Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation

Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, White M, Reichelt J,

Levine B (2012). Science 338: 956-959

Speaker: Shu-Ching Lin (林紓晴)                                 Time: 14:00~15:00, Mar. 27, 2013

Commentator: Dr. Bei-Chang Yang (楊倍昌老師)      Place: Room 601

Abstract:

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is a key signaling pathway linked to both tumorigenesis and resistance to therapy in many solid tumors¹. Autophagy regulates cellular homeostasis by degrading unfolding protein and defective organelles. It suppresses tumorigenesis by limiting inflammation and removing damaged mitochondria, which produce reactive oxygen species. It is known that autophagy could be inhibited by Akt activated mTOR. In this study, the authors revealed that Akt suppressed autophagy through mTOR-independent mechanisms. They found that Beclin 1, an essential autophagy and tumor suppressor protein, was phosphorylated by Akt on residue 295 and 234. Furthermore, the phosphorylated Beclin1 was associated with three tumor cell lines, melanoma, glioblastoma and breast cancer, in whichAkt was activated. It indicates that the Becilin 1 phosphorylation is related to Akt activated human cancer. However, Akt inhibited autophagy through both Beclin1 phosphorylation dependent and independent pathways. They also found that Akt suppressed Beclin 1–associated Vps34 activity andautophagy. This suppression can be reversed by a Beclin 1 mutant (Beclin 1 AA), which is resistant to Akt-mediated phosphorylation. Beclin 1 AA also suppresses myr-Akt-driven tumorigenesis in vivo. The authors further clarified how Akt-phosphorylated Beclin 1 inhibits autophagy. They found Akt-mediated Beclin 1 phosphorylation generated a 14-3-3 binding motif. This 14-3-3 protein binding site enhanced its binding with Beclin 1 and with the cytoskeletal protein vimentin, the major intermediate filament protein expressed in fibroblasts. When vimentin expression was silenced by shRNA, autophagy activity was increased. This finding reveals that Akt regulating the interaction of Beclin 1 and vimentin is the mechanism for inhibition of autophagy. In conclusion, Akt-phosphorylated Beclin 1 interacted with vimentin through 14-3-3 protein to inhibit autophagy andtumorigenesis. This study demonstrates a novel mechanism by which autophagy may be suppressed in human cancer.

References:

1. Bitting RL, Armstrong AJ (2013) Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer [Epub ahead of print].

2. Koren I, Kimchi A (2012) Promoting tumorigenesis by suppressing autophagy. Science 338: 889.