An expanded Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1

By L. Bar-Peled, Lawrence D. Schweitzer, Roberto Zoncu, David M. Sabatini. Cell, 2012

912 citations recorded by the source corpus.

The mTOR Complex 1 (mTORC1) pathway promotes cell growth in response to a diverse set of cues, including growth factors as well as energy and amino acid levels. Amino acids signal through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. The four mammalian Rag proteins form obligate heterodimers consisting of RagA or RagB bound to RagC or RagD. A key upstream component of the Rag GTPases is Ragulator, a trimeric complex that tethers them to the lysosome and also interacts with the v-ATPase, which is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of GTP to RagB, a critical step in the sensing mechanism, but the factors that regulate Rag nucleotide loading are unknown. Here, we identify the proteins encoded by the HBXIP and C7orf59 genes as novel Ragulator components that are required for mTORC1 activation by amino acids. The pentameric Ragulator has nucleotide exchange activity towards RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by revealing Ragulator to be a scaffold with guanine nucleotide exchange factor (GEF) activity for the Rag GTPases.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/82cda7c59c1e4b64a0aa40702205780e9d809d95

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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): “RAG GTPase exists as a heterodimer of RAGA/B (RRAGA/B) with RAGC/D (RRAGC/D) and is anchored to the lysosome by the Ragulator complex (Bar-Peled et al., 2012).”
The amino acid transporter SLC38A9 is a key component of a lysosomal membrane complex that signals arginine sufficiency to mTORC1 (2015, background): “(B and C) The interaction with Ragulator requires the presence of the intact N-terminal domain of SLC38A9.”
mTOR: a pharmacologic target for autophagy regulation. (2015, neutral): “…a pharmacologic target for autophagy regulation R e v i e w S eRi eS: a u t o p h a g y the requirement of vacuolar H + -ATPase (v-ATPase, a proton pump for lysosomal acidification) in mTORC1 activation (41–45), the signaling mechanism from amino acids to a Rag GEF and/or GAP is still unknown.”
Lysosomal Physiology (2015, background): “For example, mTOR senses AA contents both outside and within the organelle (10, 66).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “49,50 SLC38A9, lysosomal amino acid transporter was displayed to interact with the Rag-v-ATPase complex which is responsible for arginine transport and activation of mTORC1.”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “The Rags are obligate heterodimers of RagA or RagB with RagC or RagD and are tethered to the lysosomal membrane through their association with the pentameric Ragulator complex comprising MP1, p14, p18, HBXIP, and C7ORF59 (Sancak et al., 2010; Bar-Peled et al., 2012).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “nucleotide exchange factor (GEF) activity of Ragulator towards RagA/B (Zoncu et al., 2011; Bar-Peled et al., 2012).”
A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 (2013, neutral): “Lysis of HEK-293T cells stably expressing FLAG-tagged DEPDC5, WDR24 or Metap2, was identical to the procedure described in (7).”
Regulation of mTORC1 by amino acids (2014, neutral): “Early experiments with Ragulator hinted at the auxiliary roles of this complex: Ragulator preferentially bound to Rags in their inactive state, an interaction that was driven by the nucleotide state of RagA/B (48).”