Amino acids and mTORC1: from lysosomes to disease
Open accessAbstract
The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.
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Activation of the pro-aging and pro-cancer mTOR pathways is modulated by energy intake and by a cocktail of essential amino acids, with branched-chain amino acids leucine and isoleucine playing a fundamental role.
“The activation of the pro-aging and pro-cancer mTOR pathways is modulated by energy intake but also by a cocktail of different essential amino acids, with the branched-chain amino acids leucine and isoleucine playing a fundamental role (82).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [82]
AMPK has a direct inhibitory action on raptor, the adaptor protein for mTORC1, and can also stimulate TSC1/2.
“AMPK has a direct inhibitory action on raptor, the adaptor protein for mTORC1, and can also stimulate the tuberous sclerosis complex TSC1/2 (164).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [164]
A Ragulator-RAG GTPases multiprotein complex associated with the lysosomal surface regulates mTOR activity by controlling its sub-cellular location, recruiting it to the lysosome.
“More recent research has identified a Ragulator-RAG GTPases multiprotein complex associated with the lysosomal surface that regulates mTOR activity by controlling its sub-cellular location, recruiting it to the lysosome (164).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [164]
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Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T., et al. (2007) · Nature · doi:10.1038/nature06161 · Cited by 591 · cited 1× · see citing works
“The AMP-activated protein kinase (AMPK) is allosterically activated by the high AMP and ADP levels that occur under low energetic states [8,9].”
BackgroundKhamzina, L., Veilleux, A., Bergeron, S., & Marette, A. (2005) · Endocrinology · doi:10.1210/en.2004-0921 · Cited by 562 · see citing works
Dong, J., Qiu, H., Garcia-Barrio, M., Anderson, J., & Hinnebusch, A. G. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00028-9 · Cited by 545 · see citing works
Dissecting eIF4E action in tumorigenesis.Preprint
Wendel, H., Silva, R. L. A., Malina, A., Mills, J., Zhu, H., Ueda, T., Watanabe‐Fukunaga, R., Fukunaga, R., Teruya-Feldstein, J., Pelletier, J., et al. (2007) · Genes & Development · doi:10.1101/gad.1604407 · Cited by 512 · cited 1× · see citing works
“As part of mTORC1, mTOR activity drives translation of a subset of genes that activate the cell division programs and block the induction of programmed cell death [77,78].”
Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)
García‐Martínez, J. M., Moran, J., Clarke, R. G., Gray, A., Cosulich, S. C., Chresta, C. M., & Alessi, D. R. (2009) · Biochemical Journal · doi:10.1042/bj20090489 · Cited by 459 · see citing works
Regulation of TFEB and V‐ATPases by mTORC1
Peña‐Llopis, S., Vega-Rubín-de-Celis, S., Schwartz, J. C., Wolff, N. C., Tran, T. A. T., Zou, L., Xie, X., Corey, D. R., & Brugarolas, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.257 · Cited by 456 · cited 2× · see citing works
“Moreover, reports that constitutive mTORC1 activation upregulates the expression of important lysosomal genes suggests that mTORC1 may affect cellular clearance through multiple pathways that involve both positive and negative regulation of substrates [69,70].”
BackgroundThe yeast lysosome-like vacuole: Endpoint and crossroads
Li, S. C., & Kane, P. M. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.08.003 · Cited by 453 · cited 1× · see citing works
“In light of these results, it is noteworthy that the yeast vacuole contains multiple transporters that ferry amino acids between the lumen and the cytoplasm (reviewed in [51,55]).”
BackgroundThe Vam6 GEF Controls TORC1 by Activating the EGO Complex
Binda, M., Gulli, M., Bonfils, G., Panchaud, N., Urban, J., Sturgill, T. W., Loewith, R., & VIRGILIO, C. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.033 · Cited by 432 · cited 2× · see citing works
“As in mammalian cells, Gtr1–Gtr2 is essential for mTORC1 activation by amino acids [45].”
mTOR Complex 2 Is Required for the Development of Prostate Cancer Induced by Pten Loss in Mice
Guertin, D. A., Stevens, D. M., Saitoh, M., Kinkel, S., Crosby, K., Sheen, J.-H., Mullholland, D. J., Magnuson, M. A., Wu, H., & Sabatini, D. M. (2009) · Cancer Cell · doi:10.1016/j.ccr.2008.12.017 · Cited by 402 · cited 1× · see citing works
“Recent evidence also suggests that aberrant mTORC2 activity may contribute to tumor formation [82], and several efforts were undertaken to generate ATP-competitive inhibitors able to block all mTOR-related activity [81,83–86], with most yielding promising results in preclinical trials.”
BackgroundRheb Binding to Mammalian Target of Rapamycin (mTOR) Is Regulated by Amino Acid Sufficiency
Long, X., Ortiz-Vega, S., Lin, Y., & Avruch, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500169200 · Cited by 349 · see citing works
Leucyl-tRNA Synthetase Controls TORC1 via the EGO Complex
Bonfils, G., Jaquenoud, M., Bontron, S., Ostrowicz, C. W., Ungermann, C., & VIRGILIO, C. D. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.02.009 · Cited by 338 · cited 2× · see citing works
“Two recent reports suggest that, in parallel to lysosome-based sensing, a dedicated mechanism for detecting leucine availability may exist in the cytoplasm [60,61].”
Amino acid availability regulates p70 S6 kinase and multiple translation factors
Wang, X., Campbell, L., Miller, C. M., & Proud, C. G. (1998) · Biochemical Journal · doi:10.1042/bj3340261 · Cited by 338 · see citing works
The TOR and EGO Protein Complexes Orchestrate Microautophagy in Yeast
Dubouloz, F., Deloche, O., Wanke, V., Cameroni, E., & VIRGILIO, C. D. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.05.020 · Cited by 336 · cited 1× · see citing works
“A similar idea is supported by the observation that, in yeast, the Gtrs and EGO complex are required to restore vacuolar morphology after rapamycin-induced or starvation-induced autophagy [64].”
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The fungal vacuole: composition, function, and biogenesis.
Klionsky, D. J., Herman, P. K., & Emr, S. D. (1990) · Microbiological Reviews · doi:10.1128/mmbr.54.3.266-292.1990 · Cited by 306 · cited 2× · see citing works
“In light of these results, it is noteworthy that the yeast vacuole contains multiple transporters that ferry amino acids between the lumen and the cytoplasm (reviewed in [51,55]).”
Novel G Proteins, Rag C and Rag D, Interact with GTP-binding Proteins, Rag A and Rag B*
Sekiguchi, T., Hirose, E., Nakashima, N., Ii, M., & Nishimoto, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m004389200 · Cited by 249 · cited 1× · see citing works
“These small GTPases, the Rags, belong to the Ras superfamily and are quite unusual: they exist as heterodimers where the highly similar RagA and RagB bind to either RagC or RagD, which are also similar to one another [27], leading to four possible dimer combinations.”
BackgroundFonseca, B. D., Smith, E. M., Lee, V. H.-Y., MacKintosh, C., & Proud, C. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704406200 · Cited by 240 · see citing works
Identification and characterization of a lysosomal transporter for small neutral amino acids
Sagné, C., Agulhon, C., Ravassard, P., Darmon, M. C., Hamon, M., Mestikawy, S. E., Gasnier, B., & Bruno Giros, A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121183498 · Cited by 233 · see citing works
Tor Kinases Are in Distinct Membrane-associated Protein Complexes inSaccharomyces cerevisiae
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“Zhou X, et al. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes.”
InfluentialSingle amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer
Sato, T., Nakashima, A., Guo, L., Coffman, K., & Tamanoi, F. (2010) · Oncogene · doi:10.1038/onc.2010.28 · Cited by 214 · cited 1× · see citing works
“In addition, it is intriguing that only a very few mutations in mTOR have been found in human sporadic cancers [100,101].”
BackgroundSirolimus Therapy in Tuberous Sclerosis or Sporadic Lymphangioleiomyomatosis
Davies, D. M., Johnson, S. R., Tattersfield, A. E., Kingswood, J. C., Cox, J. A., McCartney, D. L., Doyle, T., Elmslie, F., Saggar, A., de Vries, P. J., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmc072500 · Cited by 210 · see citing works
Bohn, G., Saborowski, A. L., Brandes, G., Thiel, J., Glocker, E. O., Schäffer, A. A., Rathinam, C., Taub, N., Teis, D., Zeidler, C., et al. (2006) · Nature Medicine · doi:10.1038/nm1528 · Cited by 202 · cited 2× · see citing works
“Interestingly, a partial loss of function of LAMTOR2 in humans underlies the first identified disease of hypoactive mTORC1 signaling, characterized by stunted growth, immunodeficiency, and albinism [42] (Box 2 and Figure 2).”
Localization of Rheb to the endomembrane is critical for its signaling function
Buerger, C., DeVries, B., & Stambolic, V. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.03.220 · Cited by 192 · cited 18× · see citing works
“Among its many targets, AMPK directly phosphorylates TSC2 [10,11]; but in contrast to Akt, AMPK-dependent phosphorylation of TSC2 stimulates the GTPase activity of TSC, inhibiting Rheb.”
BackgroundInfluentialDynamic aspects of vacuolar and cytosolic amino acid pools of Saccharomyces cerevisiae
Kitamoto, K., YOSHIZAWA, K., Ohsumi, Y., & Anraku, Y. (1988) · Journal of Bacteriology · doi:10.1128/jb.170.6.2683-2686.1988 · Cited by 191 · cited 1× · see citing works
“Basic amino acids arginine, lysine, and histidine preferentially accumulate in the vacuole, whereas they are relatively less abundant in the cytoplasm [52].”
Berchtold, D., & Walther, T. C. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-10-1001 · Cited by 190 · see citing works
A Family of Yeast Proteins Mediating Bidirectional Vacuolar Amino Acid Transport
Russnak, R., Konczal, D., & McIntire, S. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008028200 · Cited by 180 · cited 1× · see citing works
“Several such transporters, including those belonging to the Avt family, utilize the proton gradient established by the v-ATPase in symport or antiport mechanisms [56].”
An Activating Mutation of AKT2 and Human Hypoglycemia
Hussain, K., Challis, B., Rocha, N., Payne, F., Minic, M., Thompson, A., Daly, A., Scott, C. L., Harris, J. R., Smillie, B. J. L., et al. (2011) · Science · doi:10.1126/science.1210878 · Cited by 178 · cited 1× · see citing works
“Interestingly, somatic mutations in the Akt2 gene do not cause cancer, but are the cause of a syndrome characterized by severe hypoglycemia, asymmetrical growth, and increased adiposity [99].”
Gao, M., & Kaiser, C. A. (2006) · Nature Cell Biology · doi:10.1038/ncb1419 · Cited by 174 · see citing works
Class III PI-3-kinase activates phospholipase D in an amino acid–sensing mTORC1 pathway
Yoon, M., Du, G., Backer, J., Frohman, M. A., & Chen, J. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201107033 · Cited by 161 · see citing works
The Late Endosome is Essential for mTORC1 Signaling
Flinn, R. J., Yan, Y., Goswami, S., Parker, P. J., & Backer, J. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-09-0756 · Cited by 158 · see citing works
TOR1 and TOR2 Have Distinct Locations in Live Cells
Sturgill, T. W., Cohen, A., Diefenbacher, M., Trautwein, M., Martin, D. E., & Hall, M. N. (2008) · Eukaryotic Cell · doi:10.1128/ec.00088-08 · Cited by 156 · see citing works
Response of Adult Rats to Low Dietary Levels of Essential Amino Acids
Said, A. K., & Hegsted, D. M. (1970) · Journal of Nutrition · doi:10.1093/jn/100.11.1363 · Cited by 146 · cited 1× · see citing works
“In a striking series of early experiments, depriving rats of a single amino acid, leucine, caused profound weight loss and muscle waste, followed by death [20].”
Heublein, S., Kazi, S., Ogmundsdottir, M. H., Attwood, E. V., Kala, S., Boyd, C. A. R., WILSON, C. G., & Goberdhan, D. C. I. (2010) · Oncogene · doi:10.1038/onc.2010.177 · Cited by 140 · see citing works
Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome
Orloff, M. S., & Eng, C. (2008) · Oncogene · doi:10.1038/onc.2008.237 · Cited by 140 · see citing works
Protein misfolding disorders and macroautophagy
Menzies, F. M., Moreau, K., & Rubinsztein, D. C. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.10.010 · Cited by 129 · cited 1× · see citing works
“Moreover, disruption of lysosomal and autophagic function by the accumulation of misfolded protein aggregates may drive progression of Huntington’s, Parkinson’s, and Alzheimer’s diseases (reviewed in [110]).”
Saito, K. (2005) · The Journal of Biochemistry · doi:10.1093/jb/mvi046 · Cited by 128 · cited 18× · see citing works
“Among its many targets, AMPK directly phosphorylates TSC2 [10,11]; but in contrast to Akt, AMPK-dependent phosphorylation of TSC2 stimulates the GTPase activity of TSC, inhibiting Rheb.”
InfluentialSTRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice
Orlova, K. A., Parker, W. E., Heuer, G. G., Tsai, V., Yoon, J. T., Baybis, M., Fenning, R. S., Strauss, K. A., & Crino, P. B. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41592 · Cited by 112 · cited 2× · see citing works
“Orlova KA, et al. STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.”
Gong, R., Li, L., Liu, Y., Wang, P., Yang, H., Wang, L., Cheng, J., Guan, K.-L., & Xu, Y. (2011) · Genes & Development · doi:10.1101/gad.16968011 · Cited by 98 · cited 1× · see citing works
“Even more intriguingly, the recently reported crystal structure of the Gtr1–Gtr2 C-terminal domain displays a remarkable similarity to both the Ego2–3 and the LAMTOR2–3 dimer [48], and the same structural feature is predicted to exist in the Cterminal domain of the mammalian RagA–RagC heterodimer.”
BackgroundLevdikov, V. M., Blagova, E. V., Joseph, P., Sonenshein, A. L., & Wilkinson, A. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513015200 · Cited by 97 · cited 1× · see citing works
“Many prokaryotes possess proteins dedicated to sensing amino acids, which allow them to couple nutrient availability to the regulation of multiple physiological processes [16,17].”
BackgroundBun‐ya, M., Harashima, S., & Oshima, Y. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.7.2958 · Cited by 95 · see citing works
Kurzbauer, R., Teis, D., de Araujo, M. E. G., Maurer-Stroh, S., Eisenhaber, F., Bourenkov, G. P., Bartunik, H. D., Hekman, M., Rapp, U. R., Huber, L. A., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403435101 · Cited by 95 · cited 3× · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript crystal structure of Ego2–3 was recently solved and found to be very similar to that of LAMTOR2–3 [46,47].”
ResultRagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway
Hirose, E., Nakashima, N., Sekiguchi, T., & Nishimoto, T. (1998) · Journal of Cell Science · doi:10.1242/jcs.111.1.11 · Cited by 89 · see citing works
Zurita-Martinez, S. A., Puria, R., Pan, X., Boeke, J. D., & Cardenas, M. E. (2007) · Genetics · doi:10.1534/genetics.107.072835 · Cited by 88 · cited 1× · see citing works
“Remarkably, many of these genes were membrane traffic regulators, including lipid kinases such as the type III PI3-Kinase Vps34 as well as small GTPases and endosomal tethering complexes [36,37].”
BackgroundAttractant Signaling by an Aspartate Chemoreceptor Dimer with a Single Cytoplasmic Domain
Gardina, P. J., & Manson, M. D. (1996) · Science · doi:10.1126/science.274.5286.425 · Cited by 86 · cited 1× · see citing works
“Many prokaryotes possess proteins dedicated to sensing amino acids, which allow them to couple nutrient availability to the regulation of multiple physiological processes [16,17].”
Kogan, K., Spear, E. D., Kaiser, C. A., & Fass, D. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.07.034 · Cited by 56 · cited 3× · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript crystal structure of Ego2–3 was recently solved and found to be very similar to that of LAMTOR2–3 [46,47].”
Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin
Ruivo, R., Bellenchi, G. C., Chen, X., Zifarelli, G., Sagné, C., Debacker, C., Pusch, M., Supplisson, S., & Gasnier, B. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115581109 · Cited by 50 · see citing works
Puria, R., Zurita-Martinez, S. A., & Cardenas, M. E. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801087105 · Cited by 48 · see citing works
Lysosomal pool of free-amino acids
Harms, E., Gochman, N., & Schneider, J. A. (1981) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(81)91239-0 · Cited by 35 · cited 1× · see citing works
“Similarly, there is evidence that mammalian lysosomes may maintain a stable pool of luminal amino acids [53].”
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Signals from the lysosome: a control centre for cellular clearance and energy metabolism
Settembre, C., Fraldi, A., Medina, D. L., & Ballabio, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3565 · Cited by 1,689 · see citing works
Sestrin2 is a leucine sensor for the mTORC1 pathway
Wolfson, R. L., Chantranupong, L., Saxton, R. A., Shen, K., Scaria, S. M., Cantor, J. R., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aab2674 · Cited by 1,306 · see citing works
Self-citationPromoting Health and Longevity through Diet: From Model Organisms to Humans
Fontana, L., & Partridge, L. (2015) · Cell · doi:10.1016/j.cell.2015.02.020 · Cited by 1,245 · see citing works
“Dietary protein intake is an important regulator of the IGF-1/mTOR network (Efeyan et al, 2012).”
InfluentialNutrient-sensing mechanisms and pathways
Efeyan, A., Comb, W. C., & Sabatini, D. M. (2015) · Nature · doi:10.1038/nature14190 · Cited by 1,110 · see citing works
The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway
Chantranupong, L., Scaria, S. M., Saxton, R. A., Gygi, M. P., Shen, K., Wyant, G. A., Wang, T., Harper, J. W., Gygi, S. P., & Sabatini, D. M. (2016) · Cell · doi:10.1016/j.cell.2016.02.035 · Cited by 843 · see citing works
“…effects stem at least in part from the ability of arginine to activate mTORC1, a master growth controller that integrates diverse environmental inputs to coordinate many anabolic and catabolic processes in cells (Ban et al., 2004; Dibble and Manning, 2013; Efeyan et al., 2012; Hara et al., 1998).”
Self-citationWang, S., Tsun, Z., Wolfson, R. L., Shen, K., Wyant, G., Plovanich, M. E., Yuan, E. D., Jones, T. D., Chantranupong, L., Comb, W. C., et al. (2015) · Science · doi:10.1126/science.1257132 · Cited by 772 · see citing works
Regulation of mTORC1 by amino acids
Bar-Peled, L., & Sabatini, D. M. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.03.003 · Cited by 773 · see citing works
“Although it was clear for over a decade that amino acids were vital for mTORC1 activation, precisely how this signal functioned remained a mystery (32, 33).”
p62/ SQSTM 1 functions as a signaling hub and an autophagy adaptor
Katsuragi, Y., Ichimura, Y., & Komatsu, M. (2015) · FEBS Journal · doi:10.1111/febs.13540 · Cited by 795 · see citing works
The lysosome: from waste bag to potential therapeutic target
Appelqvist, H., Wäster, P., Kågedal, K., & Öllinger, K. (2013) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjt022 · Cited by 772 · see citing works
“The mammalian target of rapamycin (mTOR) is central for regulation of the autophagic activity and senses the energy status by integrating signals from, for example, growth factors, amino acids, and glucose (Efeyan et al., 2012).”
BackgroundHealth Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms
Tosti, V., Bertozzi, B., & Fontana, L. (2018) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glx227 · Cited by 762 · see citing works
“The activation of the pro-aging and procancer mTOR pathways is modulated by energy intake but also by a cocktail of different essential amino acids, with the branched-chain amino acids leucine and isoleucine playing a fundamental role (82).”
Nutrient sensing and TOR signaling in yeast and mammals
González, A., & Hall, M. (2017) · EMBO Journal · doi:10.15252/embj.201696010 · Cited by 684 · see citing works
“Finally, mutations affecting mammalian amino acid sensing components are linked to immunodeficiency, epilepsy, and cancer (Shimobayashi & Hall, 2015), and mTOR is often deregulated in metabolic disorders such as obesity, diabetes, and cancer (Efeyan et al , 2012; Liko & Hall, 2015).”
Neinast, M. D., Murashige, D., & Arany, Z. P. (2018) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114455 · Cited by 727 · see citing works
Placental Origins of Chronic Disease
Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · see citing works
The role of ubiquitination in tumorigenesis and targeted drug discovery
Deng, L., Meng, T., Chen, L., Wei, W., & Wang, P. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0107-0 · Cited by 744 · see citing works
The 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
“…as a cellular nutrient depot, a function that is evolutionarily conserved from fungi to higher eukaryotes (Chantranupong et al. 2015, Efeyan et al. 2012, Li & Kane 2009). mTORC1 is found on the surfaces of lysosomes and vacuoles in both yeast and metazoan cells, and the mechanisms…”
BackgroundInfluentialmTORC1 signaling and the metabolic control of cell growth
Ben‐Sahra, I., & Manning, B. D. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.02.012 · Cited by 641 · see citing works
“However, cells and organisms possess distinct systems to sense fluctuations in nutrients and energy to properly adapt their metabolic state to nutrient availability (feast) or depletion (famine) [1].”
BackgroundStress granules and cell signaling: more than just a passing phase?
Kedersha, N., Ivanov, P. V., & Anderson, P. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.07.004 · Cited by 633 · see citing works
Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae
Conrad, M., Schothorst, J., Kankipati, H., Zeebroeck, G. V., Rubio‐Texeira, M., & Thevelein, J. (2014) · FEMS Microbiology Reviews · doi:10.1111/1574-6976.12065 · Cited by 616 · see citing works
“Gtr1 and Gtr2 are Ras-family GTPases represented in metazoans by the orthologous Rag GTPases, Rag A-D (Sancak et al., 2008; Efeyan et al., 2012).”
BackgroundDisrupting proton dynamics and energy metabolism for cancer therapy
Parks, S. K., Chiche, J., & Pouysségur, J. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3579 · Cited by 613 · see citing works
Tsun, 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
“When RagA/B is loaded with GTP, the Rag heterodimer recruits mTORC1 to the lysosomal surface where it binds Rheb and becomes activated (Bar-Peled et al., 2013; Bar-Peled et al., 2012; Efeyan et al., 2012).”
Colacurcio, D. J., & Nixon, R. A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.004 · Cited by 548 · see citing works
“This process occurs via amino acid-regulated associations between the v-ATPase, Rag-GTPases, and Ragulator, ultimately allowing the v-ATPase to promote lysosomal function while functioning as a signaling molecule for nutrient sensing (Efeyan et al., 2012; Sancak et al., 2010; Sancak et al., 2008).”
BackgroundThe MAPK and AMPK signalings: interplay and implication in targeted cancer therapy
Yuan, J., Dong, X., Yap, J., & Hu, J. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00949-4 · Cited by 500 · see citing works
“The mTORC1 is a central sensor of cellular amino acids that samples amino acids in both cytosol and lysosome [184, 185].”
BackgroundChantranupong, 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 must be present in the cellular environment for mTORC1 to be active and are sensed through a signaling pathway that culminates with the nucleotide loading of the Rag GTPases (reviewed in Bar-Peled and Sabatini, 2014; Efeyan et al., 2012; Kim et al., 2013; Yuan et al., 2013).”
Paull, T. T. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-034335 · Cited by 458 · see citing works
Grabiner, B., Nardi, V., Birsoy, K., Possemato, R., Shen, K., Sinha, S., Jordan, A. A., Beck, A. H., & Sabatini, D. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0929 · Cited by 418 · see citing works
“The kinase activity of mTOR is tightly regulated by nutrient availability; when cells are starved of nutrients (specifically glucose and amino acids), they downregulate mTORC1 signaling, while retreatment of cells with these nutrients restores mTORC1-mediated signaling (26).”
BackgroundRegulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2
Demetriades, C., Doumpas, N., & Teleman, A. A. (2014) · Cell · doi:10.1016/j.cell.2014.01.024 · Cited by 412 · see citing works
Nutrient signaling to mTOR and cell growth
Jewell, J. L., & Guan, K. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.01.004 · Cited by 407 · see citing works
Brief update on endocytosis of nanomedicines
Patel, S., Kim, J., Herrera‐Barrera, M., Mukherjee, A., Kabanov, A. V., & Sahay, G. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.08.004 · Cited by 402 · see citing works
“However, long overlooked as a static organelle, lysosomes are now known to be a dynamic hub of cellular activity, including cellular metabolism, nutrient sensing, subcellular localization-dependent pH control, plasma membrane repair, secretion, and spatiotemporal intracellular signaling [52,21,53,22,20].”
BackgroundAmmonium as a signal for physiological and morphological responses in plants
Liu, Y., & Nicolaus Von Wirén, A. (2017) · Journal of Experimental Botany · doi:10.1093/jxb/erx086 · Cited by 395 · see citing works
MYC and metabolism on the path to cancer
Hsieh, A. L., Walton, Z. E., Altman, B. J., Stine, Z. E., & Dang, C. V. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.08.003 · Cited by 337 · see citing works
The 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
“For instance, budding yeast lacks a canonical insulin-PI3K pathway, thus negating the need for a coincidence detection mechanism (Efeyan et al., 2012). mTORC1 activation by the PI3K-RHEB axis The small GTPase Ras homologue enriched in brain (RHEB) contains a C-terminal farnesylation motif that…”
BackgroundArginine dependence of tumor cells: targeting a chink in cancer’s armor
Patil, M. D., Bhaumik, J., Babykutty, S., Banerjee, U. C., & Fukumura, D. (2016) · Oncogene · doi:10.1038/onc.2016.37 · Cited by 268 · see citing works
Liu, P., Gan, W., Inuzuka, H., Lazorchak, A. S., Gao, D., Arojo, O., Liu, D., Wan, L., Zhai, B., Yu, Y., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2860 · Cited by 256 · see citing works
“As most mTORC1 functions are high energy consuming, regulation of mTORC1 activity is tightly coupled to the energy status of the cell and regulated by nutrients, energy, stress and growth factors, thereby ensuring that cells stop growing under unfavorable conditions 1,8,21,22 .”
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
“These discoveries set the stage for several important reports detailing how amino acids contribute to mTORC1 activation in animal cells (Efeyan et al., 2012).”
BackgroundRestraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency
Liang, R. H.-S., Arif, T., Kalmykova, S., Kasianov, A. S., Miao, L., Menon, V., Qiu, J., Bernitz, J. M., Moore, K. A., Lin, F., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.01.013 · Cited by 248 · see citing works
“, mitochondria in quiescent HSCs) reduces ROS levels, possibly modulates amino acid efflux and mTOR activation toward HSC priming (Figure S7C, model), and contributes to carbon mass for cell proliferation (Efeyan et al., 2012; Hosios et al., 2016).”
BackgroundBoosting intracellular delivery of lipid nanoparticle-encapsulated mRNA
Patel, S., Ashwanikumar, N., Robinson, E., DuRoss, A., Sun, C., Murphy-Benenato, K. E., Mihai, C., Almarsson, Ö., & Sahay, G. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b02664 · Cited by 251 · see citing works
The crucial impact of lysosomes in aging and longevity
Carmona‐Gutiérrez, D., Hughes, A. L., Madeo, F., & Ruckenstuhl, C. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.04.009 · Cited by 244 · see citing works
Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A
Son, S. M., Park, S. J., Lee, H., Siddiqi, F. H., Lee, J. E., Menzies, F. M., & Rubinsztein, D. C. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.08.013 · Cited by 243 · see citing works
“Activation of the mTORC1 pathway by AAs correlates with the translocation of mTORC1 from undefined locations to lysosomes where it encounters RHEB, a potent mTORC1 activator (Efeyan et al., 2012; Sancak et al., 2008).”
The S6K protein family in health and disease
Tavares, M. R., Pavan, I. C. B., do Amaral, C. L., Meneguello, L., Luchessi, A. D., & Simabuco, F. M. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.03.001 · Cited by 237 · see citing works
Gallinetti, J., Harputlugil, E., & Mitchell, J. R. (2012) · Biochemical Journal · doi:10.1042/bj20121098 · Cited by 231 · see citing works
Role of amino acid transporters in amino acid sensing
Taylor, P. M. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.070086 · Cited by 215 · see citing works
AMPK and autophagy in glucose/glycogen metabolism
Ha, J., Guan, K., & Kim, J. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2015.08.002 · Cited by 211 · see citing works
The role of TRPMLs in endolysosomal trafficking and function
Venkatachalam, K., Wong, C., & Zhu, M. X. (2014) · Cell Calcium · doi:10.1016/j.ceca.2014.10.008 · Cited by 202 · see citing works
“As a consequence, increased lysosomal rotein degradation ensues resulting in amino acid replenishment, eactivation of MTORC1, and cessation of autophagosome biogensis [117,118].”
Autophagy and Its Normal and Pathogenic States in the Brain
Yamamoto, A., & Yue, Z. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014149 · Cited by 204 · see citing works
“…level, starvation is translated into signaling through the large, serine/threonine kinase mTOR (mammalian target of rapamycin). mTOR is found in two different complexes (reviewed in Efeyan et al. 2012) and in the form of mTORC1 (mTOR complex I) acts as a negative regulator of macroautophagy.”
BackgroundThe renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives
Cherqui, S., & Courtoy, P. J. (2016) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.182 · Cited by 203 · see citing works
“In turn, impaired proteolysis could affect lysosomal amino acid sensors , such as mTORC1, thereby affecting lysosomal signalling 132 (FIG.”
High dietary protein intake, reducing or eliciting insulin resistance?
Rietman, A., Schwarz, J., Tomé, D., Kok, F. J., & Mensink, M. (2014) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2014.123 · Cited by 202 · see citing works
Tumor Suppression and Promotion by Autophagy
Ávalos, Y., Canales, J., Bravo, R., Criollo, A., Lavandero, S., & Quest, A. F. G. (2014) · BioMed Research International · doi:10.1155/2014/603980 · Cited by 197 · see citing works
“Here, in this brief review,wewill focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.”
Eukaryotic V-ATPase: Novel structural findings and functional insights
Marshansky, V. N., Rubinstein, J. L., & Grüber, G. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.01.018 · Cited by 196 · see citing works
Regulation of autophagy by amino acids and MTOR-dependent signal transduction
Meijer, A., Lorin, S., Blommaart, E., & Codogno, P. (2014) · Amino Acids · doi:10.1007/s00726-014-1765-4 · Cited by 175 · see citing works
“the participation of other amino acid transporters in the lysosomal membrane cannot be ruled out (Efeyan et al. 2012).”
BackgroundEukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles
Kenney, J. W., Moore, C. E., Xuemin, W., & Proud, C. G. (2014) · Advances in Biological Regulation · doi:10.1016/j.jbior.2014.04.003 · Cited by 182 · see citing works
Optimal body weight for health and longevity: bridging basic, clinical, and population research
Fontana, L., & Hu, F. B. (2014) · Aging Cell · doi:10.1111/acel.12207 · Cited by 157 · see citing works
“Excessive intake of energy and essential amino acids stimulates this pathway, whereas calorie and protein restriction inhibits its activity (Giovannucci et al., 2003; Fontana et al., 2008, 2010; Efeyan et al., 2012; Mercken et al., 2013).”
BackgroundLysosomal recruitment of TSC2 is a universal response to cellular stress
Demetriades, C., Plescher, M., & Teleman, A. A. (2016) · Nature Communications · doi:10.1038/ncomms10662 · Cited by 160 · see citing works
Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney
Festa, B. P., Chen, Z., Berquez, M., Debaix, H., Tokonami, N., Prange, J. A., van de Hoek, G., Cremonesi, A., Raimondi, A., Névo, N., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02536-7 · Cited by 154 · see citing works
“…in LSD may include the following: storage of cholesterol in the endolysosome membranes 45 ; luminal oxidation of lysosomal thiols by free cystine 10 ; and accumulation of cystine sustaining mTORC1 activity and negatively regulating lysosome biogenesis by suppressing TFE/MiTF signaling 46,47 .”
The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease
Eaton, A. F., Merkulova, M., & Brown, D. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00442.2020 · Cited by 157 · see citing works
Guan, B.-J., Krokowski, D., Majumder, M., Schmotzer, C., Kimball, S., Merrick, W., Koromilas, A., & Hatzoglou, M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.543215 · Cited by 159 · see citing works
“Therefore, it is possible that the degree of mTORC1 inhibition will be reflected from differential responses of the mRNAs that are reported as being under the translational control of mTORC1-dependent signaling (78, 79).”
BackgroundKinghorn, K. J., Grönke, S., Castillo-Quan, J. I., Woodling, N. S., Li, L., Sirka, E., Gegg, M. E., Mills, K. A., Hardy, J., Bjedov, I., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4527-15.2016 · Cited by 157 · see citing works
“The nutrient-sensing mTOR is localized to the lysosomal surface (Efeyan et al., 2012; Betz and Hall, 2013), where it modulates autophagy (Yu et al., 2010; Zoncu et al., 2011).”
BackgroundRegulation of autophagy by protein post-translational modification
Wani, W. Y., Boyer‐Guittaut, M., Dodson, M. B., Chatham, J. C., Darley-Usmar, V. M., & Zhang, J. (2014) · Laboratory Investigation · doi:10.1038/labinvest.2014.131 · Cited by 156 · see citing works
“ATG9 (6) and LC3 (7) are also regulated by phosphorylation.”
BackgroundBone and skeletal muscle: Key players in mechanotransduction and potential overlapping mechanisms
Goodman, C. A., Hornberger, T. A., & Robling, A. G. (2015) · Bone · doi:10.1016/j.bone.2015.04.014 · Cited by 155 · see citing works
“The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.”
BackgroundMitochondrial long non-coding RNA GAS5 tunes TCA metabolism in response to nutrient stress
Sang, L., Ju, H., Yang, Z., Ge, Q., Zhang, Z., Liu, F., Yang, L.-J., Gong, H., Shi, C., Qu, L., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00325-z · Cited by 153 · see citing works
Valapala, M., Wilson, C., Hose, S., Bhutto, I. A., Grebe, R., Dong, A., Greenbaum, S., Gu, L., Sengupta, S., Cano, M., et al. (2014) · Autophagy · doi:10.4161/auto.27292 · Cited by 144 · see citing works
“MTORC1 is a kinase that regulates the cellular response to amino acids, growth factors, and changing energy levels within the cell.(46) We have previously shown that in astrocytes, CRYBA1 can regulate MTOR signaling by modulating IGF2 (insulin-like growth factor 2 [somatomedin A]).”
Nowosad, A., Jeannot, P., Callot, C., Creff, J., Perchey, R. T., Joffre, C., Codogno, P., Manenti, S., & Besson, A. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0554-4 · Cited by 144 · see citing works
Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism
Dubland, J. A., & Francis, G. A. (2015) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2015.00003 · Cited by 143 · see citing works
“The reader is directed elsewhere for further information regarding upstream signaling mechanisms of autophagy through mTORC1 (He and Klionsky, 2009; Efeyan et al., 2012; Shanware et al., 2013; Sergin and Razani, 2014).”
BackgroundLassen, K. G., McKenzie, C. I., Mari, M. C., Murano, T., Begun, J., Baxt, L. A., Goel, G., Villablanca, E. J., Kuo, S.-Y., Huang, H., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.007 · Cited by 139 · see citing works
“…differences between WT and Gpr65 (cid:1) / (cid:1) BMDMs identified differential regulation of genes implicated in lysosomal function ( Atp6v1d and Atp6v1e1 ) and vesicular transport ( Snx10 ), suggesting potential dysregulation of these processes (Figure S5A; Efeyan et al., 2012; Qin et al., 2006).”
Role of p62/SQSTM1 in liver physiology and pathogenesis
Manley, S., Williams, J. A., & Ding, W.-X. (2013) · Experimental Biology and Medicine · doi:10.1177/1535370213489446 · Cited by 135 · see citing works
“Growth factors or insulin activates classI-phosphatidylinosital-3 kinase (PI3K) and AKT, which leads to mTOR activation through the tuberous sclerosis complex protein (TSC)-Rheb signalling cascade.(142) Activation of mTOR then shuts down autophagy, which is a cellular catabolic process, by regulating the ULK1-FIP200At…”
BackgroundGoodman, C. A. (2013) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/112_2013_17 · Cited by 139 · see citing works
“the role of Rag GTPases see (Efeyan et al. 2012)].”
Effects of Interferons and Viruses on Metabolism
Fritsch, S. D., & Weichhart, T. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00630 · Cited by 134 · see citing works
“Only if sufficient amino acids are present, full mTORC1 activation by growth factors or PRR ligands occurs (142, 143).”
BackgroundDechant, R. C., Saad, S., Ibáñez, A. J., & Peter, M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.06.002 · Cited by 135 · see citing works
“…to be regulated by glucose in yeast andmammals (Csibi et al., 2013; Efeyan et al., 2013; Fingar and Blenis, 2004; Kalender et al., 2010; Urban et al., 2007), it is Cytosolic pH Regulates Cell Growth best known for its function in sensing amino acid availability (Broach, 2012; Efeyan et al., 2012).”
Foster, D. A., Salloum, D., Menon, D., & Frías, M. A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.566091 · Cited by 133 · see citing works
“This is an open access article under the CC BY license. essential amino acids activate mTOR via Rag GTPases at the lysosomal membrane (27), it was surprising that suppression of mTOR blocked cell cycle progression at a site later in G1 than the checkpoints that monitor the presence of essential amino acids and Gln (25…”
BackgroundFontana, L., Adelaiye-Ogala, R. M., Rastelli, A. L., Miles, K. M., Ciamporcero, E. S., Longo, V. D., Nguyen, H. M., Vessella, R. L., & Пили, Р. (2013) · Oncotarget · doi:10.18632/oncotarget.1586 · Cited by 132 · see citing works
“High circulating levels of IGF-1 are associated with increased risk of PCa and BC [9-11], Moreover, multiple lines of evidence have shown that activation of the PI3K/ AKT/mTOR pathway, through insulin/IGF-1 stimulation and/or high levels of essential amino acids, play a crucial role in maintaining the malignant phenot…”
BackgroundMegat, S., Ray, P. R., Moy, J. K., Lou, T., Barragán‐Iglesias, P., Li, Y., Pradhan, G., Wangzhou, A., Ahmad, A., Burton, M. D., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2661-18.2018 · Cited by 128 · see citing works
“We discovered a large number of translationally upregulated mRNAs that compose the interface of mTORC1 signaling with the lysosome (Efeyan et al., 2012; Bar-Peled and Sabatini, 2014) (Fig.”
BackgroundLigand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration
Rainero, E., Howe, J. D., Caswell, P. T., Jamieson, N. B., Anderson, K. I., Critchley, D. R., Machesky, L. M., & Norman, J. C. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.037 · Cited by 126 · see citing works
“406 Cell Reports 10, 398–413, January 20, 2015 a2015 The Authors is integral to this (Efeyan et al., 2012).”
Lysosomal adaptation: how the lysosome responds to external cues
Settembre, C., & Ballabio, A. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016907 · Cited by 126 · see citing works
“The mTORC1 complex includes the regulatory proteins RAPTOR (regulatory-associated protein of mTOR), mLST8 (mammalian lethal with SEC13 protein), and DEPTOR (DEP domain-containing mTOR-interacting protein) (Efeyan et al. 2012).”
BackgroundThe ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation.
Deng, L., Jiang, C., Chen, L., Jin, J.-L., Wei, J., Zhao, L., Chen, M., Pan, W., Xu, Y., Chu, H., et al. (2015) · Molecules and Cells · doi:10.1016/j.molcel.2015.03.033 · Cited by 113 · see citing works
“Because the amino-acid-induced activation of mTORC1 requires the formation of heterodimers of RagA with RagC or RagD (Sekiguchi et al., 2001), we determined whether RagA ubiquitination is affected by the presence of RagC.”
BackgroundInfluentialLipid sensing by mTOR complexes via de novo synthesis of phosphatidic acid
Menon, D., Salloum, D., Bernfeld, E., Sher, E. F., Akselrod, A., Frías, M. A., Sudderth, J., Chen, P.-H., DeBerardinis, R. J., & Foster, D. A. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.772988 · Cited by 124 · see citing works
“Althoughmuchisknownaboutthedependence of mTORC1 on amino acids (4), less is known about the ability of mTOR to respond to the presence of other nutrients essential for cell growth, such as glucose and lipids.”
BackgroundWill calorie restriction work in humans?
Cava, E., & Fontana, L. (2013) · Aging · doi:10.18632/aging.100581 · Cited by 122 · see citing works
“regulating mTOR activity, serum IGF-1 concentrations, and longevity [2, 38, 49-54].”
BackgroundPathogenicity and Virulence of Legionella : Intracellular replication and host response
Chauhan, D., & Shames, S. R. (2021) · Virulence · doi:10.1080/21505594.2021.1903199 · Cited by 113 · see citing works
Krokowski, D., Han, J., Saikia, M., Majumder, M., Yuan, C. L., Guan, B., Bevilacqua, E., Bussolati, O., Bröer, S., Arvan, P. R., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.466920 · Cited by 115 · see citing works
“It is well established that Leu uptake or feeding increases protein synthesis in cells and tissues via mechanisms that activate mTORC1 (48, 49).”
BackgroundPoncet, N., Mitchell, F. E., Ibrahim, A. F. M., McGuire, V. A., English, G., Arthur, J. S. C., Shi, Y., & Taylor, P. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089547 · Cited by 114 · see citing works
“The exact mechanism by which leucine activates mTORC1 signalling is still not fully resolved but both cytosolic and lysosomal leucine-sensors have been described [1,2].”
BackgroundSEACing the GAP that nEGOCiates TORC1 activation
Panchaud, N., Péli-Gulli, M.-P., & Virgilio, C. D. (2013) · Cell Cycle · doi:10.4161/cc.26000 · Cited by 112 · see citing works
“When RagA, RagB, or Gtr1 is bound to GTP, and RagC, RagD, or Gtr2 to GDP, the respective heterodimer is in its active, TORC1-stimulating conformation.8-11 In mammalian cells, Rag GTPases do not directly activate TORC1, but trigger TORC1 relocalization from the cytoplasm to the limiting membrane of the lysosome, where…”
BackgroundMacropinocytosis, mTORC1 and cellular growth control
Yoshida, S., Pacitto, R., Inoki, K., & Swanson, J. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2710-y · Cited by 114 · see citing works
Starved epithelial cells uptake extracellular matrix for survival
Muranen, T. E., Iwanicki, M., Curry, N. L., Hwang, J., DuBois, C. D., Coloff, J. L., Hitchcock, D. S., Clish, C. B., Brugge, J. S., & Kalaany, N. Y. (2017) · Nature Communications · doi:10.1038/ncomms13989 · Cited by 110 · see citing works
“I3K and mTOR signalling plays a key role in mediating cellular responses to growth factor and nutrient availability 1,2 .”
Ramalingam, M., Huh, Y.-J., & Lee, Y. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01028 · Cited by 108 · see citing works
Lundquist, M. R., Goncalves, M. D., Loughran, R. M., Possik, E., Vijayaraghavan, T., Yang, A., Pauli, C., Ravi, A., Verma, A., Yang, Z., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.03.037 · Cited by 106 · see citing works
“In particular, the amino acid arginine, a known activator of mTORC1 (Ban et al., 2004; Dibble and Manning, 2013; Efeyan et al., 2012; Hara et al., 1998), was remarkably decreased (Figure S1F).”
BackgroundGrowth factor signaling to mTORC1 by amino acid–laden macropinosomes
Yoshida, S., Pacitto, R., Yao, Y., Inoki, K., & Swanson, J. A. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201504097 · Cited by 105 · see citing works
“Cell growth is regulated by mechanistic target of rapamycin complex-1 (mTORC1), a complex of cytosolic proteins that is activated by growth factor receptor signaling, tumor-promoting phorbol esters, and increased levels of amino acids inside endolysosomes (Roux et al., 2004; Efeyan et al., 2012).”
BackgroundCaloric restriction and cellular senescence
Fontana, L., Nehme, J., & Demaria, M. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.10.005 · Cited by 104 · see citing works
“Energy and amino acids restriction cause an inhibition of mTORC1 activity, which in turn enhances autophagy, improves proteostasis and stem cell function 61 .”
BackgroundFirst we eat, then we do everything else: The dynamic metabolic regulation of efferocytosis
Trzeciak, A. J., Wang, Y., & Perry, J. S. A. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.001 · Cited by 107 · see citing works
Säftig, P., & Haas, A. (2016) · Nature Cell Biology · doi:10.1038/ncb3409 · Cited by 102 · see citing works
Functional role of branched chain amino acids in poultry: a review
Kim, W. K., Singh, A. K., Wang, J., & Applegate, T. J. (2022) · Poultry Science · doi:10.1016/j.psj.2022.101715 · Cited by 102 · see citing works
“In addition to being utilized in various metabolic pathways, BCAA regulate gene expression and signal transduction for protein synthesis (Efeyan et al., 2012; Bai et al., 2015).”
BackgroundLeucine is a major regulator of muscle protein synthesis in neonates
Columbus, D. A., Fiorotto, M. L., & Davis, T. A. (2014) · Amino Acids · doi:10.1007/s00726-014-1866-0 · Cited by 102 · see citing works
“1 3 acids act to stimulate protein synthesis through mTOR is less well understood, however, it is widely accepted that amino acids stimulate protein synthesis through a pathway independent of the insulin signaling cascade (Efeyan et al. 2012).”
New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators
Sun, X., Su, Y., He, Y., Zhang, J., Liu, W., Zhang, H., Hou, Z., Liu, J., & Li, J. (2015) · Cell Cycle · doi:10.1080/15384101.2014.995496 · Cited by 101 · see citing works
“Heterodimeric complex of tuberous sclerosis complex 1 (TSC1 or hamartin) and TSC2 (or tuberin) is one of the most important sensors involved in the negative regulation of mTORC1 activity.(16) Mice lacking Tsc1 or Tsc2 genes in oocytes all showed an identical phenotype with premature activation of all primordial follic…”
BackgroundLysosomes and Cancer Progression: A Malignant Liaison
Machado, E., Annunziata, I., van de Vlekkert, D., Grosveld, G., & d'Azzo, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.642494 · Cited by 92 · see citing works
“Last but not least, activation and deregulation of mTORC1 affecting autophagy and lysosomal biogenesis have been implicated in malignant transformation and in sustaining cancer growth, but this subject has been extensively discussed in several reviews (McCarty, 2011; Efeyan et al., 2012; Kimmelman and White, 2017; Sax…”
BackgroundFOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis
Zhang, X., Campreciós, G., Rimmelé, P., Liang, R. H.-S., Yalcin, S., Mungamuri, S. K., Barminko, J., d’Escamard, V., Baron, M. H., Brugnara, C., et al. (2014) · American Journal of Hematology · doi:10.1002/ajh.23786 · Cited by 93 · see citing works
“While transcripts for Tsc1 that is an upstream negative regulator of mTOR signaling [63] were highly reduced in Foxo3 mutant”
BackgroundParikh, P., Semba, R. D., MANARY, M. J., Swaminathan, S., Udomkesmalee, E., Bos, R., Poh, B. K., Rojroongwasinkul, N., Geurts, J. M. W., Sekartini, R., et al. (2021) · Maternal and Child Nutrition · doi:10.1111/mcn.13264 · Cited by 95 · see citing works
“The mammalian (or mechanistic) target of rapamycin (mTOR) is a master growth regulator (Laplante & Sabatini, 2012) that functions as a signal integrator combining regulatory inputs from nutrients, growth factors, energy levels and stress signals (Efeyan et al., 2012).”
BackgroundHuman Skeletal Muscle Protein Metabolism Responses to Amino Acid Nutrition
Mitchell, W. K., Wilkinson, D. J., Phillips, B. E., Lund, J. N., Smith, K., & Atherton, P. J. (2016) · Advances in Nutrition · doi:10.3945/an.115.011650 · Cited by 95 · see citing works
“, p70S6K1) because the kinase activity of mTORC1 has multiple inputs (beyond phosphorylation), including cellular localization and varying affinity to its binding partners (89).”
BackgroundAutophagy, Cellular Aging and Age-related Human Diseases
Cheon, S. Y., Kim, H. J., Rubinsztein, D. C., & Lee, J. E. (2019) · Experimental Neurobiology · doi:10.5607/en.2019.28.6.643 · Cited by 92 · see citing works
“Amino acids negatively regulate autophagy via mammalian target of rapamycin (mTOR) signaling, a negative regular of autophagy [14].”
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“for Clinical Nutrition and Metabol cell growth or activate energy sparing processes (for a more detailed review see [3,4]).”
BackgroundSubcellular Trafficking of Mammalian Lysosomal Proteins: An Extended View
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“The multiprotein complex mTORC1, which regulates cellular growth and metabolism, localizes in the cytosol under low amino acids conditions, and is recruited on the lysosomal membrane when amino acids are abundant [149,150].”
BackgroundLysosomes: regulators of autophagy in the retinal pigmented epithelium
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“The mTORC1 pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes and neurodegeneration (Efeyan et al., 2012).”
BackgroundRab1 in cell signaling, cancer and other diseases
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mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership
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“Activation of mTORC1 by nutrients and/or growth factors typically promotes protein synthesis while, at the same time, suppressing catabolic processes [79,80].”
Background
- Authors
- Efeyan, A., Zoncu, R., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Zoncu, Roberto
- Sabatini, David M.
- Venue
- Trends in Molecular Medicine
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 18
- Issue
- 9
- Pages
- 524-533
- ISSN
- 1471-4914 (ISSN-L)
- PMC
- PMC3432651
- OpenAlex
- W2059716825
- Cited by
- 436
- References
- 112
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 14 · 2023: 21 · 2022: 22 · 2021: 36 · 2020: 34 · 2019: 29 · 2018: 29 · 2017: 36 · 2016: 50 · 2015: 60 · 2014: 52 · 2013: 31 · 2012: 1
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Trends in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health (CA129105)
- National Cancer Institute (R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R37AI047389)
- 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
- mTORC1, amino acid signaling, lysosomes, Rag GTPases, Ragulator complex, V-ATPase, nutrient sensing, cancer, neurodegeneration, diabetes mellitus
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Diabetes Mellitus, Humans, Lysosomes, Neoplasms, Neurodegenerative Diseases, Multiprotein Complexes, TOR Serine-Threonine Kinases
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