PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex.
PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex.
复制标题
MTORC2激酶复合物的PTDINS（3,4,5）P3依赖性激活。
DOI：
10.1158/2159-8290.cd-15-0460
复制
发表时间：
2015-11
期刊：
影响因子：
28.2
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Liu P;Gan W;Chin YR;Ogura K;Guo J;Zhang J;Wang B;Blenis J;Cantley LC;Toker A;Su B;Wei W
mTOR通过形成两种不同的复合物mTORC 1和mTORC 2作为细胞生长和代谢的中心调节剂。虽然mTORC 1激活的生长因子和氨基酸的机制已被广泛研究，上游调控机制导致mTORC 2激活仍然在很大程度上难以捉摸。在这里，我们报告说，PH域Sin 1，mTORC 2的一个重要的和独特的组成部分，与mTOR激酶域相互作用，抑制mTOR活性。更重要的是，PtdIns（3，4，5）P3，而不是其他PtdInsPn种类，与Sin 1-PH相互作用以释放其对mTOR激酶结构域的抑制，从而触发mTORC 2激活。突变介导PtdIns（3，4，5）P3相互作用的关键Sin 1残基使mTORC 2失活，而mTORC 2活性通过Sin 1-PH结构域中患者来源的突变而病理性增加，从而促进细胞生长和肿瘤形成。总之，我们的研究揭示了mTORC 2激活的PI 3 K依赖性机制，允许mTORC 2以PtdIns（3，4，5）P3在时间和空间上调节的方式激活Akt。
mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the PH domain of Sin1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with Sin1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical Sin1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the Sin1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate Akt in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3.