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CELL SIGNALLING

RAG-ulating mTORC1 with amino acids

Nature Reviews Molecular Cell Biology volume 22, page 587 (2021)Cite this article

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Organisms sense amino acid fluctuations and respond accordingly to control cell growth. Disruption in these sensing mechanisms can be detrimental, often leading to human diseases, including cancer, type 2 diabetes, metabolic disorders and neurodegeneration. Central to this process is the mammalian target of rapamycin (mTOR) that was identified in the early 1990s and controls some of the most essential signalling networks in biology. mTOR is an evolutionarily conserved serine/threonine kinase and is the key component of a protein complex termed mTOR complex 1 (mTORC1). mTORC1 is a ‘master regulator’ of multiple metabolic signalling pathways, whereby it controls cellular and organismal homeostasis by coordinating anabolic and catabolic processes with nutrient availability.

In alignment with its role as a master regulator, multiple stimuli converge on mTORC1, including amino acids, growth factors, energy status and stress. In 2008, the RAG GTPases were identified independently by two groups to link amino acids to mTORC1 activation. David Sabatini’s lab identified the RAG GTPases as mTORC1 interacting proteins through the combination of immunoprecipitation, mass spectrometry analysis and biochemical experiments (Sancak et al.). Another key finding from this study was that under amino acid rich conditions, endogenous mTOR localized to RAB7-positive perinuclear structures, later determined to be lysosomes. In a parallel work, Kun-Liang Guan’s lab — using an RNA interference screen in fly cells to search for small GTPases that play a role in amino acid signalling to mTORC1 — independently discovered fly orthologues of the RAG GTPases.

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References

Original articles

  • Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008)

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Related articles

  • Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020)

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  • Kim, J. & Guan, K-L. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 21, 63–71 (2019)

    Article  CAS  Google Scholar 

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  1. Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA

    Jenna L. Jewell

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  1. Jenna L. Jewell
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Correspondence to Jenna L. Jewell.

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Jewell, J.L. RAG-ulating mTORC1 with amino acids. Nat Rev Mol Cell Biol 22, 587 (2021). https://doi.org/10.1038/s41580-021-00378-2

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