active-site inhibitors of mtor target rapamycin-resistant outputs of mtorc1 and mtorc2的活性位点抑制剂mtor mtorc1和mtorc2 rapamycin-resistant输出目标.pdfVIP

PLoS BIOLOGY Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2 1 1 2 2 1¤ 3 Morris E. Feldman , Beth Apsel , Aino Uotila , Robbie Loewith , Zachary A. Knight , Davide Ruggero , 1* Kevan M. Shokat 1 Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, United States of America, 2 Department of Molecular Biology, University of Geneva, Switzerland, 3 School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)!Akt!mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and