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

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

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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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