Teran Pumar Oriana Y, Zanotelli Matthew R, Lin Miao-Chong Joy, Schmitt Rebecca R, Green Kai Su, Rojas Katherine S, Hwang Irene Y, Cerione Richard A, Wilson Kristin F
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
These authors contributed equally.
bioRxiv. 2024 Oct 1:2023.01.03.522657. doi: 10.1101/2023.01.03.522657.
The ability of cancer cells to survive microenvironmental stresses is critical for tumor progression and metastasis; however, how they survive these challenges is not fully understood. Here, we describe a novel multiprotein complex (DockTOR) essential for the survival of cancer cells under stress, triggered by the GTPase Cdc42 and a signaling partner Dock7, which includes AKT, mTOR, and the mTOR regulators TSC1, TSC2, and Rheb. DockTOR enables cancer cells to maintain a low but critical mTORC2-dependent phosphorylation of AKT during serum deprivation by preventing AKT dephosphorylation through an interaction between phospho-AKT and the Dock7 DHR1 domain. This activity stimulates a Raptor-independent but Rapamycin-sensitive mTOR/S6K activity necessary for survival. These findings address long-standing questions of how Cdc42 signals result in mTOR activation and demonstrate how cancer cells survive conditions when growth factor-dependent activation of mTORC1 is off. Determining how cancer cells survive stress conditions could identify vulnerabilities that lead to new therapeutic strategies.
癌细胞在微环境应激下存活的能力对于肿瘤进展和转移至关重要；然而，它们如何在这些挑战中存活尚未完全明确。在此，我们描述了一种新型多蛋白复合物（DockTOR），它对于应激条件下癌细胞的存活至关重要，由GTP酶Cdc42和信号伴侣Dock7触发，其中包括AKT、mTOR以及mTOR调节因子TSC1、TSC2和Rheb。DockTOR通过磷酸化的AKT与Dock7 DHR1结构域之间的相互作用防止AKT去磷酸化，从而使癌细胞在血清剥夺期间维持低水平但关键的mTORC2依赖性AKT磷酸化。这种活性刺激了一种不依赖Raptor但对雷帕霉素敏感的mTOR/S6K活性，这对于存活是必需的。这些发现解决了长期存在的关于Cdc42信号如何导致mTOR激活的问题，并证明了在mTORC1的生长因子依赖性激活关闭时癌细胞如何在这些条件下存活。确定癌细胞如何在应激条件下存活可能会识别出导致新治疗策略的脆弱点。
