Regulation of Neuronal Cell Death by c-Abl-Hippo/MST2 Signaling Pathway

Weizhe Liu,Junbing Wu,Aiqin Qu,Zheng Zheng,Zengqiang Yuan,Lei Xiao,Yujie Bai

doi:10.1371/journal.pone.0036562

Weizhe Liu, Junbing Wu + Show 5 more

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https://doi.org/10.1371/journal.pone.0036562

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BackgroundMammalian 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 FindingsUsing 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/SignificanceThe 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.

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MST2 shares the highest degree of homology with the Drosophila Hippo and plays an important role in apoptotic cell death [1]
It is noted that the phosphorylation site is not conserved in MST1’s ortholog, such as MST2 and Hippo (Figure 1A), we found that recombinant GST-fused MST2 as well as MST1 protein was directly phosphorylated by c-Abl by using an in vitro kinase assay followed by immunoblotting with an anti-pan-tyrosine antibody (Figure 1B)
Sequence analysis revealed that Y81 of human MST2, which is absent in MST1, is conserved among mouse, rat, Drosophila (Hippo), and C. elegans

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Introduction

MST2 shares the highest degree of homology with the Drosophila Hippo and plays an important role in apoptotic cell death [1]. 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. There is no conserved tyrosine in the cterminal motif of MST2 and it is interesting to explore the possibility and molecular mechanism that c-Abl could regulate MST2 in the oxidative stress-mediated neuronal cell death.

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