Regulation of TOR by small GTPases
Open accessAbstract
TOR is a conserved serine/threonine kinase that responds to nutrients, growth factors, the bioenergetic status of the cell and cellular stress to control growth, metabolism and ageing. A diverse group of small GTPases including Rheb, Rag, Rac1, RalA and Ryh1 play a variety of roles in the regulation of TOR. For example, while Rheb binds to and activates TOR directly, Rag and Rac1 regulate its localization and RalA activates it indirectly through the production of phosphatidic acid. Here, we review recent findings on the regulation of TOR by small GTPases.
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Recruitment of (m)TORC1 to the lysosome is controlled predominantly in response to signals corresponding to the intracellular nutrient and energy state, whereas its activation once there is controlled by RhebGTP in response to a wide variety of external and survival signals feeding into a single point of control.
“Whereas recruitment of (m)TORC1 to the lysosome is controlled in response predominantly to signals corresponding to the intracellular nutrient and energy state, its activation once there is controlled by RhebGTP in response to a wide variety of external and survival signals feeding into a single point of control.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Durán and Hall, 2012
The Rag and Rheb GTPases constitute a coincidence detector which cooperate synergistically to robustly induce mTORC1 activity and fail to do so when either is only singly activated under physiologic conditions.
“Together, these GTPases constitute a coincidence detector which cooperate synergistically to robustly induce mTORC1 activity and fail to do so when either is only singly activated under physiologic conditions (Durán and Hall, 2012; Groenewoud and Zwartkruis, 2013).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Durán and Hall, 2012
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Dibble, C. C., & Cantley, L. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.06.002 · Cited by 770 · see citing works
Glutaminolysis Activates Rag-mTORC1 Signaling
Durán, R. V., Oppliger, W., Robitaille, A. M., Heiserich, L., Skendaj, R., Gottlieb, E., & Hall, M. N. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.043 · Cited by 723 · see citing works
“The small GTPases Rheb and Rag directly bind and activate mTORC1 (Durán and Hall, 2012; Kim et al., 2008; Long et al., 2005; Sancak et al., 2008).”
BackgroundSelf-citationStructural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Saxton, R. A., Knockenhauer, K. E., Wolfson, R. L., Chantranupong, L., Pacold, M. E., Wang, T., Schwartz, T. U., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aad2087 · Cited by 457 · see citing works
“Lysosomal amino acids including arginine are thought to signal to the Rags through a lysosomal membrane associated complex consisting of the v-ATPase (15), Ragulator complex (16), and the putative arginine sensor SLC38A9 (17, 18).”
BackgroundTOR Signaling and Nutrient Sensing
Dobrenel, T., Caldana, C., Hanson, J., Robaglia, C., Vincentz, M., Veit, B. E., & Meyer, C. (2016) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-043014-114648 · Cited by 449 · see citing works
mTOR in Brain Physiology and Pathologies
Bockaert, J., & Marin, P. (2015) · Physiological Reviews · doi:10.1152/physrev.00038.2014 · Cited by 360 · see citing works
“In addition to being targets of mTORC2, Rac-GTP and Rac-GDP activate mTORC2 and mTORC1, providing a positive regulatory loop for actin polymerization (69, 249).”
BackgroundBidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling
Appenzeller‐Herzog, C., & Hall, M. N. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.02.006 · Cited by 316 · see citing works
Self-citationRibosomal Protein S6 Phosphorylation: Four Decades of Research.
Meyuhas, O. (2015) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2015.07.006 · Cited by 259 · see citing works
“Members of the Rag subfamily of Ras small GTPases (RagA, B, C, and D) and the trimeric complex, Ragulator, are essential transducers of amino acids signals to mTORC1 activity (Duran and Hall, 2012).”
BackgroundLysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy
Arias, E., Koga, H., Díaz, A., Mocholí, E., Patel, B., & Cuervo, A. M. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.030 · Cited by 280 · see citing works
“Immunoblot for different GTPases previously described to modulate TORC (Duran and Hall, 2012) demonstrated that Rac1, Rheb, RagD and RagB were all present in CMA-active and inactive lysosomes although with different abundance (Fig.”
Rho GTPase signaling in cancer progression and dissemination
Crosas‐Molist, E., Samain, R., Kohlhammer, L., Orgaz, J. L., George, S. L., Maiques, Ó., Barcelo, J., & Sanz‐Moreno, V. (2021) · Physiological Reviews · doi:10.1152/physrev.00045.2020 · Cited by 277 · see citing works
K63 Polyubiquitination and Activation of mTOR by the p62-TRAF6 Complex in Nutrient-Activated Cells
Linares, J. F., Durán, Á., Yajima, T., Pasparakis, M., Moscat, J., & Díaz-Meco, M. T. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.020 · Cited by 256 · see citing works
The race to decipher the top secrets of TOP mRNAs
Meyuhas, O., & Kahan, T. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.08.015 · Cited by 224 · see citing works
“Likewise, members of the Rag subfamily of Ras small GTPases (RagA, B, C and D) and the trimeric complex, Ragulator, are essential transducers of amino acids signals to mTORC1 activity [70].”
BackgroundRole 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
“Rag (Ras-related GTPase) proteins exist as heterodimers of Rag A/B combined with Rag C/D: Rag A/B-GTP and Rag C/D-GDP constitute the “active” forms and the reversed nucleotide orientation the “inactive” forms (27, 28).”
BackgroundEndocytosis and autophagy: Shared machinery for degradation
Lamb, C. A., Dooley, H. C., & Tooze, S. A. (2012) · BioEssays · doi:10.1002/bies.201200130 · Cited by 183 · see citing works
“Rheb Small GTPase Ras homologue enriched in brain; required for mTORC1 activity [98]”
BackgroundRho GTPases in platelet function
Aslan, J. E., & McCarty, O. J. T. (2012) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12051 · Cited by 184 · see citing works
Diverse nitrogen signals activate convergent ROP2-TOR signaling in Arabidopsis
Liu, Y., Duan, X., Zhao, X., Ding, W., Wang, Y., & Xiong, Y. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.03.022 · Cited by 166 · see citing works
Architecture of human Rag GTPase heterodimers and their complex with mTORC1
Anandapadamanaban, M., Masson, G., Perisic, O., Berndt, A., Kaufman, J., Johnson, C. M., Santhanam, B., Rogala, K. B., Sabatini, D., & Williams, R. L. (2019) · Science · doi:10.1126/science.aax3939 · Cited by 124 · see citing works
The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth ControlPreprint
Hindupur, S. K., González, A., & Hall, M. N. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019141 · Cited by 140 · see citing works
Self-citationFoster, 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
“However, knock-out of both PLD1 and PLD2 yields viable mice (32, 33), whereas mTOR knockouts are embryonic lethal (34, 35).”
BackgroundAmino acid activation of mTORC1 by a PB1-domain-driven kinase complex cascade
Linares, J., Duran, A., Reina-Campos, M., Aza-Blanc, P., Campos, A., Moscat, J., & Diaz-Meco, M. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.045 · Cited by 120 · see citing works
“[PubMed: 25201530] Groenewoud MJ, Goorden SM, Kassies J, Pellis-van Berkel W, Lamb RF, Elgersma Y, Zwartkruis FJ. Mammalian target of rapamycin complex I (mTORC1) activity in ras homologue enriched in brain (Rheb)-deficient mouse embryonic fibroblasts.”
BackgroundInfluentialATF6 Regulates Cardiac Hypertrophy by Transcriptional Induction of the mTORC1 Activator, Rheb
Blackwood, E. A., Hofmann, C. P., Domingo, M. S., Bilal, A. S., Sarakki, A., Stauffer, W. T., Arrieta, A., Thuerauf, D. J., Kolkhorst, F. W., Müller, O. J., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.313854 · Cited by 120 · see citing works
Sharma, M., Bhattacharyya, S., Nain, M., Kaur, M., Sood, V., Gupta, V., Khasa, R., Abdin, M. Z., Vrati, S., & Kalia, M. (2014) · Autophagy · doi:10.4161/auto.29455 · Cited by 112 · see citing works
Do, D. N., Ostersen, T., Strathe, A. B., Mark, T., Jensen, J., & Kadarmideen, H. N. (2014) · BMC Genetics · doi:10.1186/1471-2156-15-27 · Cited by 112 · see citing works
“RRAGC encodes for a members of Rag small GTPases, which regulate the growthcontrolling TOR signaling pathway (reviewed in [62]).”
BackgroundRegulation of CD8+ T memory and exhaustion by the mTOR signals
Chen, Y., Xu, Z., Sun, H., Ouyang, X.-X., Han, Y.-H., Yu, H., Wu, N.-B., Xie, Y., & Su, B. (2023) · Cellular & Molecular Immunology · doi:10.1038/s41423-023-01064-3 · Cited by 91 · see citing works
“For example, a Ras homolog enriched in the striatum has been shown to interact with both complexes and activate mTOR activity [200].”
BackgroundMiloslavski, R., Cohen, E., Avraham, A., Iluz, Y., Hayouka, Z., Kasir, J., Mudhasani, R., Jones, S. N., Cybulski, N., Rüegg, M. A., et al. (2014) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mju008 · Cited by 87 · see citing works
“This phosphorylation blocks TSC2 ability to act as a GTPase-activating protein (GAP) for Ras-homolog enriched in brain (Rheb), thereby allowing Rheb-GTP to operate as an activator of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) (Duran and Hall, 2012).”
BackgroundTor forms a dimer through an N-terminal helical solenoid with a complex topology
Baretić, D., Berndt, A., Ohashi, Y., Johnson, C. M., & Williams, R. L. (2016) · Nature Communications · doi:10.1038/ncomms11016 · Cited by 80 · see citing works
Powis, K., Zhang, T., Panchaud, N., Wang, R., Virgilio, C. D., & Ding, J. (2015) · Cell Research · doi:10.1038/cr.2015.86 · Cited by 80 · see citing works
Lu, Q., Wang, M., Gui, Y., Hou, Q., Gu, M., Liang, Y., Xiao, B., Zhao, A. Z., & Dai, C. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2539-4 · Cited by 66 · see citing works
Gordon, B. S., Kazi, A. A., Coleman, C., Dennis, M. D., Chau, V., Jefferson, L., & Kimball, S. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.11.035 · Cited by 61 · see citing works
Wu, D., Klaw, M. C., Connors, T. M., Kholodilov, N. G., Burke, R. E., & Tom, V. J. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0719-15.2015 · Cited by 62 · see citing works
“Another way to activate mTOR is with a constitutively active Rheb (caRheb; Ras homolog enriched in brain), the GTPase that is directly upstream of mTOR (Durán and Hall, 2012).”
BackgroundEndocytic Rabs in membrane trafficking and signaling
Numrich, J., & Ungermann, C. (2013) · Biological Chemistry · doi:10.1515/hsz-2013-0258 · Cited by 59 · see citing works
“This raises the possibility that the maintenance of the lysosome/vacuole homeostasis and thus Rab5 and Rab7 GTPase function is directly linked to TOR signaling ( Dur á n and Hall, 2012 ).”
Numrich, J., Péli-Gulli, M.-P., Arlt, H., Sardu, A., Griffith, J. M., Levine, T. P., Engelbrecht-Vandré, S., Reggiori, F., Virgilio, C. D., & Ungermann, C. (2015) · Journal of Cell Science · doi:10.1242/jcs.164905 · Cited by 47 · see citing works
“Likewise, Rab5 and its yeast homolog Vps21 have functions beyond membrane fusion (Durán and Hall, 2012; Numrich and Ungermann, 2014).”
BackgroundPHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Roles for insulin-supported skeletal muscle growth1,2
Rhoads, R. P., Baumgard, L. H., El‐Kadi, S. W., & Zhao, L. D. (2016) · Journal of Animal Science · doi:10.2527/jas.2015-0110 · Cited by 56 · see citing works
“Although this is a possible mechanism by which insulin could increase protein deposition, in fed and fasted neonatal pigs, evidence indicates that there is no effect of feeding on peptide elongation (El-Kadi et al., 2012).”
Multiple crosstalk between TOR and the cell integrity MAPK signaling pathway in fission yeast
Madrid, M., Vázquez-Marín, B., Franco, A., Soto, T., Vicente‐Soler, J., Gacto, M., & Cansado, J. (2016) · Scientific Reports · doi:10.1038/srep37515 · Cited by 53 · see citing works
“The small Rab GTPase Ryh1, ortholog to human Rab6, is the main TORC2 activator in fission yeast and the only known activator of a TORC2 complex within this class of proteins 5,21 .”
Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose
Hatano, T., Morigasaki, S., Tatebe, H., Ikeda, K., & Shiozaki, K. (2015) · Cell Cycle · doi:10.1080/15384101.2014.1000215 · Cited by 49 · see citing works
mTORC2 Is Required for Rit-Mediated Oxidative Stress Resistance
Cai, W., & Andres, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115602 · Cited by 48 · see citing works
“For example, activation of mTORC1 by amino acids requires Rheb, but also involves a second family of GTPases, the Rag proteins, which direct mTORC1 to Rheb containing membranes [17].”
Cong, X. X., Gao, X. K., Rao, X. S., Wen, J., Liu, X. C., Shi, Y. P., He, M. Y., Shen, W., Shen, Y. L., Ouyang, H., et al. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0508-1 · Cited by 47 · see citing works
Sharma, S., Mathre, S., Visvanathan, R., Shinde, D. D., & Raghu, P. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.084 · Cited by 46 · see citing works
The flipside of the TOR coin – TORC2 and plasma membrane homeostasis at a glance
Riggi, M., Kuśmider, B., & Loewith, R. (2020) · Journal of Cell Science · doi:10.1242/jcs.242040 · Cited by 46 · see citing works
“Indeed, given the well-documented regulation of mTORC1 by Rag and Rheb GTPases (Durán and Hall, 2012), it perhaps should not come as a surprise that TORC2 is similarly regulated by multiple GTPases.”
BackgroundThe Rac1 hypervariable region in targeting and signaling
Lam, B. D., & Hordijk, P. L. (2013) · Small GTPases · doi:10.4161/sgtp.23310 · Cited by 45 · see citing works
Diet-induced obesity in mice reduces placental efficiency and inhibits placental mTOR signaling
Lager, S., Samulesson, A.-M., Taylor, P. D., Poston, L., Powell, T. L., & Jansson, T. (2014) · Physiological Reports · doi:10.1002/phy2.242 · Cited by 44 · see citing works
“However, this finding is consistent with the lower fetal/placental weight ratio, indicating reduced placental efficiency.”
ResultThe Fission Yeast Cell Integrity Pathway: A Functional Hub for Cell Survival upon Stress and Beyond
Cansado, J., Soto, T., Franco, A., Vicente‐Soler, J., & Madrid, M. (2021) · Journal of Fungi · doi:10.3390/jof8010032 · Cited by 43 · see citing works
Saliba, E., Evangelinos, M., Gournas, C., Corrillon, F., Georis, I., & André, B. (2018) · eLife · doi:10.7554/elife.31981 · Cited by 40 · see citing works
“GFs act through activation of Rheb, a GTPase present at the lysosomal membrane that stimulates mTORC1 activity (Durán and Hall, 2012; Zheng et al., 2014).”
BackgroundLYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR
Bayly-Jones, C., Lupton, C. J., Keen, A. C., Dong, S., Mastos, C., Luo, W., Qian, C., Jones, G. D., Venugopal, H., Chang, Y.-G., et al. (2024) · Nature · doi:10.1038/s41586-024-08012-9 · Cited by 28 · see citing works
“Lysosomes provide a platform for mTORC1 activity, with cell growth cues triggering the allosteric activation of mTORC1 after it binds to the small GTPase Rheb at the lysosomal membrane 7 .”
So, Y.-S., Lee, D.-G., Idnurm, A., Ianiri, G., & Bahn, Y.-S. (2019) · Genetics · doi:10.1534/genetics.119.302191 · Cited by 36 · see citing works
Srinivas, K. P., Remadevi, V., Dan, V. M., Sajitha, I. S., Prakash, R., Rahul, P. V., Santhoshkumar, T. R., Lakshmi, S., & Pillai, M. R. (2016) · Oncotarget · doi:10.18632/oncotarget.8131 · Cited by 36 · see citing works
“The pathways controlled by these complexes are frequently de-regulated in cancers [1-3].”
BackgroundBopp, A., Wartlick, F., Henninger, C., Kaina, B., & Fritz, G. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.57 · Cited by 35 · see citing works
Environmental control of cell size at division
Davie, E., & Petersen, J. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.08.003 · Cited by 35 · see citing works
Role of Rab GTPases and their interacting proteins in mediating metabolic signalling and regulation
Chua, C. E. L., & Tang, B. L. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1862-x · Cited by 33 · see citing works
ArfGAP1 inhibits mTORC1 lysosomal localization and activation
Meng, D.-L., Yang, Q., Melick, C. H., Park, B., Hsieh, T.-S., Curukovic, A., Jeong, M.-H., Zhang, J.-M., James, N. G., & Jewell, J. L. (2021) · EMBO Journal · doi:10.15252/embj.2020106412 · Cited by 29 · see citing works
“Multiple small GTPases like Rheb, Rags, Rab1A, Rab5, RalA, Rac1, and Arf1 have been shown to alter mTORC1 lysosomal localization and activity (Duran & Hall, 2012; Nguyen et al, 2017; Zhu & Wang, 2020).”
Wu, D., Klaw, M. C., Connors, T. M., Kholodilov, N. G., Burke, R. E., Côté, M., & Tom, V. J. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.08.011 · Cited by 28 · see citing works
Patursky-Polischuk, I., Kasir, J., Miloslavski, R., Hayouka, Z., Hausner-Hanochi, M., Stolovich-Rain, M., Tsukerman, P., Biton, M., Mudhasani, R. R., Jones, S. N., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109410 · Cited by 31 · see citing works
“Rheb-GTP operates as an activator of mTORC1 (reviewed in [8]).”
BackgroundSin1-mediated mTOR signaling in cell growth, metabolism and immune response
Ruan, C.-H., Ouyang, X.-X., Liu, H.-Z., Li, S., Jin, J.-S., Tang, W.-T., Xia, Y.-J., & Su, B. (2019) · National Science Review · doi:10.1093/nsr/nwz171 · Cited by 20 · see citing works
“cross-regulation of mTORC1 by mTORC2 is mediated directly through a small GTPase RheB, it is interesting to know if mTORC2 could also regulate mTORC1 by targeting its upstream nutrientsensing components [12,146].”
BackgroundMrak, P., Krastel, P., Lukančič, P. P., Tao, J., Pistorius, D., & Moore, C. M. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005314 · Cited by 26 · see citing works
“Although the role of TORC1 has been investigated in relative detail, the understanding of its rapamycin-insensitive counterpart, the TORC2, is relatively poor (41).”
BackgroundInfluentialVeliça, P., Zech, M., Henson, S. M., Holler, A., Manzo, T., Pike, R., Sousa, P. S. E., Zhang, L., Schiedlmeier, B., Pulè, M. A., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3283 · Cited by 25 · see citing works
“In this study, we used overexpression of RAS homolog enriched in brain (RHEB) and proline-rich Akt substrate of 40 kDa (PRAS40), two key molecules involved in positive and negative regulation of the mTORC1 pathway, respectively (10, 11), to explore the relative roles of effector function and memory (1)Department of Ha…”
MethodShi, S., Ji, H., Siewers, V., & Nielsen, J. (2015) · FEMS Yeast Research · doi:10.1093/femsyr/fov108 · Cited by 25 · see citing works
“Recently, Rheb was shown to directly bind the target of rapamycin complex (TOR) and to enhance its activity (Long et al. 2005; Durán and Hall 2012).”
BackgroundGankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer
Qin, X., Wang, X., Liu, F., Morris, L. E., Wang, X., Jiang, B., & Zhang, Y. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.03.013 · Cited by 23 · see citing works
Leucyl-tRNA synthetase: double duty in amino acid sensing
Durán, R. V., & Hall, M. N. (2012) · Cell Research · doi:10.1038/cr.2012.68 · Cited by 22 · see citing works
Self-citationWu, D., Klaw, M. C., Kholodilov, N. G., Burke, R. E., Detloff, M. R., Côté, M., & Tom, V. J. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00049 · Cited by 22 · see citing works
“Interestingly, caRheb + ChABC animals had significantly more c-Fos+ nuclei indicating that caRheb expression in DRGs promoted functional synaptogenesis of their axons that regenerated beyond a ChABC-treated DREZ.”
BackgroundInfluentialNguyen, T.-L., Nokin, M., Egorov, M., Tomé, M., Bodineau, C., Primo, C. D., Minder, L., Wdzieczak‐Bakala, J., Garcia-Alvarez, M. C., Bignon, J. S., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0232 · Cited by 22 · see citing works
“In the control of mTORC1 by growth factors, the tuberous sclerosis complex (TSC) and the mTORC1 coactivator Rheb play a crucial role (7, 8).”
BackgroundSelf-citationThe Ectocarpus Genome and Brown Algal Genomics
Cock, J. M., Sterck, L., Ahmed, S., Allen, A. E., Amoutzias, G. D., Anthouard, V., Artiguenave, F., Arun, A., Aury, J., Badger, J. H., et al. (2012) · Advances in botanical research · doi:10.1016/b978-0-12-391499-6.00005-0 · Cited by 22 · see citing works
Differential Effects of MicroRNAs on Glioblastoma Growth and Migration
Jeansonne, D. P., Pacifici, M., Lassak, A., Krzysztof Reiss, F., Russo, G. M., Zabaleta, J., & Peruzzi, F. (2013) · Genes · doi:10.3390/genes4010046 · Cited by 21 · see citing works
“These kinases phosphorylate and inhibit the activity of Tuberin/TSC2, a protein that forms a complex with Hamartin/TSC1 to act as a principle negative regulator of mTORC1 [21].”
BackgroundLoss of TSC2 confers resistance to ceramide and nutrient deprivation
Guenther, G., Liu, G., Ramirez, M. U., McMonigle, R. J., Kim, S. M., McCracken, A. N., Joo, Y., Ushach, I., Nguyen, N., & Edinger, A. L. (2013) · Oncogene · doi:10.1038/onc.2013.139 · Cited by 19 · see citing works
Rab23’s genetic structure, function and related diseases: a review
Zheng, L., Chi, S., & Li, C. (2017) · Bioscience Reports · doi:10.1042/bsr20160410 · Cited by 19 · see citing works
Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner
Chen, Z., Cordero, J. B., Alqarni, A. M., Slack, C., Zeidler, M. P., & Bellantuono, I. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab172 · Cited by 17 · see citing works
“One key group of isoprenylated proteins are small GTPases (11), important signaling molecules which play central roles in multiple cellular processes, including cellular morphology, integrin function, and longevity-associated pathways such as mammalian traget of rapamycin (mTOR) (12).”
Li, X., Nie, T., Lu, F., Huang, L. H., Shi, X., Ren, D., Lu, J., Li, X., Xu, T., Cui, B., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2259735 · Cited by 17 · see citing works
“To monitor and integrate multiple environmental cues such as growth factors and nutrients sufficiency, MTORC1 integrates these inputs by two types of small G proteins-RHEB (Ras homolog, mTORC1 binding) and the RRAG (Ras related GTP binding) guanosine triphosphatases [9,10].”
BackgroundLi, M., Huang, W., Zhang, Y., Du, Y., Zhao, S., Wang, L., Sun, Y., Sha, B., Yan, J., Ma, Y., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06808-1 · Cited by 17 · see citing works
“Several upstream kinases, such as Akt, MK2, AMP-activated protein kinase (AMPK), ERK, p90 ribosomal S6 kinase, and GSK-3 β , control Rheb activity through direct modulation of TSC1 and TSC2 [2, 13].”
BackgroundCharacterization of the pumpkin Translationally-Controlled Tumor ProteinCmTCTP
Hinojosa-Moya, J., Xoconostle‐Cázares, B., Toscano-Morales, R., Ramírez-Ortega, F. A., Cabrera‐Ponce, J. L., & Ruíz‐Medrano, R. (2013) · Plant Signaling & Behavior · doi:10.4161/psb.26477 · Cited by 17 · see citing works
Cicco, M. D., Rahim, M. S. A., & Dames, S. A. (2015) · Membranes · doi:10.3390/membranes5040553 · Cited by 16 · see citing works
“In 2012, the regulation of TOR by small GTPases was shown to include Rheb, Rags, RalA (Ras-related protein A), Rac1 (Ras-related C3 botulinum toxin substrate 1), and some Rab (Ras-related protein) family members [102].”
Backgroundγ‐Crystallins of the chicken lens: remnants of an ancient vertebrate gene family in birds
Chen, Y., Sagar, V., Len, H., Peterson, K. M., Fan, J., Mishra, S., McMurtry, J. P., Wilmarth, P. A., David, L. L., & Wistow, G. J. (2016) · FEBS Journal · doi:10.1111/febs.13689 · Cited by 15 · see citing works
Urban, M. W., Ghosh, B., Strojny, L. R., Block, C. G., Blazejewski, S. M., Wright, M. C., Smith, G. M., & Lepore, A. C. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.02.007 · Cited by 15 · see citing works
“Rheb directly binds to the mTOR complex, and the active GTP-bound form of Rheb is required for mTOR activation (Durán and Hall, 2012; Long et al., 2005).”
BackgroundControl of cell growth: Rag GTPases in activation of TORC1
Yang, H., Gong, R., & Xu, Y. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1195-y · Cited by 15 · see citing works
“TORC1 integrates extracellular and intracellular signals and functions as a central regulator of cell growth (mass and size) and proliferation through regulation of a variety of cellular processes including translation, lipid synthesis, autophagy, and metabolism [1–9].”
BackgroundStructure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.
Lupton, C. J., Bayly-Jones, C., Dong, S., Lam, T., Luo, W., Jones, G. D., Mastos, C., Frescher, N. J., Lim, S. S., Keen, A. C., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.005 · Cited by 13 · see citing works
Lu, Q., Hu, X., Hou, Q., Yu, L., Cao, K., Ding, D., Lu, Y., & Dai, C. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111451 · Cited by 13 · see citing works
Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12 · see citing works
Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation
Wu, P., Chiang, S.-Y., Midence, R., Kao, W.-C., Lai, C.-L., Cheng, I., Chou, S., Chen, C., Huang, C., & Chen, R. (2023) · Cell Death and Disease · doi:10.1038/s41419-022-05442-z · Cited by 11 · see citing works
“For instance, Rac1 promotes cell cycle progression by increasing the activity of mTORC [34, 47] and by activating the transcription of CCND2 (encoding cyclin D2) to facilitate G1/S transition [48].”
BackgroundStructure of the human TSC:WIPI3 lysosomal recruitment complex
Bayly-Jones, C., Lupton, C. J., D’Andrea, L., Chang, Y., Jones, G. D., Steele, J. R., Venugopal, H., Schittenhelm, R. B., Halls, M. L., & Ellisdon, A. M. (2024) · Science Advances · doi:10.1126/sciadv.adr5807 · Cited by 10 · see citing works
“RHEB allosterically activates mTORC1, and RHEB-GTP hydrolysis by TSC acts as an off switch for cell growth ( 6 ).”
Jansen, G., Al, M., Assaraf, Y. G., Kammerer, S., van Meerloo, J., Ossenkoppele, G. J., Cloos, J. J., & Peters, G. J. (2023) · Cancer Drug Resistance · doi:10.20517/cdr.2023.20 · Cited by 10 · see citing works
Taylor, J., Yeomans, A., & Packham, G. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00002 · Cited by 10 · see citing works
“mTORC1 activity is regulated by the TSC complex which inhibits mTORC1 activity by converting Rheb-GTP (an activator of mTORC1) into its inactive GDP-bound form [62].”
BackgroundHACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner
Turgu, B., Zhang, F., El-Naggar, A. M., Negri, G. L., Kögler, M., Tortola, L., Johnson, F. D., Ng, T., Li, A., Yapp, D. T. T., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01680-1 · Cited by 9 · see citing works
The HACE1 E3 ligase mediates RAC1‐dependent control of mTOR signaling complexes
Turgu, B., El-Naggar, A. M., Kögler, M., Tortola, L., Zhang, H., Hassan, M., Lizardo, M. M., Kung, S. H. Y., Lam, W. L., Penninger, J. M., et al. (2023) · EMBO Reports · doi:10.15252/embr.202356815 · Cited by 8 · see citing works
“As RAC1 has been reported to be a component of both mTORC1 and mTORC2 complexes (Duran & Hall, 2012; Xie & Proud, 2014), we hypothesized that HACE1 might target RAC1 for proteasomal degradation when it is bound to these complexes.”
BackgroundSun, X., Zhao, X., Xu, S., Zhou, Y., Jia, Z. Y., & Li, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116200 · Cited by 7 · see citing works
“More studies have found that abnormal expression of Rac1 in thyroid cancer and liver cancer can regulate the malignant behavior of tumors [43,44].”
BackgroundAmino Acid Signaling in High Definition
Gaubitz, C., & Loewith, R. (2012) · Structure · doi:10.1016/j.str.2012.11.006 · Cited by 6 · see citing works
“TOR kinases assemble into two distinct multiprotein complexes that are conserved from yeast to human (Durán and Hall, 2012).”
BackgroundWang, X., Wang, Y., Zheng, X., Hao, X., Liang, Y., Wu, M., Wang, X., & Wang, Z. (2014) · Asian-Australasian Journal of Animal Sciences · doi:10.5713/ajas.2014.14145 · Cited by 6 · see citing works
“Rheb-GTP can activate mTOR through direct interaction with it (Duran et al., 2012; Yadav et al., 2013).”
Backgroundde la Torre, A., & Pérez-Martín, J. (2022) · PLOS Genetics · doi:10.1371/journal.pgen.1010483 · Cited by 5 · see citing works
“Rheb conveys signals from environmental cues in metazoan, including growth factors, energy, and oxygen levels [21].”
BackgroundRheb1 is required for limb growth through regulating chondrogenesis in growth plate
Zhang, Y., Wen, J., Lai, R., Zhang, J., Li, K., Zhang, Y., Liu, A., & Bai, X. (2024) · Cell and Tissue Research · doi:10.1007/s00441-024-03861-2 · Cited by 3 · see citing works
“…of growth factors, activated TSC acts as a GTPase-activating protein converting Rheb1 from the GTP-bound form to the GDP-bound form, resulting in signaling inhibition of the mammalian target of rapamycin complex 1 (mTORC1) (Duran and Hall 2012; Garami et al. 2003; Li et al. 2004; Yang et al. 2017).”
BackgroundHR3/RORα-mediated cholesterol sensing regulates TOR signaling
Lassen, M., Pardee, K., Bradić, I., Pedersen, L. H., Kubrak, O. I., Ahrentløv, N., Clancy, S., Koyama, T., Necakov, A., Liu, S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71059-x · Cited by 3 · see citing works
Wang, Y., Liao, Y., Sun, Y., Mitra, B., Guo, R., Piedras, B. I., White, S., Tang, H.-Y., Asara, J. M., Tempera, I., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65760-6 · Cited by 7 · see citing works
“Taken together, these data suggest that the ZMYND19 zinc fi nger supports association with MKLN1, Raptor and CTLH. mTORC1activityistightlyregulatedbyRagproteinsandRheb 75 – 77 .”
Düppe, P. M., Phuong, T. T. T., Autzen, J., Schöpel, M., Yip, K. T., Stoll, R., & Scherkenbeck, J. (2014) · ACS Chemical Biology · doi:10.1021/cb5002075 · Cited by 2 · see citing works
Characterizing the role of Rasa1 in vascular development in zebrafish
Davari, P. (2015) · Libraries and Cultural Resources (University of Calgary) · doi:10.11575/prism/25307
Activation of TOR Signaling by Metabolic Stress
Nomura, W., & Inoue, Y. (2016) · KAGAKU TO SEIBUTSU · doi:10.1271/kagakutoseibutsu.54.273
Anggraini, S. (2018) · Indonesia Jurnal Kebidanan · doi:10.26751/ijb.v2i2.564 · Cited by 2 · see citing works
“Karena obesitas merupakan suatu kondisi meningkatnya ketersediaan nutrisi, maka kemungkinan obesitas ikut mengaktifkan sinyal mTOR plasenta (Laptante and Sabatini, 2012; Duran and Hall, 2012).”
BackgroundElucidating the functions of fibroblast growth factor 9 in multiple sclerosis
McElroy, D. (2018) · Enlighten: Theses (The University of Glasgow)
Nuevas aproximaciones en el estudio de la ruta autofágica en cáncer colorrectal
Perdomo, V. C. R. (2018) · doi:10.14201/gredos.137357
Sharma, S., Mathre, S., Visvanathan, S., Shinde, D., & Raghu, P. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/333153
Avruch, J. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.726281472.793554244
Ferguson, S. M. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736741937.793574668
Collins, B. M. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736741937.793566201
Biochemical characterization of mTORC1 regulation by glutamine metabolism
Bodineau, C. (2020) · theses.fr (ABES) · doi:10.70675/9d5aaabdz81bdz4118zb3edze237bdd8dee0
- Authors
- Durán, R. V., & Hall, M. N.
- Affiliations
- University of Basel (CH)
- Corresponding author
- Hall, Michael N
- Venue
- The EMBO Reports
- Published
- 2012-01-13
- Volume
- 13
- Issue
- 2
- Pages
- 121-128
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC3271343
- OpenAlex
- W2123960043
- Cited by
- 102
- References
- 90
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 3 · 2016: 9 · 2015: 17 · 2014: 10 · 2013: 10 · 2012: 9
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- EMBO Reports (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- edoc (University of Basel)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TOR kinase, small GTPases, Rheb, Rag GTPases, Rac1, RalA, phosphatidic acid, nutrient signaling, growth regulation, aging, cellular stress
- MeSH terms
- Animals, Humans, Models, Biological, Signal Transduction, Monomeric GTP-Binding Proteins, TOR Serine-Threonine Kinases
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