Regulation of TORC1 by Rag GTPases in nutrient response

By Eunjung Kim, Pankuri Goraksha-Hicks, Li Li, T. P. Neufeld, K. Guan. Nature Cell Biology, 2008

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TORC1 (target of rapamycin complex 1) has a crucial role in the regulation of cell growth and size. A wide range of signals, including amino acids, is known to activate TORC1. Here, we report the identification of Rag GTPases as activators of TORC1 in response to amino acid signals. Knockdown of Rag gene expression suppressed the stimulatory effect of amino acids on TORC1 in Drosophila melanogaster S2 cells. Expression of constitutively active (GTP-bound) Rag in mammalian cells activated TORC1 in the absence of amino acids, whereas expression of dominant-negative Rag blocked the stimulatory effects of amino acids on TORC1. Genetic studies in Drosophila also show that Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Our studies establish a function of Rag GTPases in TORC1 activation in response to amino acid signals.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/66d497c325c47dbbc4ea41736a910fc4212e48bb

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Citations in the corpus

Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks (2011, background): “Amino acids, in contrast, stimulate the Rag-GTPase-dependent recruitment of mTORC1 to lysosomes and its subsequent activation by Rheb-GTPases (54, 89, 90).”
Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models (2011, background): “(AMPK), an energy status sensor activated by ATP depletion, inhibits mTORC1 by phosphorylating and inactivating Raptor [23], and by phosphorylating and activating TSC2 [24].”
An expanded Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1 (2012, neutral): “Drosophila S2 cells were transfected with a control dsRNA or dsRNAs targeting dRagC, dC7orf59, or dHBXIP, starved for amino acids for 90min or starved and stimulated with amino acids for 30min and analyzed as in (A).”
Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. (2012, neutral): “LRS Interacts with the GTP-Bound Form of RagD Rag GTPases are Ras family GTP-binding proteins, and heterodimers of GTP-bound RagA or RagB and GDP-bound RagC or RagD bind strongly to mTORC1 (Sancak et al., 2008; Kim et al., 2008).”
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB (2012, background): “The phosphorylation status of TFEB and its subcellular localization were entirely determined by the activation state of the Rag GTPases, which regulate mTORC1 activity downstream of amino acids (Kim et al, 2008; Sancak et al, 2008).”
mTOR signaling in growth control and disease (2012, background): “In 2008, two groups independently discovered that amino acid-dependent activation of mTORC1 requires the Rag GTPases (Kim et al., 2008; Sancak et al., 2008).”
Oxidative stress and autophagy: the clash between damage and metabolic needs (2014, background): “, RAG A–D) to bind guanine nucleotides (GTP or GDP in dependence of the member), leading to their activation and, subsequently, to the recruitment of mTORC1 on the lysosome membrane (Figure 1).(20,21) Here, mTORC1 can be targeted by”
With TOR less is more: a key role for the conserved nutrient sensing TOR pathway in aging (2010, neutral): “A causal role for mitochondrial respiration in tumorigenesis is supported by findings that succinate dehydrogenase and fumarate hydratase are tumor suppressor genes (King et al., 2006).”
Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment (2013, background): “The MEK/ERK signaling activation and Rag inactivation contribute to amino acid depletioninduced autophagy.(7,21) Many anticancer drugs including Tumor heterogeneity Drug efflux and metabolism”
mTOR signaling at a glance (2009, background): “Recently, two independent teams, including ours, have shown that the Rag proteins, a family of four related small GTPases, interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids (Kim et al., 2008; Sancak et al., 2008).”
mTOR: a pharmacologic target for autophagy regulation. (2015, neutral): “A genetic screen using a shRNA library targeting small GTPases and biochemical analysis using immunoaffinity-purified mTORC1-interacting proteins independently identified Rag proteins (RagA/B/C/D), a family of Ras-like small GTPases, as key mediators of amino acid–induced mTORC1 activation (35, 36).”
Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner (2010, background): “Moreover, although Sancak et al. concluded that energy-depleting agents, such as 2DG, appeared not to mediate their inhibitory affects through the Rag GTPases (Sancak et al., 2008), we found that ectopic expression of a constitutively active, but not wild-type (WT), Rag GTPase protected mTORC1 signa”