酸激酶作为MST2的一个新的上游激活因子,这表明保守的c-Abl-MST信号级联反应在氧化应激诱导的神经元细胞死亡中起着至关重要的作用。
Hippo/MST1是一个从低等到高等动物保守的蛋白激酶,其介导的细胞凋亡通路已成为该领域的研究热点。袁增强研究员一直致力于Hippo/MST1介导的信号转导通路研究。其研究成果极大地拓展了与神经细胞凋亡密切相关的FOXO转录因子和MST1蛋白激酶在细胞凋亡方面的分子调控机制。更重要的是,为研究许多与细胞凋亡相关疾病的病理机制打下了基础,并为治疗这些疾病提供了潜在的靶位。(生物谷Bioon.com)
doi: 10.1371/journal.pone.0036562
PMC:
PMID:
Regulation of Neuronal Cell Death by c-Abl-Hippo/MST2 Signaling Pathway
Weizhe Liu, Junbing Wu, Lei Xiao, Yujie Bai, Aiqin Qu, Zheng Zheng, Zengqiang Yuan.
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.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.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.