Department of Molecular & Cellular Biology, Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, 85721, USA.
Department of Molecular & Cellular Biology, Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, 85721, USA
J Cell Sci. 2020 Oct 8;133(19):jcs234930. doi: 10.1242/jcs.234930.
The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate - which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.
Ras 癌基因是众所周知的难以用特定的治疗方法来靶向。因此，人们有兴趣更好地了解 Ras 信号通路，以确定潜在的可靶向效应物。最近，雷帕霉素复合物 2 (mTORC2) 的机械靶点被确定为一种进化上保守的 Ras 效应物。mTORC2 调节包括代谢、存活、生长、增殖和迁移在内的基本细胞过程。此外，越来越多的证据表明 mTORC2 与肿瘤发生有关。关于 mTORC2 活性的调节知之甚少，但提出的机制包括磷脂酰肌醇 (3,4,5)-三磷酸 (PI3K) 的作用，PI3K 是一种特征明确的 Ras 效应物。因此，Ras、PI3K 和 mTORC2 在正常生理和癌症中的关系尚不清楚；此外，还报道了一些看似相互矛盾的观察结果。在这里，我们回顾了 Ras、PI3K 和 mTORC2 之间潜在联系的证据。有趣的是，数据表明 Ras 和 PI3K 都是 mTORC2 的直接调节因子，但它们作用于 mTORC2 的不同池：Ras 在质膜上激活 mTORC2，而 PI3K 在细胞内隔室中激活 mTORC2。因此，我们提出了一个模型来解释 Ras 和 PI3K 如何能够差异调节 mTORC2，并强调了 mTORC2 调节机制的多样性，这似乎取决于刺激、细胞类型以及分子和空间上不同的 mTORC2 池。
