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

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.

Pubmed ID: 19940129


  • Yuan Z
  • Kim D
  • Shu S
  • Wu J
  • Guo J
  • Xiao L
  • Kaneko S
  • Coppola D
  • Cheng JQ


The Journal of biological chemistry

Publication Data

February 5, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA107078
  • Agency: NCI NIH HHS, Id: CA137041
  • Agency: NCI NIH HHS, Id: P50 CA119997
  • Agency: NCI NIH HHS, Id: R01 CA137041
  • Agency: NCI NIH HHS, Id: R01 CA137041-02
  • Agency: NCI NIH HHS, Id: R01 CA137041-03

Mesh Terms

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