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 RIS Download
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