The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging  Brian K. Kennedy, Dudley W. Lamming  Cell Metabolism  Volume 23, Issue 6, Pages 990-1003 (June 2016) DOI: 10.1016/j.cmet.2016.05.009 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 mTORC1, a Central Regulator of Metabolism Regulation of metabolic processes downstream of mTORC1, with major known substrates and metabolic processes highlighted. Protein kinases, including mTORC1, are boxed in red. The core proteins of mTORC1—mTOR, Raptor, and mLST8—are depicted as interacting directly with the mTOR kinase, whereas proteins with nutrient-sensitive or transient interactions with the mTORC1 core—DEPTOR, PRAS40, and Tel2/Tti1—are depicted in a separate, adjacent box. Proteins that regulate the localization of mTORC1 to the lysosome, e.g., the Rag GTPases and the Ragulator and GATOR complexes, are not depicted. Cell Metabolism 2016 23, 990-1003DOI: (10.1016/j.cmet.2016.05.009) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 mTORC2, a Major Effector of the Insulin/IGF-1 Signaling Pathway Regulation of metabolic processes downstream of mTORC2, with major known substrates and metabolic processes highlighted. Protein kinases, including mTORC2, are boxed in red. The core proteins of mTORC2—mTOR, Rictor, mLST8, mSin1, and Protor—are depicted as interacting directly with the mTOR kinase, whereas proteins with nutrient-sensitive or transient interactions with the mTORC2 core—DEPTOR, IKK, Sestrin3, Tel2/Tti1, and Xpln—are depicted in a separate, adjacent box. The TSC complex—in particular, TSC2—interacts with and regulates mTORC2 (Huang et al., 2008), but it is not clear if or how this interaction is regulated. Dashed box: insulin stimulates mTORC1 through the AKT-mediated phosphorylation of specific sites on TSC2 and PRAS40 (Menon et al., 2014; Sancak et al., 2007), but the requirement for mTORC2 in the insulin-mediated activation of mTORC1 remains unclear. Extracellular signals in addition to insulin, IGF-1, and leptin that regulate PI3K or PIP3 may also regulate mTORC2 activity, but these are not depicted here. Cell Metabolism 2016 23, 990-1003DOI: (10.1016/j.cmet.2016.05.009) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Regulation of mTORC1 Activity by Amino Acids and Insulin (A) In the absence of amino acids and insulin, mTORC1 is found in the cytoplasm, while TSC localizes to the lysosome. (B) Amino acids result in the inhibition of GATOR1 by GATOR2, the activation of the Rag GTPases, the localization of mTORC1 to the lysosome, and the recruitment of Rheb to the lysosome by MCRS1. TSC continues to inhibit Rheb, and thus mTORC1 remains inactive. (C) Insulin induces TSC to leave the lysosome, permitting Rheb to bind to GTP; insulin also stimulates the disassociation of PRAS40 from mTORC1. mTORC1 can then interact with GTP-bound Rheb and become active. Cell Metabolism 2016 23, 990-1003DOI: (10.1016/j.cmet.2016.05.009) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 4 The Action of Rapamycin against mTORC1 or mTORC2 Is Dependent upon FK506-Binding Proteins Rapamycin binding to either FKBP12 or FKBP51 forms a complex that can then act to inhibit mTORC1. However, inhibition of mTORC2 activity by rapamycin is dependent upon a rapamycin-FKBP12 complex that can prevent the formation of mTORC2 by binding to free mTOR, preventing the incorporation of mTOR into mTORC2. The relative expression level of FKBP12 and FKBP51 determines the rapamycin sensitivity of mTORC2 in each cell line or tissue. Cell Metabolism 2016 23, 990-1003DOI: (10.1016/j.cmet.2016.05.009) Copyright © 2016 Elsevier Inc. Terms and Conditions