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

Angela Alexander, Sheng Li Cai, Jinhee Kim, Adrian Nanez, Mustafa Sahin, Kirsteen H. MacLean, Ken Inoki, Kun Liang Guan, Jianjun Shen, Maria D. Person, Donna Kusewitt, Gordon B. Mills, Michael B. Kastan, Cheryl Lyn Walker

    Research output: Contribution to journalArticle

    435 Scopus citations

    Abstract

    Ataxia-telangiectasiamutated (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, identifyingan integrationnodefor thecellulardamage response with key pathways involved in metabolism, protein synthesis, and cell survival.

    Original languageEnglish (US)
    Pages (from-to)4153-4158
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number9
    DOIs
    StatePublished - Mar 2 2010

    Keywords

    • Autophagy
    • Cytoplasm
    • Damage
    • Oxidative stress
    • Signal transduction

    ASJC Scopus subject areas

    • General

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  • Cite this

    Alexander, A., Cai, S. L., Kim, J., Nanez, A., Sahin, M., MacLean, K. H., Inoki, K., Guan, K. L., Shen, J., Person, M. D., Kusewitt, D., Mills, G. B., Kastan, M. B., & Walker, C. L. (2010). ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proceedings of the National Academy of Sciences of the United States of America, 107(9), 4153-4158. https://doi.org/10.1073/pnas.0913860107