title: Regulation of neuronal cell death by c-Abl-Hippo/MST2 signaling pathway.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Liaoning, China.
authors.forename: Weizhe
authors.initials: W
authors.lastname: Liu
authors.forename: Junbing
authors.initials: J
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Yujie
authors.initials: Y
authors.lastname: Bai
authors.forename: Aiqin
authors.initials: A
authors.lastname: Qu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zheng
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D016923:Cell Death / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009474:Neurons / Q000201:enzymology*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000502:physiology*; D000099317:Hippo Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D016315:Proto-Oncogene Proteins c-abl; D000090742:Serine-Threonine Kinase 3; C097835:STK3 protein, human; D000099317:Hippo Kinases