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

http://www.ncbi.nlm.nih.gov/pubmed/19940129

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 RIS Download

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

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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

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