Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
Open accessAbstract
The mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Here, we identify HBXIP and C7orf59 as two additional Ragulator components that are required for mTORC1 activation by amino acids. The expanded Ragulator has nucleotide exchange activity toward 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 identifying Ragulator as a guanine nucleotide exchange factor (GEF) for the Rag GTPases.
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None of the Rag proteins contain lipid modification motifs that would result in their lysosomal localization.
“None of the Rag proteins contain any lipid modification motifs that would result in their lysosomal localization, and therefore five proteins, MP1, p14, p18, HBXIP and C7orf59, which form a lysosomally-localized complex and which interact with the Rag GTPases, were found to be required to recruit them to their cognate compartment (Bar-Peled et al., 2012;Sancak et al., 2010).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2012
Presence of amino acids decreases the amount of Ragulator coimmunoprecipitating with RagB; the interaction is strengthened when the Rags are in a nucleotide-free state, and addition of GTP to an in vitro binding assay weakens the interaction.
“Presence of amino acids decreases the amount of Ragulator coimmunoprecipitating with RagB; furthermore, this interaction is strengthened when the Rags are in a nucleotide-free state, as the addition of GTP to an in vitro binding assay weakened the interaction (Bar-Peled et al., 2012).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2012
Ragulator acts as the GEF for RagA/B, accelerating the release of both GDP and GTP from this subunit of the Rag heterodimer.
“In addition to being a scaffold, Ragulator acts as the GEF for RagA/B, accelerating the release of both GDP and GTP from this subunit of the Rag heterodimer (Bar-Peled et al., 2012).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2012
The Rag GTPases and their associated complex, Ragulator, are the essential platform for (m)TORC1 recruitment to the lysosome.
“The Rag GTPases and their associated complex, ‘Ragulator’, are the essential platform for (m)TORC1 recruitment to the lysosome.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2012
p18 is the key determinant of lysosome localization by virtue of lipid modifications within its N-terminal region.
“The protein p18 was shown to be the key determinant of lysosome localization by virtue of lipid modifications within its N-terminal region (Bar-Peled et al., 2012; Nada et al., 2009).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2012
Five proteins, MP1, p14, p18, HBXIP and C7orf59, form a lysosomally-localized complex, interact with the Rag GTPases, and are required to recruit the Rag GTPases to their cognate compartment.
“None of the Rag proteins contain any lipid modification motifs that would result in their lysosomal localization, and therefore five proteins, MP1, p14, p18, HBXIP and C7orf59, which form a lysosomally-localized complex and which interact with the Rag GTPases, were found to be required to recruit them to their cognate compartment (Bar-Peled et al., 2012;Sancak et al., 2010).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2012
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“(B and C) The interaction with Ragulator requires the presence of the intact N-terminal domain of SLC38A9.”
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“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).”
InfluentialSelf-citationMenon, S., Dibble, C. C., Talbott, G., Hoxhaj, G., Valvezan, A., Takahashi, H., Cantley, L., & Manning, B. (2014) · Cell · doi:10.1016/j.cell.2013.11.049 · Cited by 787 · see citing works
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“GATOR1 is composed of DEPDC5 (DEP domain-containing protein 5), NPRL2 (nitrogen permease regulator 2-like protein), and NPRL3 where DEPDC5 is thought to possess the GAP activity toward RAGA/B (Bar-Peled et al , 2013; Panchaud et al , 2013a).”
InfluentialSignal integration by mTORC1 coordinates nutrient input with biosynthetic output
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SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
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“GATOR2 dissociates from Sestrin2/CASTOR1/2 and activates RagA/ B by inhibiting the activity of GATOR1, which consists of DEPDC5, NPRL3 and NPRL2, and displays GAP activity to RagA/ B.(129,130,132,137) In addition, ubiquitination is also involved in the regulation of GATOR1 activity, in which Cullin3-KLHL22 E3 ligase p…”
BackgroundRegulation of mTORC1 and its impact on gene expression at a glance
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“At the surface of the lysosome, the v-ATPase directly interacts with the Ragulator, a pentameric protein complex that is essential for amino acid regulation of mTORC1 (Bar-Peled et al., 2012; Sancak et al., 2010).”
BackgroundSelf-citationThe Lysosome as a Regulatory Hub
Perera, R. M., & Zoncu, R. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-125125 · Cited by 664 · see citing works
“The first such factor to be identified is a protein complex termed Ragulator, which is specifically localized to the lysosome and is composed of five proteins known as LAMTOR1–5 (Bar-Peled et al. 2012, Nada et al. 2009, Sancak et al. 2010, Teis et al. 2002) (Figure 2b).”
BackgroundSelf-citationmTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide
Matsumoto, A., Pasut, A., Matsumoto, M., Yamashita, R., Fung, J., Monteleone, E., Saghatelian, A., Nakayama, K., Clohessy, J., & Pandolfi, P. (2016) · Nature · doi:10.1038/nature21034 · Cited by 594 · see citing works
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“ww the guanine nucleotide exchange factor (GEF) activity of Ragulator, thus triggering the GTP loading and activation of RagA/B proteins (5).”
BackgroundTsun, Z.-Y., Bar-Peled, L., Chantranupong, L., Zoncu, R., Wang, T., Kim, C., Spooner, E., & Sabatini, D. M. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.09.016 · Cited by 565 · see citing works
“…RagCS75N) disrupt the coordination of the magnesium cofactor (Feig, 1999; Feig and Cooper, 1988; John et al., 1993), resulting in mutants with much lower affinity for all nucleotides, but with likely preferential binding of GDP over GTP within cells (Bar-Peled et al., 2012; Sancak et al., 2008).”
InfluentialSelf-citationmTORC1 as the main gateway to autophagy
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“In mammalian cells, amino acids are sensed by the vacuolar-type H + -translocating ATPase, which is present in the lysosome membrane, in conjunction with RRAG proteins and the Ragulator complex [52], which can coordinately direct MTORC1 to the lysosome membrane where it becomes activated by the GTPase RHEB [53].”
SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway
Gu, X., Orozco, J. M., Saxton, R., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S., & Sabatini, D. (2017) · Science · doi:10.1126/science.aao3265 · Cited by 533 · see citing works
Self-citationLysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex
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“…of LAMTOR1 through LAMTOR5 (late endosomal/lysosomal adaptor, MAPK and mTOR activator 1–5), is a critical pentamer complex that not only anchors RAG proteins to the endosome but also functions as their GEF (guanine nucleotide exchange factor) (Bar-Peled et al., 2012; Sancak et al., 2010).”
InfluentialThe dawn of the age of amino acid sensors for the mTORC1 pathway
Wolfson, R. L., & Sabatini, D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.001 · Cited by 500 · see citing works
Self-citationThe mechanistic target of rapamycin: the grand conducTOR of metabolism and aging
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Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor
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Where is mTOR and what is it doing there?
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“Rag is a heterodimeric GTPase consisting of RagA or B in complex with RagC or D. Ragulator, the GEF and lysosomal anchor for Rag, is a pentameric complex consisting of p14, p18, MP1, HBXIP, and C7orf59 (also known as LAMTOR1–5; Bar-Peled et al., 2012).”
Twenty-five years of mTOR: Uncovering the link from nutrients to growth
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Self-citationLysosome biogenesis: Regulation and functions
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“The multi-subunit complex Ragulator and GATOR1 were respectively identified as the guanine exchange factor and GTPase activating protein (GAP) of RagA/B (Bar-Peled et al., 2013; Bar-Peled et al., 2012).”
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“Lastly, a fourth is Ragulator, which anchors the Rag GTPase heterodimer to the lysosomal surface and also regulates its nucleotide state (Bar-Peled et al., 2012).”
Self-citationChantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., & Sabatini, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.014 · Cited by 466 · see citing works
“Amino acids regulate the interaction between multiple critical components of the amino acid pathway (Bar-Peled et al., 2012; Sancak et al., 2008, 2010; Tsun et al., 2013; Zoncu et al., 2011).”
Self-citationStructural basis for leucine sensing by the Sestrin2-mTORC1 pathway
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Self-citationAMPK: restoring metabolic homeostasis over space and time
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The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective
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TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress
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“Ragulator then transmits the information regarding amino acid availability by modulating the nucleotide status of the small GTPases Rags (Bar-Peled et al 2012).”
BackgroundThe Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism
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“Moreover, Ragulator also functions as a guanine exchange factor (GEF) for both Rag A and Rag B by preferentially binding to them in the nucleotide-free state [34].”
BackgroundInfluentialMechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting
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“We also found previously unreported interactors, including the five subunits of Ragulator (LAMTOR1–5; Table S1), a multimeric complex that regulates activation of the target of rapamycin complex 1 (mTORC1) kinase at the lysosomal membrane (Bar-Peled et al., 2012).”
BackgroundNutrient signaling to mTOR and cell growth
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PtdIns(3,4,5) P 3-Dependent Activation of the mTORC2 Kinase Complex
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“Triggered by amino acids or nutrients, mTORC1 is recruited to the surface of lysosomes in an amino-acid transporter SLC38A9 ( 7, 8 ), Rag-GTPase ( 9 ), Ragulator ( 10 ), and vacuolar adenosine triphosphatase ( 11 )–dependent manner through an “inside-out” mechanism ( 12 ).”
BackgroundRecruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases
Petit, C. S., Roczniak-Ferguson, A., & Ferguson, S. M. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201307084 · Cited by 355 · see citing works
“The sole RagA/B GEF identified to date is the Ragulator complex that is also responsible for the recruitment of Rag heterodimers to the lysosomal membrane (Bar-Peled et al., 2012).”
BackgroundRegulation of Autophagy by mTOR Signaling Pathway.
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“The Ragulator complex functions as a guanine nucleotide exchange factor (GEF) for RagA/B (Bar-Peled et al., 2012), although the precise mechanism remains to be uncovered.”
Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes
Martina, J. A., & Puertollano, R. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201209135 · Cited by 350 · see citing works
“The amino acid–dependent translocation of mTOR requires Rag GTPases and Ragulator, a pentameric protein complex that comprises p18, p14, MP1, HBXIP, and C7orf59 and anchors the Rag GTPases to the lysosomes (Sancak et al., 2008, 2010; Bar-Peled et al., 2012).”
BackgroundAt the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy
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“The first, the lysosomal v-ATPase, contributes to mTORC1 signaling through an unknown mechanism that involves an interaction with Ragulator (Bar-Peled et al., 2012; Zoncu et al., 2011).”
BackgroundInfluentialSelf-citationNutrient-Sensing Mechanisms across Evolution
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“Ragulator binds the Rag GTPases to the lysosome and also has nucleotide exchange activity for RagA/B (Bar-Peled et al., 2012; Sancak et al., 2010), but the function of the v-ATPase in the pathway is unknown.”
Self-citationThe Roles of mTOR Complexes in Lipid Metabolism
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TFEB and TFE3 are novel components of the integrated stress response
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“This is due in part to the fact that mTORC1, a master regulator of nutrient sensing, is activated on the surface of lysosomal membranes in response to amino acids and growth factors (Sancak et al , 2008, 2010; Bar-Peled et al , 2012).”
Molecular logic of mTORC1 signalling as a metabolic rheostat
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Growing knowledge of the mTOR signaling network
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Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes
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“The initial experiment suggested that Ragulator acts as a GEF toward RagA/B to control its nucleotide-bound state [66].”
BackgroundThe role of mammalian target of rapamycin (mTOR) in insulin signaling
Yoon, M.-S. (2017) · Nutrients · doi:10.3390/nu9111176 · Cited by 300 · see citing works
“It also acts as a guanine nucleotide exchange factor (GEF) for Rag A or Rag B [32,33].”
BackgroundInterferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation
Su, X., Yu, Y., Zhong, Y., Giannopoulou, E. G., Hu, X., Liu, H., Cross, J. R., Rätsch, G., Rice, C. M., & Ivashkiv, L. B. (2015) · Nature Immunology · doi:10.1038/ni.3205 · Cited by 298 · see citing works
mTOR Pathways in Cancer and Autophagy
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“The Ragulator serves as a scaffold [31,34], but has also been shown to act as a guanine-exchange factor (GEF) toward RagA/B, thus promoting Rag activity [34,35].”
BackgroundThe lysosome as a command-and-control center for cellular metabolism
Lim, C.-Y., & Zoncu, R. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201607005 · Cited by 274 · see citing works
“Specifically, Ragulator acts as a GEF that promotes the loading of Rag-A/B with GTP and thus activates mTORC1 (Binda et al., 2009; Bar-Peled et al., 2012).”
BackgroundInfluentialSelf-citationGalectins Control mTOR in Response to Endomembrane Damage
Jia, J., Abudu, Y. P., Claude‐Taupin, A., Gu, Y., Kumar, S. G., Choi, S. W., Peters, R. S., Mudd, M. H., Allers, L., Salemi, M., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.03.009 · Cited by 288 · see citing works
“The Ragulator-Rag interaction increases during amino acid starvation (Bar-Peled et al., 2012) or cholesterol depletion (Castellano et al., 2017), believed to reflect increased affinity of GEFs (in this case Ragulator) for inactive (GDP-bound) cognate GTPases such as Rags (Bar-Peled et al., 2012;…”
InfluentialPanchaud, N., Gulli, M., & VIRGILIO, C. D. (2013) · Science Signaling · doi:10.1126/scisignal.2004112 · Cited by 290 · see citing works
“It has been proposed that lysosomal amino acids, through an inside-out mechanism that requires the vacuolar H+-ATPase (H+-translocating adenosine triphosphatase) (v-ATPase) (8), stimulate the GEF activity of the Ragulator complex toward RagA or RagB (9, 10).”
BackgroundInfluentialGuardia, C. M., Farías, G. G., Jia, R., Pu, J., & Bonifacino, J. S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.062 · Cited by 269 · see citing works
“Lysosomes were stained with an antibody to the LAMTOR4 (C7orf59) subunit of the ragulator complex, a well-established lysosome marker (Bar-Peled et al., 2012).”
Metformin as an Anticancer Agent
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The Function of V-ATPases in Cancer
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“However, whether these functions are conserved in the mammalian orthologues of Vps39 and LRS is unclear 69,103 .”
BackgroundInfluentialSelf-citationLysosome trafficking and signaling in health and neurodegenerative diseases
Lie, P. P. Y., & Nixon, R. A. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.015 · Cited by 265 · see citing works
Metabolomics of type 1 and type 2 diabetes
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Emerging Roles for the Lysosome in Lipid Metabolism
Thelen, A. M., & Zoncu, R. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.07.006 · Cited by 268 · see citing works
“The pentameric Ragulator complex is thought to be a GEF that mediates the loading of RagA/B with GTP, thus promoting mTORC1 recruitment to the lysosome [56,140].”
Self-citationAmino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9
Jung, J., Genau, H. M., & Behrends, C. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00125-15 · Cited by 266 · see citing works
“Cycling of mTOR between cytosol and lysosome generally is coupled to its inactive and active states, respectively, and depends on Rag GTPases, Ragulator, TSC, and RHEB GTPase (9, 16, 23, 31).”
BackgroundInfluentialAmino acid metabolism in tumor biology and therapy
Chen, J., Cui, L., Lu, S., & Xu, S. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06435-w · Cited by 268 · see citing works
Nutrient Regulation of the mTOR Complex 1 Signaling Pathway
Kim, S. G., Buel, G. R., & Blenis, J. (2013) · Molecules and Cells · doi:10.1007/s10059-013-0138-2 · Cited by 259 · see citing works
“In addition to its role in targeting the Rags to the lysosomal surface, Ragulator also functions as a guanine nucleotide exchange factor (GEF) toward RagA/B in the presence of amino acids, promoting the exchange of GDP with GTP and thereby triggering activation of RagA/B GTPases (Bar-Peled et al., 2012).”
BackgroundComplement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses
Kolev, M. V., Dimeloe, S., Friec, G. L., Navarini, A. A., Arbore, G., Povoleri, G. A. M., Fischer, M., Belle, R., Loeliger, J., Develioglu, L., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.05.024 · Cited by 257 · see citing works
K63 Polyubiquitination and Activation of mTOR by the p62-TRAF6 Complex in Nutrient-Activated Cells
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AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3
Paquette, M., El–Houjeiri, L., Zirden, L. C., Puustinen, P., Blanchette, P., Jeong, H., Dejgaard, K., Siegel, P. M., & Pause, A. (2021) · Autophagy · doi:10.1080/15548627.2021.1898748 · Cited by 260 · see citing works
“RRAGA, RRAGB, RRAGC, and RRAGD activation status is regulated by several guanineexchange factors (GEF) and GTP-ase activating proteins (GAP), particularly by the ragulator complex, which uses ATP6V (V-type ATPases) to detect the abundance of amino acids [50,54,55,72,73].”
BackgroundTranslational reprogramming in cellular stress response
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The vacuolar-type H+-ATPase at a glance – more than a proton pump
Maxson, M. E., & Grinstein, S. (2014) · Journal of Cell Science · doi:10.1242/jcs.158550 · Cited by 234 · see citing works
“Components of the mTORC1 pathway – the Ragulator complex (comprising LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5) and the Ras-related GTP-binding proteins (RRAGA, RRAGB, RRAGC and RRAGD; hereafter referred to as Rag GTPases) – localize to the lysosomal membrane in an inactive form (see poster panel ‘Amino-acid- ind…”
BackgroundInfluentialMultistep regulation of TFEB by MTORC1
Vega-Rubín-de-Celis, S., Peña-Llopis, S., Konda, M., & Brugarolas, J. (2017) · Autophagy · doi:10.1080/15548627.2016.1271514 · Cited by 215 · see citing works
Pollizzi, K. N., Sun, I., Patel, C. H., Lo, Y.-C., Oh, M. H., Waickman, A. T., Tam, A. J., Blosser, R. L., Wen, J., Delgoffe, G. M., et al. (2016) · Nature Immunology · doi:10.1038/ni.3438 · Cited by 231 · see citing works
- Authors
- Bar-Peled, L., Schweitzer, L. D., Zoncu, R., & Sabatini, D. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 150
- Issue
- 6
- Pages
- 1196-1208
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3517996
- OpenAlex
- W1990960113
- Cited by
- 918
- References
- 64
- Citations by year
- 2026: 31 · 2025: 25 · 2024: 41 · 2023: 63 · 2022: 63 · 2021: 88 · 2020: 57 · 2019: 70 · 2018: 71 · 2017: 87 · 2016: 86 · 2015: 94 · 2014: 81 · 2013: 55 · 2012: 6
- FWCI
- 30.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 397 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (F31CA167872, CA103866, R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R37AI047389, AI47389), R01AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Ragulator complex, Rag GTPases, mTORC1, amino acid sensing, guanine nucleotide exchange factor, HBXIP, V-ATPase, lysosomal signaling, cell growth regulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acid Sequence, Amino Acids, Animals, Drosophila, Humans, Molecular Sequence Data, Proteins, Signal Transduction, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, HEK293 Cells, TOR Serine-Threonine Kinases
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