Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-Kinase/Akt pathway
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-Kinase/Akt pathway
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DOI：
10.1016/s1097-2765(02)00568-3
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发表时间：
2002-07-01
期刊：
影响因子：
16
通讯作者：
Cantley, LC
中科院分区：
文献类型：
--
作者：
Manning, BD;Tee, AR;Cantley, LC
由磷酸肌醇 3 激酶 (PI3K) 激活的 S/T 蛋白激酶调节多种细胞过程。在这里，我们展示了一种结合生物化学和生物信息学的方法可以识别这些激酶的底物。该方法将结节性硬化症复合体 2 基因产物马铃薯蛋白确定为 Akt/PKB 的潜在靶标。我们证明，在 PI3K 激活后，马铃薯蛋白在 PI3K 依赖性 S/T 激酶的共有识别位点上被磷酸化。此外，Akt/PKB 可以在体外和体内磷酸化马铃薯蛋白。我们还表明，马铃薯球蛋白的 S939 和 T1462 是 PI3K 调节的磷酸化位点，并且 T1462 在 PTEN-/(-) 肿瘤来源的细胞系中被组成型磷酸化。最后，我们发现缺乏主要 PI3K 依赖性磷酸化位点的马铃薯蛋白突变体可以阻断 S6K1 的激活，这表明 PI3K-Akt 途径调节 S6K1 活性的一种方式。
The S/T-protein kinases activated by phosphoinositide 3-kinase (PI3K) regulate a myriad of cellular processes. Here, we show that an approach using a combination of biochemistry and bioinformatics can identify substrates of these kinases. This approach identifies the tuberous sclerosis complex-2 gene product, tuberin, as a potential target of Akt/PKB. We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN-/(-) tumor-derived cell lines. Finally, we find that a tuberin mutant lacking the major PI3K-dependent phosphorylation sites can block the activation of S6K1, suggesting a means by which the PI3K-Akt pathway regulates S6K1 activity.