SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity
SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity
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DOI：
10.1016/j.cell.2006.08.033
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发表时间：
2006-10-06
期刊：
影响因子：
64.5
通讯作者：
Su, Bing
中科院分区：
文献类型：
--
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
哺乳动物雷帕霉素靶蛋白 (mTOR) 通过 raptor-mTOR (TORC1) 和 rictor-mTOR (TORC2) 蛋白复合物控制细胞生长和增殖。最近的生化研究表明，TORC2 是疏水基序中 Akt/PKB Ser473 磷酸化的难以捉摸的 PDK2。尽管每个磷酸化位点的调节机制和生理重要性仍有待充分了解，但 Ser473 及其激活环的 Thr308 的磷酸化被认为是 Akt 功能所必需的。在这里，我们报告 SIN1/MIP1 是一个重要的 TORC2/PDK2 亚基。 sin 1 的基因消除消除了 Akt-Ser473 磷酸化并破坏了 rictor-mTOR 相互作用，但维持了 Thr308 磷酸化。令人惊讶的是，有缺陷的 Ser473 磷酸化仅影响体内 Akt 靶标的子集，包括 FoxO1/3a，而其他 Akt 靶标 TSC2 和 GSK3 以及 TORC1 效应子 S6K 和 4E-BP1 不受影响。我们的研究结果表明，Akt-Ser473 磷酸化中的 SIN1-rictor-mTOR 功能是细胞存活中 TORC2 功能所必需的，但对于 TORC1 功能来说是可有可无的。
Mammalian target of rapamycin (mTOR) controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. Phosphorylation at Ser473, along with Thr308 of its activation loop, is deemed necessary for Akt function, although the regulatory mechanisms and physiological importance of each phosphorylation site remain to be fully understood. Here, we report that SIN1/MIP1 is an essential TORC2/PDK2 subunit. Genetic ablation of sin 1 abolished Akt-Ser473 phosphorylation and disrupted rictor-mTOR interaction but maintained Thr308 phosphorylation. Surprisingly, defective Ser473 phosphorylation affected only a subset of Akt targets in vivo, including FoxO1/3a, while other Akt targets, TSC2 and GSK3, and the TORC1 effectors, S6K and 4E-BP1, were unaffected. Our findings reveal that the SIN1-rictor-mTOR function in Akt-Ser473 phosphorylation is required for TORC2 function in cell survival but is dispensable for TORC1 function.