The expanding role of mTOR in cancer cell growth and proliferation

Abstract

The mechanistic/mammalian target of rapamycin (mTOR) is a conserved protein kinase that controls several anabolic processes required for cell growth and proliferation. As such, mTOR has been implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes and neurodegeneration. As part of the mTOR complex 1 (mTORC1), mTOR regulates cell growth by promoting the biosynthesis of proteins, lipids and nucleic acids. Several mTORC1 substrates have been shown to regulate protein synthesis, including the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and the ribosomal S6 kinases (S6Ks) 1 and 2. In this work, we focus on the signalling pathways that lie both upstream and downstream of mTORC1, as well as their relevance to human pathologies. We further discuss pharmacological approaches that target mTOR and their applications for the treatment of cancer.

Figure 1.

Structural organisation of mTOR and composition of mTORC1 and mTORC2. The N-terminal region of mTOR is composed of tandem HEAT repeats that mediate protein–protein interactions. The kinase domain is located between the FRB (recognised by the FKBP12/rapamycin complex) and the FATC domains. mTOR is found in two protein complexes, mTORC1 and mTORC2, that are defined by their association with Raptor and Rictor, respectively. Deptor and mLST8 are found in both complexes, while PRAS40 is strictly associated with mTORC1, and mSIN1 and Protor interact only with mTORC2.

Figure 2.

mTORC1 activation by amino acids and growth factors. Growth factors stimulate mTORC1 through the activation of the Ras/MAPK and PI3K/Akt signalling pathways, which are triggered by RTK dimerisation and autophosphorylation. The Akt, ERK and RSK kinases directly phosphorylate and inhibit the TSC2 subunit of the TSC complex that functions as a GAP towards Rheb and prevents its ability to stimulate mTORC1. Once activated, mTORC1 promotes cell growth by regulating several anabolic processes including protein, lipid and nucleotide synthesis, which contribute to the increase in cell biomass.

Figure 3.

Integration of amino acids and growth factors at the lysosome. In the absence of amino acids and growth factors, Rag and Rheb GTPases are repressed by the GATOR1 and TSC complexes, which both localise at the lysosome. In the presence of amino acids, the Ragulator complex is activated in a v-ATPase-dependent manner and stimulates the active conformation of Rag proteins, leading to their direct interaction with mTORC1. Growth factors promote TSC complex release from the lysosome, thereby allowing the full activation of mTORC1 by Rheb.

Figure 4.

Stimulation of protein synthesis by mTORC1. In quiescent cells, 4E-BP is hypophosphorylated and tightly associated with eIF4E, thus preventing translation initiation. When activated, mTORC1 phosphorylates 4E-BP leading to its dissociation from eIF4E and assembly of the eIF4F complex. 4E-BP repression by mTORC1 stimulates global protein synthesis.