Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Jun 14;23(6):990-1003.
doi: 10.1016/j.cmet.2016.05.009.

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

Brian K Kennedy  1 , Dudley W Lamming  2
Affiliations
Review

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

Brian K Kennedy et al. Cell Metab. .

Abstract

Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.

PubMed Disclaimer

Figures

Figure 1
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 which regulate the localization of mTORC1 to the lysosome – e.g., the Rag GTPases and the Ragulator and GATOR complexes – are not depicted.
Figure 2
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 how or if 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.
Figure 3
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 becomes active.
Figure 4
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Albert V, Svensson K, Shimobayashi M, Colombi M, Munoz S, Jimenez V, Handschin C, Bosch F, Hall MN. mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue. EMBO Mol Med. 2016;8:232–246. - PMC - PubMed
    1. Arriola Apelo SI, Lamming DW. Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island. J Gerontol A Biol Sci Med Sci in press. - PMC - PubMed
    1. Arriola Apelo SI, Neuman JC, Baar EL, Syed FA, Cummings NE, Brar HK, Pumper CP, Kimple ME, Lamming DW. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell. 2016a;15:28–38. - PMC - PubMed
    1. Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J Gerontol A Biol Sci Med Sci 2016b - PMC - PubMed
    1. Aylett CH, Sauer E, Imseng S, Boehringer D, Hall MN, Ban N, Maier T. Architecture of human mTOR complex 1. Science. 2016;351:48–52. - PubMed

Substances