A Multiprotein Signaling Complex Sustains AKT and MTOR/S6K Activity Necessary for the Survival of Cancer Cells Undergoing Stress

Overview

Journal bioRxiv

Date 2023 Jan 30

PMID 36711811

Authors

Oriana Y Teran Pumar

Matthew R Zanotelli

Miao-Chong Joy Lin

Rebecca R Schmitt

Kai Su Green

Katherine S Rojas

Irene Y Hwang

Richard A Cerione

Kristin F Wilson

Affiliations

Soon will be listed here.

Abstract

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.

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