Differential regulation of mTORC1 by leucine and glutamine

By Jenna L. Jewell, Young Chul Kim, R. Russell, Fa-Xing Yu, H. Park, Steven W Plouffe, Vincent S. Tagliabracci, K. Guan. Science, 2015

693 citations recorded by the source corpus.

Getting specific about amino acid sensing The protein kinase complex mTORC1 regulates growth and metabolism, and its activity is controlled in response to the abundance of cellular amino acids. Jewell et al. report that control of mTORC1 in response to glutamine does not require the Rag guanosine triphosphatase (GTPase) implicated in the sensing of other amino acids such as leucine (see the Perspective by Abraham). For sensing of glutamine, another GTPase, Arf1, was required. Distinct mechanisms thus appear to couple various amino acids to signaling by the mTORC1 complex. Science, this issue p. 194; see also p. 128 Distinct mechanisms sense amino acids leucine and glutamine at the lysosome. [Also see Perspective by Abraham] The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H+–adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosome in RagA and RagB knockout cells and required the v-ATPase but not the Ragulator. Furthermore, we identified the adenosine diphosphate ribosylation factor–1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8c888cf59d764141c6915fbfac2852be0d5e7631

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Citations in the corpus

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination (2016, background): “…activation is induced by amino acids, particularly leucine, glutamine and arginine through both RAG GTPase-dependent and -independent mechanisms (Jewell et al., 2015; Carroll et al., 2016), and also activates feedback mechanisms that further increase nutrient uptake to fuel anabolic reactions.”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, background): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Nutrient sensing and TOR signaling in yeast and mammals (2017, positive): “Consistent with the observations reported in yeast, glutamine stimulates lysosomal translocation and activation of mTORC1 in a RAGA/B and RAGULATOR-independent manner via the small GTPase ARF1 (ADP-ribosylation factor 1) and v-ATPase (vacuolar ATPase; Jewell et al , 2015; Fig 1).”
AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. (2020, background): “…can also activate mTORC1 via glutaminolysis and consequent production of α-615 ketoglutarate upstream of RAGs (Duran et al., 2013; Durán et al., 2012), while glutamine also 616 23 activates mTORC1 independently of the RAGs via the small GTPase ARF1 and the v-ATPase 617 (Jewell et al., 2015).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “59 The long noncoding RNA-SPAR was found to cooperate with the v-ATPase-Ragulator complex.”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “A breakthrough in the understanding of amino acid sensing by mTORC1 came with the discovery of the heterodimeric Rag GTPases as components of the mTORC1 pathway (Kim et al., 2008; Sancak et al., 2008).”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, neutral): “It is likely that additional amino acid sensors exist to signal the presence of other critical amino acids for mTORC1 activity, such as glutamine (Jewell et al., 2015), as well sensors that mediate the amino acid sensitive events upstream of additional mTORC1 regulators, such as Folliculin/FNIP…”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “A breakthrough in the understanding of amino acid sensing by mTORC1 came with the discovery of the heterodimeric Rag GTPases as components of the mTORC1 pathway (Kim et al., 2008; Sancak et al., 2008).”