RT Journal Article SR Electronic T1 A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress JF bioRxiv FD Cold Spring Harbor Laboratory SP 2023.01.03.522657 DO 10.1101/2023.01.03.522657 A1 Teran Pumar, Oriana Y. A1 Zanotelli, Matthew R. A1 Lin, Miao-chong Joy A1 Schmitt, Rebecca R. A1 Green, Kai Su A1 Rojas, Katherine S. A1 Hwang, Irene Y. A1 Cerione, Richard A. A1 Wilson, Kristin F. YR 2024 UL http://biorxiv.org/content/early/2024/10/01/2023.01.03.522657.abstract AB 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.Competing Interest StatementThe authors have declared no competing interest.