Mammalian Target of Rapamycin (mTOR) Overview

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Mammalian target of rapamycin, or mTOR, is a serine-threonine protein kinase that functions downstream of a wide range of receptors to mediate cell survival, growth, and metabolism. mTOR is a component of two protein complexes that facilitate its function: mTORC1 and mTORC2. These complexes consist of binding partners raptor (mTORC1) and rictor (mTORC2) and the shared components mLST8 and dector1. mTOR and the mTORC1 and mTORC2 complexes are found in all eukaryotes and are highly conserved2.

Despite sharing many components, including the kinase mTOR, mTORC1 and mTORC2 are activated via different pathways and this activation initiates different intracellular processes, with the mTORC1 pathway being more well-defined. A cascade in the lysosome downstream of growth factor signaling phosphorylates and activates the serine-threonine protein kinase Akt, which by phosphorylation releases a protein complex called the tuberous sclerosis complex (TSC) from inhibition. The function of TSC activates Rheb, the GTP-ase that is directly responsible for activating mTORC13. Akt also phosphorylates a direct inhibitor of mTORC1, PRAS40, leading to its degradation. Therefore, Akt is crucial in multiple ways for the activation of mTORC14 and this process may be partially regulated by the activity of mTORC25,6. Downstream targets of mTORC1 phosphorylation, such as Sin1, may also counter-regulate mTORC2 activity7.

Activation of mTORC2 is less well-defined, and several models have been proposed. One study described a role for the PI3K family member phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in directly activating mTORC2; mTORC2 can then activate Akt8. It has also been proposed that Akt can directly activate mTORC2, leading to a positive feedback loop9. TSC may also be involved in mTORC2 activation, through direct physical interaction with mTORC2 leading to its activation10. Or, while mTORC1 is activated at the lysosome, mTORC2 may be activated via interactions with the ribosome11.

mTORC1 and mTORC2 are further defined by their capacity to be inhibited by rapamycin, an antifungal and immunosuppressive drug with both clinical and experimental uses12. Rapamycin binds to a non-catalytic domain of mTOR; however this only inhibits the activity of mTORC1 while mTORC2 is insensitive to rapamycin13. The mechanism directing this difference is unclear, but provides a useful tool for experimentally elucidating differences in mTORC1 and mTORC2 effects.

As the mTORC complexes are required for key cellular processes, dysregulation of mTORC is implicated in a variety of diseases. In cancer, defects in the crosstalk between mTORC1 and mTORC2 can lead to hyperactivation of mTORC2 in cells, driving tumorigenesis7, and high levels of rictor (mTORC2) predicts early recurrence in hepatocellular carcinoma14. Rapamycin and analogs are FDA-approved to treat a variety of cancers including renal cell carcinoma, breast cancer, and pancreatic cancer15. Hyperactivation of mTORC1 is implicated in several diseases that lead to benign tumor growth throughout the body, including the disease tuberous sclerosis, named because it is caused by mutations that lead to loss of function of TSC, and neurofibromatosis16,17. Studies in mice further suggest a role for mTOR dysregulation in aging, neurodegenerative diseases, and metabolic diseases including type 2 diabetes18.

Below is the entire list of targets involved in mTOR research. Can’t find what you are looking for? Bethyl offers a custom antibody service.

 

References

1. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594 . doi: 10.1242/jcs.051011

2. Hall MN (2008) mTOR—What Does It Do? Transplant Proc 40:S5–S8 . doi: 10.1016/j.transproceed.2008.10.009

3. Avruch J, Long X, Lin Y, Ortiz-Vega S, Rapley J, Papageorgiou A, Oshiro N, Kikkawa U (2009) Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor 1. Biochem Soc Trans 37:223–226 . doi: 10.1042/BST0370223

4. Dibble CC, Cantley LC (2015) Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 25:545–555 . doi: 10.1016/j.tcb.2015.06.002

5. Dan HC, Antonia RJ, Baldwin AS (2016) PI3K/Akt promotes feedforward mTORC2 activation through IKKα. Oncotarget 7:21064–75 . doi: 10.18632/oncotarget.8383

6. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217–22 . doi: 10.1042/BST0370217

7. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W (2013) Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 15:1340–1350 . doi: 10.1038/ncb2860

8. Gan X, Wang J, Su B, Wu D (2011) Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 286:10998–1002 . doi: 10.1074/jbc.M110.195016

9. Humphrey SJ, Yang G, Yang P, Fazakerley DJ, Stöckli J, Yang JY, James DE (2013) Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab 17:1009–20 . doi: 10.1016/j.cmet.2013.04.010

10. Huang J, Dibble CC, Matsuzaki M, Manning BD (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28:4104–15 . doi: 10.1128/MCB.00289-08

11. Zinzalla V, Stracka D, Oppliger W, Hall MN (2011) Activation of mTORC2 by association with the ribosome. Cell 144:757–68 . doi: 10.1016/j.cell.2011.02.014

12. Ballou LM, Lin RZ (2008) Rapamycin and mTOR kinase inhibitors. J Chem Biol 1:27–36 . doi: 10.1007/s12154-008-0003-5

13. Dos D. Sarbassov DD, Ali SM, Kim D-H, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton. Curr Biol 14:1296–1302 . doi: 10.1016/j.cub.2004.06.054

14. Kaibori M, Shikata N, Sakaguchi T, Ishizaki M, Matsui K, Iida H, Tanaka Y, Miki H, Nakatake R, Okumura T, Tokuhara K, Inoue K, Wada J, Oda M, Nishizawa M, Kon M (2015) Influence of Rictor and Raptor Expression of mTOR Signaling on Long-Term Outcomes of Patients with Hepatocellular Carcinoma. Dig Dis Sci 60:919–928 . doi: 10.1007/s10620-014-3417-7

15. Kim LC, Cook RS, Chen J (2017) mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene 36:2191–2201 . doi: 10.1038/onc.2016.363

16. Franz DN, Capal JK (2017) mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders. Orphanet J Rare Dis 12:51 . doi: 10.1186/s13023-017-0596-2

17. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, Gusella JF, Ramesh V (2009) NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1, and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth. Mol Cell Biol 29:4250–4261 . doi: 10.1128/MCB.01581-08

18. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–93 . doi: 10.1016/j.cell.2012.03.017