The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy

Sundaresan, N.R. et al. Sci. Signal. 4 (182), ra46- (2011)

Speaker: Chao-Ho Li (李兆和)                             Date: 15:00-16:00 Nov. 23, 2011

Commentator: Dr. Ling Pin (凌斌老師)               Place: Classroom 601

Abstract:

Akt is a well-known disease-related signaling molecule, such as diabetes, cancer and vascular disorder. Act can be post-translationally regulated by phosphorylation, ubiquitination, and binding to phospholipids. It takes three steps for Akt activation; the first is binding to phosphatidylinositol3,4,5-trisphosphate (PIP3), resulting in membrane localization and phosphorylation of Akt by the upstream kinase PDK1 (phosphoinositide-dependent protein kinase 1). However, its mechanism is not clear so far. In this study, the authors uncovered reversible acetylation as a potential regulatory mechanism that controls Akt activity. They identified SIRT1, a HDAC III, which can de-acetylate Akt in the PH domain and trigger the downstream phosphorylation of Akt. Furthermore, PDK1 can also be acetylated by SIRT1, and then binds to PIP3. When PDK1 and Akt are bothphosphorylated in the downstream of SIRT1, they would move from cytoplasm to membrane for advanced signaling activation. SIRT1 knockout mice exhibited continuous Akt acetylation with smaller tumors and less cardiac hypertrophy problem. Taken together, discovery of the Akt activation by SIRT1 for downstream PIP3 binding help us not only to understand more about tumorigenesis and cardiac hypertrophy, but also to develop drugs using Akt as a therapeutic target in the future.

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