Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids

By Y. Sancak, L. Bar-Peled, Roberto Zoncu, Andrew L. Markhard, S. Nada, David M. Sabatini. Cell, 2010

2,430 citations recorded by the source corpus.

The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0c7e1a5ec8fceb8454e78f34b80d9e69495d6066

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Citations in the corpus

Sestrin2 is a leucine sensor for the mTORC1 pathway (2015, background): “Ragulator anchors the Rag heterodimers to the lysosome and has nucleotide exchange activity for RagA and RagB (21, 25).”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “Dotted lines indicate connections between proteins that are not known to be direct. a conformation that allows the kinase subunit to be phosphorylated by the upstream activating kinase LKB1 (Sanders et al., 2007), thus slowing cell growth and its many ATP-consuming processes (Shaw, 2009).”
The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis (2012, background): “Thus, we focused our attention on the kinase mTOR because (i) mTOR localizes to the cytoplasmic surface of lysosomes as part of the mTORC1 complex (26–28) and (ii) the loss of lysosomal localization and activity of mTOR under starvation conditions promotes autophagy (15, 17, 27).”
Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae (2014, background): “Ego1 and 3 are functional homologs of the Ragulator complex in vertebrates (Kogan et al., 2010; Sancak et al., 2010).”
The Nutrient-Responsive Transcription Factor TFE3, Promotes Autophagy, Lysosomal Biogenesis, and Clearance of Cellular Debris (2014, background): “To assess the regulation of TFE3 under a more physiological condition, cells were starved by incubation with amino acid–free medium for 1 hour, a treatment that inactivates mTORC1 (6, 7).”
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.”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, positive): “…a complex interplay between multiple distinct factors, including Ragulator, which serves as a lysosomal scaffold for RagA/B (Bar-Peled et al., 2012; Sancak et al., 2010); FLCN/FNIP2, a GAP for RagC/D (Petit et al., 2013; Tsun et al., 2013); and GATOR1, a GAP for RagA/B and a critical negative…”
Nutritional Control of Growth and Development in Yeast (2012, background): “The Rag complex, activated by the presence of amino acids, promotes relocalization of TORC1 from discrete cytoplasmic sites to a late endosomal or lysosomal compartment at which Rheb resides (Sancak et al. 2010).”