14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells.

ABSTRACT: Akt activation has been associated with proliferation, differentiation, survival and death of epithelial cells. Phosphorylation of Thr308 of Akt by phosphoinositide-dependent kinase 1 (PDK1) is critical for optimal stimulation of its kinase activity. However, the mechanism(s) regulating this process remain elusive. Here, we report that 14-3-3 proteins control Akt Thr308 phosphorylation during intestinal inflammation. Mechanistically, we found that IFN? and TNF? treatment induce degradation of the PDK1 inhibitor, 14-3-3?, in intestinal epithelial cells. This mechanism requires association of 14-3-3? with raptor in a process that triggers autophagy and leads to 14-3-3? degradation. Notably, inhibition of 14-3-3 function by the chemical inhibitor BV02 induces uncontrolled Akt activation, nuclear Akt accumulation and ultimately intestinal epithelial cell death. Our results suggest that 14-3-3 proteins control Akt activation and regulate its biological functions, thereby providing a new mechanistic link between cell survival and apoptosis of intestinal epithelial cells during inflammation.

SUBMITTER: Gomez-Suarez M 

PROVIDER: S-EPMC4987727 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature