mTOR Signaling

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• Reviews
• Pathway Key
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Pathway Description:

The mammalian target of rapamycin (mTOR) is an atypical serine/threonine kinase that is present in two distinct complexes. mTOR complex 1 (mTORC1) is composed of mTOR, Raptor, and GβL (mLST8) and is inhibited by rapamycin. mTORC1 integrates multiple signals reflecting the availability of growth factors, nutrients, or energy to promote either cellular growth when conditions are favorable or catabolic processes during stress or when conditions are unfavorable. Growth factors (e.g. insulin) signal to mTORC1 via Akt or ERK1/2, which inactivates TSC2 to prevent TSC2 inhibition of mTORC1. Alternatively, low ATP levels lead to the AMPK-dependent activation of TSC2 to reduce mTORC1 signaling. Amino acid availability is signaled to mTORC1 via a pathway involving the Rag proteins. Active mTORC1 has a number of downstream biological effects including translation of mRNA via the phosphorylation of downstream targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy, ribosome biogenesis and activation of transcription leading to mitochondrial metabolism or adipogenesis. The mTOR complex 2 (mTORC2) is composed of mTOR, Rictor, GβL, and Sin1 and promotes cellular survival by activating Akt. mTORC2 also regulates cytoskeletal dynamics by activating PKCα and/or Rho GTPase. Aberrant mTOR signaling is involved in many disease states including cancer, cardiovascular disease and metabolic disorders.

Selected Reviews:

• Corradetti MN, Guan KL (2006) Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 25(48), 6347–60.
• Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1), 9–22.
• Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17(6), 596–603.
• Schieke SM, Finkel T (2006) Mitochondrial signaling, TOR, and life span. Biol. Chem. 387(10-11), 1357–61.
• Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3), 471–84.
• Yang Q, Guan KL (2007) Expanding mTOR signaling. Cell Res. 17(8), 666–81.

CST would like to thank Prof. Nahum Sonenberg and Mark Livingstone, Department of Biochemistry, McGill University, Montreal, Quebec, for reviewing these diagrams.