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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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“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
In the citing paper
“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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Citations
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“RRAGC encodes for a members of Rag small GTPases, which regulate the growthcontrolling TOR signaling pathway (reviewed in [62]).”
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“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).”
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Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose
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The flipside of the TOR coin – TORC2 and plasma membrane homeostasis at a glance
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ArfGAP1 inhibits mTORC1 lysosomal localization and activation
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“Rheb-GTP operates as an activator of mTORC1 (reviewed in [8]).”
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“Although the role of TORC1 has been investigated in relative detail, the understanding of its rapamycin-insensitive counterpart, the TORC2, is relatively poor (41).”
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“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…”
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“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
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“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.”
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“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
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“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
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“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
“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
“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
Cicco, M. D., Rahim, M. S. A., & Dames, S. A. (2015) · Membranes · doi:10.3390/membranes5040553 · Cited by 19
“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
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
“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
“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 15
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 15
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
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 10
“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
“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
Taylor, J., Yeomans, A., & Packham, G. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00002 · Cited by 11
“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
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
“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
“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
“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
“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
“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
“…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
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
“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
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
The signal transduction of synapse formation and it's failure in Rett syndrome
Ebrecht, R. (2017) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-6271
Anggraini, S. (2018) · Indonesia Jurnal Kebidanan · doi:10.26751/ijb.v2i2.564 · Cited by 2
“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) · Gredos (University of Salamanca) · 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
Metadata
- 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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