Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Sci Signal. 2011 Jul 19;4(182):ra46. doi: 10.1126/scisignal.2001465.
Signaling through the kinase Akt regulates many biological functions. Akt is activated during growth factor stimulation through a process that requires binding of Akt to phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), which promotes membrane localization and phosphorylation of Akt by the upstream kinase PDK1 (phosphoinositide-dependent protein kinase 1). We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. Mice injected with cells expressing a mutant that mimicked a constitutively acetylated form of Akt developed smaller tumors than those injected with cells expressing wild-type Akt. Furthermore, impaired Akt activation in the hearts of SIRT1-deficient mice was associated with reduced cardiac hypertrophy in response to physical exercise and angiotensin II. These findings uncover a key posttranslational modification of Akt that is important for its oncogenic and hypertrophic activities.
通过激酶 Akt 进行的信号转导调节许多生物功能。Akt 在生长因子刺激过程中通过需要 Akt 与磷脂酰肌醇 3,4,5-三磷酸 (PIP(3)) 结合的过程被激活，该过程促进 Akt 通过上游激酶 PDK1（磷酸肌醇依赖性蛋白激酶 1）的膜定位和磷酸化。我们表明 Akt 和 PDK1 在其pleckstrin 同源结构域中的赖氨酸残基上被乙酰化，该结构域介导 PIP(3)结合。乙酰化阻止了 Akt 和 PDK1 与 PIP(3)的结合，从而阻止了 Akt 的膜定位和磷酸化。SIRT1 的去乙酰化增强了 Akt 和 PDK1 与 PIP(3)的结合，并促进了它们的激活。与表达野生型 Akt 的细胞相比，注射表达模拟 Akt 组成性乙酰化形式的突变体的细胞的小鼠形成的肿瘤较小。此外，SIRT1 缺陷型小鼠心脏中 Akt 激活受损与对体力活动和血管紧张素 II 的心脏肥大反应减少有关。这些发现揭示了 Akt 的一种关键翻译后修饰，对于其致癌和肥大活性很重要。
