Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation.
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Jang SW, Yang SJ, Srinivasan S, Ye K
Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation.
J Biol Chem. 2007 Oct 19;282(42):30836-44. Epub 2007 Aug 28.
- PubMed ID
- 17726016 [ View in PubMed]
- Abstract
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.