AKT Promotes Tumorigenesis via Regulation of a Core Autophagy Protein

Autophagy is a catabolic process in which damaged cellular proteins and organelles are degraded via the lysosome and can be induced by nutrient starvation. Increasing evidence suggests that autophagy has a role in tumor suppression and can be inhibited by aberrant AKT activation in human cancer, in part through its downstream target mTOR. Because AKT also inhibited autophagy in the presence of an mTOR inhibitor, Wang and colleagues examined whether AKT negatively regulates this process by directly modulating components of the core autophagy machinery, in particular the tumor suppressor Beclin 1, which contains 2 potential AKT phosphorylation motifs. AKT interacted with endogenous Beclin 1 and promoted its phosphorylation at 2 serine residues within these motifs; this Beclin 1 modification was associated with increased AKT activation in multiple human tumor cell lines and resulted in reduced Beclin 1–associated class III phosphoinositide 3-kinase VPS34 activity. Mutation of these serines to alanine impaired AKT-mediated autophagy suppression and decreased AKT-driven fibroblast transformation, suggesting that the protumorigenic effects of AKT are partially mediated via Beclin 1 phosphorylation. Indeed, tumors expressing active AKT and the nonphosphorylatable Beclin 1 mutant exhibited reduced proliferation, increased apoptosis and autophagy, and a less invasive phenotype compared with tumors expressing wild-type Beclin 1. Mechanistically, AKT-mediated phosphorylation stimulated binding of Beclin 1 to 14-3-3 and intermediate filament proteins, including keratin 18 and vimentin, whereas this interaction was blocked by starvation or by expression of dominant negative AKT or mutant Beclin 1. Importantly, this interaction of Beclin 1 with vimentin was necessary for autophagy inhibition and AKT-dependent transformation. Taken together, these results define a mechanism by which oncogenic kinase signaling promotes tumorigenesis via regulation of autophagy effectors and cytoskeletal proteins.

Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 2012 Oct 25 [Epub ahead of print].

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