Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation.
Oxidative stress can induce apoptosis through activation of MstI, subsequent phosphorylation of FOXO and nuclear translocation. MstI is a common component of apoptosis initiated by various stresses. MstI kinase activation requires autophosphorylation and proteolytic degradation by caspases. The role of Akt in regulating MstI activity has not been previously examined. Here, we show that MstI is a physiological substrate of Akt. Akt phosphorylation of MstI diminishes its apoptotic cleavage by caspases and prevents its kinase activity on FOXO3. MstI directly binds to Akt, which is regulated Akt kinase activity. Akt phosphorylates MstI on the Thr(387) residue and protects MstI from apoptotic cleavage in vitro and in apoptotic cells. Interestingly, Akt phosphorylation of MstI strongly inhibits its kinase activity on FOXO3. The phosphorylation mimetic mutant MST1 T387E blocks H2O2-triggered FOXO3 nuclear translocation and apoptosis. Thus, our findings support that Akt blocks MstI-triggered FOXO3 nuclear translocation by phosphorylating MstI, promoting cell survival.
Jang
Sung-Wuk
SW
Department of Pathology, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Yang
Seung-Ju
SJ
Srinivasan
Shanthi
S
Ye
Keqiang
K
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D020169:Caspases; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D016877:Oxidants; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C499517:FOXO3 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases