Akt Phosphorylates MstI and Prevents Its Proteolytic Activation, Blocking FOXO3 Phosphorylation and Nuclear Translocation

• Published in: The Journal of biological chemistry Vol. 282; no. 42; pp. 30836 - 30844
• Main Authors: Jang, Sung-Wuk, Yang, Seung-Ju, Srinivasan, Shanthi, Ye, Keqiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.10.2007; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Amino Acid Substitution; Apoptosis - drug effects; Apoptosis - physiology; Caspases - genetics; Caspases - metabolism; Cell Line; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Survival - drug effects; Cell Survival - physiology; Enzyme Activation - drug effects; Enzyme Activation - physiology; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Humans; Hydrogen Peroxide - pharmacology; Oxidants - pharmacology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M704542200

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 Thr387 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.