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      Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120.

      The Journal of Biological Chemistry

      Transfection, metabolism, Threonine, drug effects, Signal Transduction, Proto-Oncogene Proteins c-akt, genetics, Protein-Serine-Threonine Kinases, Protein Binding, Phosphorylation, Phosphatidylinositol 3-Kinases, Mutation, Microscopy, Fluorescence, pharmacology, Insulin-Like Growth Factor I, Immunoblotting, Humans, HeLa Cells, Green Fluorescent Proteins, Cercopithecus aethiops, Cell Nucleus, Cell Line, COS Cells, Apoptosis, Animals, Active Transport, Cell Nucleus

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          Abstract

          The protein kinase mammalian sterile 20-like kinase 1 (MST1) is a mammalian homologue of the Drosophila hippo and plays a critical role in regulation of programmed cell death. MST1 exerts pro-apoptotic function through cleavage, autophosphorylation-Thr(183) and subsequent translocation to the nucleus where it phosphorylates a number of molecules, including LATS1/2, FOXO, JNK, and histone H2B. Here, we show that the cleavage of MST1 is inhibited by the phosphatidylinositol 3-kinase/Akt pathway. Akt interacts with MST1 and phosphorylates a highly conserved residue threonine 120 of MST1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of Thr(183). Phospho-MST1-Thr(120) failed to activate downstream targets FOXO3a and JNK. Further, inverse correlation between pMST1-Thr(120) and pMST1-Thr(183) was observed in human ovarian tumors. These findings indicate that the phosphorylation of MST1-Thr(120) by Akt could be a major mechanism of regulation of the Hippo/MST1 pathway by cell survival signaling.

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          Author and article information

          Journal
          10.1074/jbc.M109.059675
          2823523
          19940129

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