mTOR Signaling

The mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that is present in two distinct complexes. The first, mTOR complex 1 (mTORC1), is composed of mTOR, Raptor, GβL, and DEPTOR and is inhibited by rapamycin. It is a master growth regulator that senses and integrates diverse nutritional and environmental cues, including growth factors, energy levels, cellular stress, and amino acids. It couples these signals to the promotion of cellular growth by phosphorylating substrates that potentiate anabolic processes such as mRNA translation and lipid synthesis, or limit catabolic processes such as autophagy. The small GTPase Rheb, in its GTP-bound state, is a necessary and potent stimulator of mTORC1 kinase activity, which is negatively regulated by its GAP, the tuberous sclerosis heterodimer TSC1/2. Most upstream inputs are funneled through Akt and TSC1/2 to regulate the nucleotide-loading state of Rheb. In contrast, amino acids signal to mTORC1 independently of the PI3K/Akt axis to promote the translocation of mTORC1 to the lysosomal surface where it can become activated upon contact with Rheb. This process is mediated by the coordinated actions of multiple complexes, notably the v-ATPase, Ragulator, the Rag GTPases, and GATOR1/2. The second complex, mTOR complex 2 (mTORC2), is composed of mTOR, Rictor, GβL, Sin1, PRR5/Protor-1, and DEPTOR. mTORC2 promotes cellular survival by activating Akt, regulates cytoskeletal dynamics by activating PKCα, and controls ion transport and growth via SGK1 phosphorylation. Aberrant mTOR signaling is involved in many disease states including cancer, cardiovascular disease, and diabetes.

Selected Reviews:

• Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim. Biophys. Acta 1804(3), 433–9.
• Dunlop EA, Tee AR (2009) Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell. Signal. 21(6), 827–35.
• Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33(2), 67–75.
• Laplante M, Sabatini DM (2013) Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell. Sci. 126(Pt 8), 1713–9.
• Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2), 274–93.
• Neufeld TP (2010) TOR-dependent control of autophagy: biting the hand that feeds. Curr. Opin. Cell Biol. 22(2), 157–68.
• Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12(1), 21–35.

We would like to thank Rachel Wolfson and Lynne Chantranupong for reviewing this diagram.

created September 2008

revised June 2014