Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation

TLDR: It is shown that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt, and Akt-mediated phosphorylation of BeClin 1 functions in Autophagy inhibition, oncogenesis, and the formation of an autophile-inhibitory BeclIn 1/14-3-3/vimentin intermediate filament complex.

Abstract: Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.