Recent research has identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as a conserved direct effector of Ras proteins. While previous studies suggested the involvement of the Switch I (SWI) effector domain of Ras in binding mTORC2 components, the regulation of the Ras-mTORC2 pathway is not entirely understood. In , mTORC2 is selectively activated by the Ras protein RasC, and the RasC-mTORC2 pathway then mediates chemotaxis to cAMP and cellular aggregation by regulating the actin cytoskeleton and promoting cAMP signal relay. Here, we investigated the role of specific residues in RasC's SWI, C-terminal allosteric domain, and hypervariable region (HVR) related to mTORC2 activation. Interestingly, our results suggest that RasC SWI residue A31, which was previously implicated in RasC-mediated aggregation, regulates RasC’s specific activation by the Aimless RasGEF. On the other hand, our investigation identified a crucial role for RasC SWI residue T36, with secondary contributions from E38 and allosteric domain residues. Finally, we found that conserved basic residues and the adjacent prenylation site in the HVR, which are crucial for RasC’s membrane localization, are essential for RasC-mTORC2 pathway activation by allowing for both RasC’s own cAMP-induced activation and its subsequent activation of mTORC2. Therefore, our findings revealed new determinants of RasC-mTORC2 pathway specificity in , contributing to a deeper understanding of Ras signaling regulation in eukaryotic cells.

中文翻译：

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Ras-mTORC2 信号传导的分子决定因素


最近的研究已确定雷帕霉素复合物 2 (mTORC2) 的机制靶标是 Ras 蛋白的保守直接效应子。虽然之前的研究表明 Ras 的 Switch I (SWI) 效应结构域参与结合 mTORC2 成分，但 Ras-mTORC2 通路的调节尚不完全清楚。在图中，mTORC2 被 Ras 蛋白 RasC 选择性激活，然后 RasC-mTORC2 通路通过调节肌动蛋白细胞骨架和促进 cAMP 信号中继介导对 cAMP 的趋化性和细胞聚集。在这里，我们研究了 RasC 的 SWI、C 端变构域和高变区 (HVR) 中与 mTORC2 激活相关的特定残基的作用。有趣的是，我们的结果表明，RasC SWI 残基 A31（之前与 RasC 介导的聚集有关）通过 Aimless RasGEF 调节 RasC 的特异性激活。另一方面，我们的研究确定了 RasC SWI 残基 T36 的关键作用，其次是 E38 和变构域残基的贡献。最后，我们发现 HVR 中保守的碱性残基和邻近的异戊二烯化位点对于 RasC 的膜定位至关重要，通过允许 RasC 自身的 cAMP 诱导激活及其随后的 mTORC2 激活，对于 RasC-mTORC2 途径激活至关重要。因此，我们的研究结果揭示了 RasC-mTORC2 通路特异性的新决定因素，有助于更深入地了解真核细胞中 Ras 信号传导的调控。