Yang Guang-Xi, Peng De-Liang, Chen Lin, Qian Yu, He Le, Chen Xiao-Yan, Hong Wen-Bin, Wu Cai-Ming, Chen Hang-Zi
The First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, PR China.
Cell Death Dis. 2025 Aug 7;16(1):595. doi: 10.1038/s41419-025-07906-4.
Protein kinase AKT plays a broad role in promoting energy production in nutrient-rich environments. However, its roles under metabolic stress remain elusive. Herein, we demonstrate a dual mechanism for AKT activation during glucose deprivation. On one hand, glucose deprivation leads to increased levels of ADP and NADP, which directly bind to spleen tyrosine kinase (SYK) and induce a conformational alteration of SYK, resulting in self-activation. The activated SYK further triggers PI3K-dependent activation of AKT. On the other hand, elevated ROS upon glucose deprivation promotes oxidative dimerization of PDK1, thereby facilitating the recognition and activation of AKT. In melanoma cells, AKT plays a critical role in elevating ROS levels and inducing cell death during glucose deprivation. Overall, this study not only establishes a novel connection between energy insufficiency and AKT activation via a dual mechanism but also provides insights into the role of AKT in sensitizing cells to metabolic stress.
蛋白激酶AKT在促进营养丰富环境中的能量产生方面发挥着广泛作用。然而，其在代谢应激下的作用仍不明确。在此，我们证明了葡萄糖剥夺期间AKT激活的双重机制。一方面，葡萄糖剥夺导致ADP和NADP水平升高，它们直接与脾酪氨酸激酶（SYK）结合并诱导SYK的构象改变，从而导致自我激活。活化的SYK进一步触发PI3K依赖的AKT激活。另一方面，葡萄糖剥夺时升高的ROS促进PDK1的氧化二聚化，从而促进AKT的识别和激活。在黑色素瘤细胞中，AKT在葡萄糖剥夺期间升高ROS水平和诱导细胞死亡方面起关键作用。总体而言，本研究不仅通过双重机制建立了能量不足与AKT激活之间的新联系，还为AKT在使细胞对代谢应激敏感化中的作用提供了见解。
