哺乳動物Ste20樣激酶(MSTs)是果蠅hippo的同源物,，在調(diào)節(jié)細胞死亡,，控制器官大小，細胞增殖及腫瘤發(fā)生過程中有著至關重要的作用,。
研究發(fā)現(xiàn),，MSTs通過剪切，自身磷酸化,，并磷酸化下游靶點（如組蛋白H2B及FOXO）,，促進了凋亡的發(fā)生。
近日,，中國科學院生物物理研究所的袁增強課題組發(fā)現(xiàn),，c-Abl-Hippo/MST2信號通路調(diào)節(jié)了神經(jīng)元細胞的死亡。相關論文發(fā)表在5月9日的PLoS ONE,。
之前他們就已經(jīng)發(fā)現(xiàn),，通過磷酸化位于Y433的MST1，蛋白激酶c-Abl介導了氧化應激誘導的神經(jīng)元細胞的死亡。
使用免疫印記及細胞死亡相關實驗,，他們發(fā)現(xiàn)c-Abl激酶磷酸化了MST2上的一個保守的位點,，即位于激酶結構域內(nèi)的Y81。
進一步研究表明,，c-Abl通過磷酸化MST2,，干擾了與Raf-1蛋白的相互作用，促進了MST2蛋白的二聚化,，因此增強了MST2的激活作用,，并誘導神經(jīng)元細胞的死亡。
c-Abl絡氨酸激酶作為MST2的一個新的上游激活因子,，這表明保守的c-Abl-MST信號級聯(lián)反應在氧化應激誘導的神經(jīng)元細胞死亡中起著至關重要的作用,。
Hippo/MST1是一個從低等到高等動物保守的蛋白激酶，其介導的細胞凋亡通路已成為該領域的研究熱點,。袁增強研究員一直致力于Hippo/MST1介導的信號轉(zhuǎn)導通路研究,。其研究成果極大地拓展了與神經(jīng)細胞凋亡密切相關的FOXO轉(zhuǎn)錄因子和MST1蛋白激酶在細胞凋亡方面的分子調(diào)控機制。更重要的是,，為研究許多與細胞凋亡相關疾病的病理機制打下了基礎,，并為治療這些疾病提供了潛在的靶位。（生物谷Bioon.com）
doi: 10.1371/journal.pone.0036562
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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.
