Mammalian target of rapamycin, commonly known as mTOR, is a central kinase that integrates signals from cellular cues to regulate many processes, including protein translation, cell survival, proliferation, metabolism, autophagy, and the cytoskeleton.
mTOR forms two functionally distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Both mTORC1 and mTORC2 are composed of mTOR and GβL. In addition, mTORC1 contains raptor while mTORC2 contains Sin1 and rictor.
Functionally, the two complexes are very different. Activation of mTORC1 leads to the phosphorylation of downstream targets including p70 ribosomal protein S6 kinase (p70S6K), ribosomal protein S6 (S6), and eukaryotic initiation factor 4E-binding protein 1 (4EBP1) that promote increased protein translation and cell growth. mTORC2 activation regulates Akt/PKB, PKCa, and Rho to control cell survival, proliferation, metabolism, and the cytoskeleton.
Regulation The mTOR signaling pathway is illustrated in Fig. Upstream of mTOR are two tumor suppressor genes, TSC1 and TSC2, that regulate mTOR activity via Rheb (Ras homologue enriched in brain). TSC1 encodes hamartin, a 140 kDa protein that physically interacts with the protein product of TSC2, tuberin.
Tuberin is a 200 kDa protein with a domain near the carboxyl terminus containing GTPase activating protein (GAP) homology. GAP proteins convert members of the Ras superfamily from their active, GTP-bound state to their inactive, GDP-bound state. Rheb, like other Ras family members, cycles between an active GTP-bound and an inactive GDP-bound state. Tuberin converts Rheb-GTP to Rheb-GDP, thereby inactivating Rheb and inhibiting mTOR.
Conversely, loss of either tuberin or hamartin, or inactivation of tuberin by upstream regulators releases the brake on Rheb resulting in mTOR activation. At least three kinases are known to directly phosphorylate and inactivate tuberin: p90 ribosomal S6 kinase 1 (RSK1), Erk2 via the Ras signaling pathway, and Akt/PKB via the phosphatidylinositol 3 kinase (PIK) signaling pathway. In addition, mTORC2 phosphorylates Akt/PKB on serine 473, thereby activating Akt/PKB and inhibiting tuberin via a feedback mechanism. In contrast, LKB1/AMPK-mediated phosphorylation activates tuberin and inhibits Rheb-dependent mTOR activation.
The mTOR pathway is regulated by many intracellular and extracellular signals and integrates both positive and negative stimuli. mTOR is activated by insulin, growth factors, nutrients, and mitogens and inhibited by numerous stress conditions, such as cellular energy depletion and hypoxia. Pharmacologically, rapamycin specifically inhibits mTORC1 thereby preventing phosphorylation of downstream effectors S6K and 4E-BP1 resulting in an inhibition of cell proliferation.
Unconstrained mTOR signaling has been noted in several human diseases. Inactivation of negative regulators of the AKT-mTOR pathway, such as PTEN (associated with Cowden Syndrome), TSC1 or TSC2 (Tuberous Sclerosis Complex), LKB1 (Peutz–Jeghers Syndrome), NF1 (Neurofibromatosis 1), and VHL (von Hippel–Lindau Disease), results in familial cancer syndromes (collectively called Phakomatoses) with similar clinical features. In addition, Akt signaling is aberrant in many sporadic human cancers resulting in elevated mTOR activity. Collectively, these observations have provided a scientific basis for mTOR inhibition using rapamycin and its derivatives as a prospective treatment for these diseases
Fig. Illustration of the mTOR signaling pathway. Tuberin and hamartin function as a complex to inactivate Rheb and inhibit mTOR. Inactivation of tuberin by upstream regulators, such as RSK1, Erk2 via the Ras signaling pathway, and Akt/PKB via the PI3K signaling pathway, releases the brake on Rheb. In contrast, LKB1/AMPK-mediated phosphorylation activates tuberin. mTOR forms two functionally distinct protein complexes, mTORC1 and mTORC2. mTORC1 leads to the phosphorylation of p70S6K, S6, and 4E-BP1 that promote increased protein translation and cell growth. mTORC2 activation regulates Akt/PKB, PKCa, and Rho to control cell survival, proliferation, metabolism, and the cytoskeleton. Arrowheads indicate activation and flat bars indicate inhibition of function