哺乳動(dòng)物Ste20樣激酶(MSTs)是果蠅hippo的同源物,，在調(diào)節(jié)細(xì)胞死亡,，控制器官大小，細(xì)胞增殖及腫瘤發(fā)生過程中有著至關(guān)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(diǎn)（如組蛋白H2B及FOXO）,，促進(jìn)了凋亡的發(fā)生。
近日,，中國科學(xué)院生物物理研究所的袁增強(qiáng)課題組發(fā)現(xiàn),，c-Abl-Hippo/MST2信號(hào)通路調(diào)節(jié)了神經(jīng)元細(xì)胞的死亡。相關(guān)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(dǎo)了氧化應(yīng)激誘導(dǎo)的神經(jīng)元細(xì)胞的死亡,。
使用免疫印記及細(xì)胞死亡相關(guān)實(shí)驗(yàn)，他們發(fā)現(xiàn)c-Abl激酶磷酸化了MST2上的一個(gè)保守的位點(diǎn),，即位于激酶結(jié)構(gòu)域內(nèi)的Y81,。
進(jìn)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(jìn)了MST2蛋白的二聚化，因此增強(qiáng)了MST2的激活作用,，并誘導(dǎo)神經(jīng)元細(xì)胞的死亡,。
c-Abl絡(luò)氨酸激酶作為MST2的一個(gè)新的上游激活因子，這表明保守的c-Abl-MST信號(hào)級(jí)聯(lián)反應(yīng)在氧化應(yīng)激誘導(dǎo)的神經(jīng)元細(xì)胞死亡中起著至關(guān)重要的作用,。
Hippo/MST1是一個(gè)從低等到高等動(dòng)物保守的蛋白激酶,，其介導(dǎo)的細(xì)胞凋亡通路已成為該領(lǐng)域的研究熱點(diǎn)。袁增強(qiáng)研究員一直致力于Hippo/MST1介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)通路研究,。其研究成果極大地拓展了與神經(jīng)細(xì)胞凋亡密切相關(guān)的FOXO轉(zhuǎn)錄因子和MST1蛋白激酶在細(xì)胞凋亡方面的分子調(diào)控機(jī)制,。更重要的是,，為研究許多與細(xì)胞凋亡相關(guān)疾病的病理機(jī)制打下了基礎(chǔ)，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.
