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.
Yuan
Zengqiang
Z
From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and. Electronic address: zqyuan@ibp.ac.cn.
Kim
Donghwa
D
the Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
Shu
Shaokun
S
the Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
Wu
Junbing
J
From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and.
Guo
Jianping
J
the Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
Xiao
Lei
L
From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and.
Kaneko
Satoshi
S
the Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
Coppola
Domenico
D
the Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
Cheng
Jin Q
JQ
From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and. Electronic address: jin.cheng@moffitt.org.
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008856:Microscopy, Fluorescence; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013912:Threonine / Q000378:metabolism*; D014162:Transfection; D000099317:Hippo Kinases
D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013912:Threonine; C095566:STK4 protein, human; D000099317:Hippo Kinases