ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 9; pp. 4153 - 4158
• Main Authors: Alexander, Angela, Cai, Sheng-Li, Kim, Jinhee, Nanez, Adrian, Sahin, Mustafa, MacLean, Kirsteen H, Inoki, Ken, Guan, Kun-Liang, Shen, Jianjun, Person, Maria D, Kusewitt, Donna, Mills, Gordon B, Kastan, Michael B, Walker, Cheryl Lyn
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02-03-2010; National Acad Sciences
• Subjects: Adenylate Kinase - metabolism; Animals; Ataxia Telangiectasia Mutated Proteins; Biological Sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell lines; Cells; Cytoplasm; Cytoplasm - metabolism; DNA damage; DNA repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression regulation; HEK293 cells; Humans; Mechanistic Target of Rapamycin Complex 1; Metabolism; Mice; Mice, Transgenic; Multiprotein Complexes; Oxidative Stress; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein synthesis; Proteins; Radiation damage; Reactive oxygen species; Reactive Oxygen Species - metabolism; Repression; Rodents; Signal Transduction; Survival analysis; TOR Serine-Threonine Kinases; Transcription Factors - metabolism; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0913860107

Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.