Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship
Abstract
Activation of Mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerous malignancies including glioblastoma (GB). The Canonical PI3K/Akt/mTOR signaling cascade is commonly upregulated due to loss of the tumor suppressorm PTEN, a phosphatase that acts antagonistically to the kinase (PI3K) in conversion of PIP2 to PIP3. mTOR forms two multiprotein complexes, mTORC1 and mTORC2 which are composed of discrete protein binding partners to regulate cell growth, motility, and metabolism. These complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients while mTORC2 is regulated via PI3K and growth factor signaling. The main function of mTORC1 is to regulate protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. On the other hand, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK and it also plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. mTORC1 and mTORC2 regulate each other, as shown by the fact that Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Allosteric inhibitors of mTOR, rapamycin and rapalogs, remained ineffective in clinical trials of Glioblastoma (GB) patients, in part due to their incomplete inhibition of mTORC1 as well as unexpected activation of mTOR via the loss of negative feedback loops. In recent years, novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6K Ser235/236, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKT Ser473. Furthermore by these novel combined mTORC1/mTORC2 inhibitors reduced the proliferation and self-renewal of GB cancer stem cells. However, a search of more effective way to target mTOR has generated a third generation inhibitor of mTOR, "Rapalink", that bivalently combines rapamycin with an ATP-binding inhibitor, which effectively abolishes the mTORC1 activity. All in all, the effectiveness of inhibitors of mTOR complexes can be judged by their ability to suppress both mTORC1/mTORC2 and their ability to impede both cell proliferation and migration along with aberrant metabolic pathways.
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mTORC1 functions as a nutrient/amino acid sensing complex, whereas mTORC2 receives intracellular signals from extracellular growth factor binding.
“Whereas mTORC1 functions as a nutrient/amino acid sensing complex, mTORC2 receives intracellular signals from extracellular growth factor binding (Jhanwar-Uniyal et al., 2019).”
From Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities (2021) · cites this paper as Jhanwar-Uniyal et al., 2019
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The nuclear import of ribosomal proteins is regulated by mTOR
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ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma
Neil, J. A., Shannon, C. M., MOHAN, A. L., Laurent, D., Murali, R., & Jhanwar‐Uniyal, M. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.3311 · Cited by 17 · see citing works
Mighty RapaLink-1 vanquishes undruggable mutant mTOR in glioblastoma
Jhanwar‐Uniyal, M. (2017) · Translational Cancer Research · doi:10.21037/tcr.2017.09.36 · Cited by 8 · see citing works
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Hyperuricemia and its related diseases: mechanisms and advances in therapy
Du, L., Yao, Z., Li, H., Wang, Q., Xie, L., Yang, B., Pang, Y., Zhang, C., Zhong, Z., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01916-y · Cited by 719 · see citing works
“253,279,280 Uric acid can enhance AKT phosphorylation, which subsequently leads to PRAS40 phosphorylation with the activation of mTOR, 281 resulting in the inhibition of autophagy, as well as inhibiting AMPK phosphorylation.”
BackgroundThe PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling
Shorning, B. Y., Dass, M. S., Smalley, M. J., & Pearson, H. B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124507 · Cited by 638 · see citing works
“mechanisms, including AKT regulation of PRAS40 to block suppression of mTORC1 activity and S6K regulation of mSIN1 to modulate mTORC2 activity [186].”
BackgroundXu, F., Na, L., Li, Y., & Chen, L. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-00416-0 · Cited by 542 · see citing works
RetractedTargeting signaling pathways in prostate cancer: mechanisms and clinical trials
He, Y., Xu, W., Xiao, Y., Huang, H., Gu, D., & Ren, S. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01042-7 · Cited by 275 · see citing works
“The serine/threonine protein kinase mTOR, the major downstream effector of AKT signaling, interacts with different proteins and forms two distinct complexes, mTORC1 and mTORC2.(393) Several types of mTOR inhibitors exist, including mTORC1 inhibitors (such as rapamycin, everolimus, and temsirolimus), mTORC1/2 dual inhi…”
BackgroundRegulation of mTORC2 Signaling
Fu, W., & Hall, M. N. (2020) · Genes · doi:10.3390/genes11091045 · Cited by 213 · see citing works
“Feedback control loops exist between mTORC1 and mTORC2 [105].”
BackgroundSanaei, M., Razi, S., Pourbagheri‐Sigaroodi, A., & Bashash, D. (2022) · Translational Oncology · doi:10.1016/j.tranon.2022.101364 · Cited by 204 · see citing works
“The phosphorylated Akt (pAkt) is able to activate mTORC1, one of the main downstream components of signaling leading to cell growth, metabolism, and protein synthesis [56].”
BackgroundMicroglia promote glioblastoma via mTOR‐mediated immunosuppression of the tumour microenvironment
Dumas, A. A., Pomella, N., Rosser, G., Guglielmi, L., Vinel, C., Millner, T. O., Rees, J. H., Aley, N., Sheer, D., Wei, J., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019103790 · Cited by 155 · see citing works
“The mTOR pathway has been extensively studied in the context of cell growth, proliferation and survival in many cancers, including GBM (Li et al , 2016; Jhanwar-Uniyal et al , 2019).”
Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer?
Prossomariti, A., Piazzi, G., Alquati, C., & Ricciardiello, L. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.04.007 · Cited by 155 · see citing works
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Charge‐Reversal Polymer Nano‐modulators for Photodynamic Immunotherapy of Cancer
He, S., Li, J., Cheng, P., Zeng, Z., Zhang, C., Duan, H., & Pu, K. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202106392 · Cited by 148 · see citing works
Glutathione metabolism in ferroptosis and cancer therapy
Xue, X., Wang, M., Cui, J., Yang, M., Ma, L., Kang, R., Tang, D., & Wang, J. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217697 · Cited by 154 · see citing works
Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma
Ferrín, G., Misas, M. G., Amado, V., Rodríguez‐Perálvarez, M., & de la Mata, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041266 · Cited by 137 · see citing works
“In addition, both mTORC1 and mTORC2 regulate each other by controlling the activity of ribosomal protein S6 kinase (S6K) and AKT respectively, although the extent of these mechanisms is not completely understood [21].”
BackgroundTargeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach
Zughaibi, T. A., Suhail, M., Tarique, M., & Tabrez, S. S. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212455 · Cited by 137 · see citing works
“This is a downstream substrate of PI3K and Akt with two distinct complexes mTORC1 and mTORC2 [66].”
BackgroundLiu, D., Wang, S., Liu, S., Wang, Q., Che, X., & Wu, G. (2024) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2024.101270 · Cited by 134 · see citing works
Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect
Lim, S. M., Hanif, E. A. M., & Chin, S. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00570-z · Cited by 128 · see citing works
“The mTOR constitutes of two distinct complexes, the mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [34, 35].”
BackgroundNeuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering
Tribble, J. R., Hui, F., Quintero, H., Hajji, S. E., Bell, K. C., Polo, A. D., & Williams, P. A. (2023) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2023.101193 · Cited by 115 · see citing works
Three dimensional in vitro models of cancer: Bioprinting multilineage glioblastoma models
Hermida, M. A., Kumar, J. D., Schwarz, D., Laverty, K. G., Bartolo, A. D., Ardron, M., Bogomolnijs, M., Clavreul, A., Brennan, P. M., Wiegand, U. K., et al. (2019) · Advances in Biological Regulation · doi:10.1016/j.jbior.2019.100658 · Cited by 105 · see citing works
Kaspy, M. S., Hannaian, S. J., Bell, Z. W., & Churchward‐Venne, T. A. (2023) · Nutrition Research Reviews · doi:10.1017/s0954422423000197 · Cited by 109 · see citing works
Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?
Braglia, L., Zavatti, M., Vinceti, M., Martelli, A. M., & Marmiroli, S. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118731 · Cited by 97 · see citing works
Programmed Cell Death in Diabetic Nephropathy: A Review of Apoptosis, Autophagy, and Necroptosis
Erekat, N. S. (2022) · Medical Science Monitor · doi:10.12659/msm.937766 · Cited by 97 · see citing works
“Once activated, mTORC1 phosphorylates Ulk1 inhibiting it and subsequently preventing autophagosome formation [85].”
BackgroundInfluential<scp>mTOR</scp> signaling and Alzheimer's disease: What we know and where we are?
Davoody, S., Asgari Taei, A., Khodabakhsh, P., & Dargahi, L. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14463 · Cited by 96 · see citing works
Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy
Hodges, S. L., & Lugo, J. N. (2020) · Epilepsy Research · doi:10.1016/j.eplepsyres.2020.106282 · Cited by 87 · see citing works
Duan, Y., Haybaeck, J., & Yang, Z. (2020) · Cancers · doi:10.3390/cancers12102972 · Cited by 85 · see citing works
“Of note, 4E-BP1 plays a significant mechanistic role in oncogenesis, such as promoting cell growth and protein translation, and is also closely related to drug resistance [66,67].”
BackgroundTwo parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis
Bodineau, C., Tomé, M., Courtois, S., Costa, A. S. H., Sciacovelli, M., Rousseau, B., Richard, É., Vacher, P., Parejo-Pérez, C., Bessède, E., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25079-4 · Cited by 84 · see citing works
A Comprehensive View on the Quercetin Impact on Colorectal Cancer
Neamțu, A.-A., Maghiar, T.-A., Alaya, A., Oláh, N.-K., Turcuș, V., Constanta, P. D., Totolici, B. D., Neamţu, C., Maghiar, A. M., & Máthé, E. (2022) · Molecules · doi:10.3390/molecules27061873 · Cited by 82 · see citing works
“The serine/threonine protein kinase mTOR consists of two multiprotein complexes: mTORC1 and mTORC2 [88], with the regulatory-associated protein of mTOR and the proline-rich AKT substrate of 40 KDa (PRAS40) being distinctive for the mTORC1 complex [89,90] and the rapamycin-insensitive companion of mTOR, the protein obs…”
BackgroundThe Athlete Gut Microbiome and its Relevance to Health and Performance: A Review
O’Brien, M., O’Sullivan, Ó., Claesson, M. J., & Cotter, P. D. (2022) · Sports Medicine · doi:10.1007/s40279-022-01785-x · Cited by 82 · see citing works
“The mTOR is a subunit of two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which regulate various vital bodily functions such as metabolism, cell survival, protein synthesis and cytoskeletal organisation [50].”
Photobiomodulation: Cellular, molecular, and clinical aspects
Felician, M. C. P., Belotto, R. A., Tardivo, J. P., Baptista, M. S., & Martins, W. K. (2023) · Journal of Photochemistry and Photobiology · doi:10.1016/j.jpap.2023.100197 · Cited by 76 · see citing works
Vanderplow, A. M., Eagle, A. L., Kermath, B. A., Bjornson, K. J., Robison, A. J., & Cahill, M. E. (2021) · Neuron · doi:10.1016/j.neuron.2021.03.008 · Cited by 74 · see citing works
mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target
Babicheva, A., Makino, A., & Yuan, J. X. ‐. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042144 · Cited by 68 · see citing works
“However, AMPK-mediated negative regulation of mTORC1 could be completely blocked by AKT [30].”
BackgroundWu, X., Fu, M., Ge, C., Zhou, H., Huang, H., Zhong, M., Zhang, M., Xu, H., Zhu, G., Hua, W., et al. (2024) · Molecular Neurobiology · doi:10.1007/s12035-023-03911-w · Cited by 67 · see citing works
Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β
Jiménez‐Uribe, A. P., Gómez‐Sierra, T., Aparicio‐Trejo, O. E., Orozco‐Ibarra, M., & Pedraza‐Chaverrí, J. (2021) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110123 · Cited by 64 · see citing works
Mesquita, P. H. C., Vann, C. G., Phillips, S. M., McKendry, J., Young, K. C., Kavazis, A. N., & Roberts, M. D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.725866 · Cited by 62 · see citing works
Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease
Benn, C., & Dawson, L. A. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00242 · Cited by 57 · see citing works
Striking a balance: PIP2 and PIP3 signaling in neuronal health and disease
Tariq, K., & Luikart, B. W. (2021) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2021.00008 · Cited by 47 · see citing works
“Broadly, mTORC1 is involved in processes of enhanced protein synthesis and growth through downstream effectors like S6 kinase; lipid synthesis through sterol responsive element binding protein (SRBEP); cellular stress responses through its negative regulator AMPK; and cell survival through autophagy and ubiquitin prot…”
BackgroundPharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain
Yousuf, M. S., Shiers, S. I., Sahn, J. J., & Price, T. J. (2020) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000030 · Cited by 55 · see citing works
Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases
Giorgi, C., Bouhamida, E., Danese, A., Previati, M., Pinton, P., & Patergnani, S. (2021) · Biomedicines · doi:10.3390/biomedicines9020149 · Cited by 50 · see citing works
“Oppositely, the primary role of mTORC1 is to play a pivotal role in cellular catabolic pathways, particularly autophagy [31].”
BackgroundPei, X., Zheng, F., Li, Y., Lin, Z., Han, X., Feng, Y., Tian, Z., Ren, D., Cao, K., & Li, C. (2022) · Cells · doi:10.3390/cells11030346 · Cited by 50 · see citing works
“In general, mTORC1 controls cell growth by regulating mRNA translation via phosphorylation of ribosomal S6 kinase (S6K) and 4E binding protein 1 (4E-BP1) [8].”
BackgroundTherapeutic strategies targeting AMPK-dependent autophagy in cancer cells
Yuan, W., Fang, W., Zhang, R., Lyu, H., Xiao, S., Guo, D. S., Ali, D. W., Michalak, M., Chen, X., Zhou, C., et al. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119537 · Cited by 51 · see citing works
Chen, R. Q., Xu, X., Liu, F., Li, C. Y., Li, Y. J., Li, X. R., Jiang, G., Hu, F., Liu, D., Pan, F., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01347 · Cited by 48 · see citing works
“For mTOR, a key downstream signaling molecule in PI3K/Akt pathway, mTOR complex 1 (mTORC1) mainly mediates PI3K/Akt-induced cell autophagy (25) and mTORC2 mediates Akt-induced cell survival (26).”
BackgroundTargeting of the cGAS-STING system by DNA viruses
Phelan, T., Little, M. A., & Brady, G. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113831 · Cited by 48 · see citing works
Zhang, L., Luo, X., & Qiao, S. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01757-y · Cited by 48 · see citing works
“Pten is a tumour-suppressive protein that modulates PI3K/Akt signalling pathway negatively [22, 23].”
BackgroundInfluentialMolecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions
Sursal, T., Ronecker, J. S., Dicpinigaitis, A. J., MOHAN, A. L., Tobias, M. E., Gandhi, C. D., & Jhanwar‐Uniyal, M. (2022) · Anticancer Research · doi:10.21873/anticanres.15703 · Cited by 47 · see citing works
Glutamine metabolism modulates chondrocyte inflammatory response
Arra, M., Swarnkar, G., Adapala, N. S., Naqvi, S. K., Cai, L., Rai, M. F., Singamaneni, S., Mbalaviele, G., Brophy, R. H., & Abu‐Amer, Y. (2022) · eLife · doi:10.7554/elife.80725 · Cited by 44 · see citing works
Emerging role and therapeutic implication of mTOR signalling in intervertebral disc degeneration
Chen, H., Zhou, J., Zhang, G., Luo, Z., Li, L., & Kang, X. (2022) · Cell Proliferation · doi:10.1111/cpr.13338 · Cited by 44 · see citing works
“in mTORC1, mTORC2 comprises three other subunits, including rapamycin-insensitive companion of mTOR (Rictor), mitogen-activated protein kinase-related protein 1 (mSin1), and Protor.(34) In mTORC1,”
BackgroundUdaya Rajesh, R., & Sangeetha, D. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155902 · Cited by 45 · see citing works
Thomas, A. C. Q., Stead, C. A., Burniston, J. G., & Phillips, S. M. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.08.010 · Cited by 52 · see citing works
Neutrophil extracellular traps promote corneal neovascularization-induced by alkali burn
Yuan, K., Zheng, J., Huang, X., Zhang, Y., Han, Y., Hu, R., & Jin, X. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106902 · Cited by 45 · see citing works
Supruniuk, E., Żebrowska, E., & Chabowski, A. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1977910 · Cited by 46 · see citing works
Chen, K.-Q., Wei, B., Hao, S.-L., & Yang, W.-X. (2022) · PubMed · doi:10.14670/hh-18-457 · Cited by 44 · see citing works
Exploring the mTOR Signalling Pathway and Its Inhibitory Scope in Cancer
Mir, S. A., Dar, A., Alshehri, S. A., Wahab, S., Hamid, L., Almoyad, M. A. A., Ali, T., & Bader, G. N. (2023) · Pharmaceuticals · doi:10.3390/ph16071004 · Cited by 42 · see citing works
Nakamura, K., Dalal, A. R., Yokoyama, N., Pedroza, A. J., Kusadokoro, S., Mitchel, O. R., Gilles, C., Masoudian, B., Leipzig, M. M., Casey, K. M., et al. (2023) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.318448 · Cited by 41 · see citing works
Chen, Y., Zhu, W., Lin, C.-Y., Yuan, Z., Li, Z.-H., & Yan, P. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s270939 · Cited by 40 · see citing works
Autophagy/Mitophagy in Airway Diseases: Impact of Oxidative Stress on Epithelial Cells
Albano, G. D., Montalbano, A. M., Gagliardo, R. P., & Profita, M. (2023) · Biomolecules · doi:10.3390/biom13081217 · Cited by 40 · see citing works
Microglia-induced neuroinflammation in hippocampal neurogenesis following traumatic brain injury
Navabi, S. P., Badreh, F., Shooshtari, M. K., Hajipour, S., Vastegani, S. M., & Khoshnam, S. E. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e35869 · Cited by 39 · see citing works
The MID1 gene product in physiology and disease
Baldini, R., Mascaro, M., & Meroni, G. (2020) · Gene · doi:10.1016/j.gene.2020.144655 · Cited by 38 · see citing works
“Moreover, mTORC1 signalling is involved in processes like autophagy, protein synthesis, cell metabolism and cell growth and proliferation (Jhanwar-Uniyal et al., 2019) and given the role of MID1/α4/PP2Ac ternary complex in regulating mTORC1 complex association (Liu et al.”
BackgroundmTOR in metabolic homeostasis and disease.
Liu, X., Guo, B., Li, Q., & Nie, J. (2024) · Experimental Cell Research · doi:10.1016/j.yexcr.2024.114173 · Cited by 35 · see citing works
Regulatory T cells suppress CD4+ effector T cell activation by controlling protein synthesis
So, L., Obata‐Ninomiya, K., Hu, A. K., MUIR, V. S., Takamori, A., Song, J., Buckner, J. H., Savan, R., & Ziegler, S. F. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20221676 · Cited by 36 · see citing works
“…growth and proliferation in lymphocytes through the eukaryotic translation initiation factor 4E (eIF4E) in translation initiation (Wardman et al., 2016). mTOR exists in two multi-protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2; Jhanwar-Uniyal et al., 2019; Zoncu et al., 2011).”
Weiss, B., Allen, G. E., Kloehn, J., Abid, K., Jaquier-Gubler, P., & Curran, J. A. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab267 · Cited by 34 · see citing works
Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials
Fairman, C. M., Lønbro, S., Cardaci, T. D., VanderVeen, B. N., Nilsen, T. S., & Murphy, A. E. (2021) · JCSM Rapid Communications · doi:10.1002/rco2.56 · Cited by 36 · see citing works
“There exists two distinct mTOR complexes, mTORC1 and mTORC2, each with diverse signalling mechanisms and functionality.(17,18) Cell growth,”
BackgroundAdvances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies
Wang, L.-H., Huang, C.-H., & Lin, I. (2024) · Pharmaceuticals · doi:10.3390/ph17101261 · Cited by 37 · see citing works
Silwal, P., Paik, S., Kim, J. K., Yoshimori, T., & Jo, E. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.633360 · Cited by 34 · see citing works
“mTOR is a serine/threonine protein kinase consisting of mTORC1 andmTORC2 (Jhanwar-Uniyal et al., 2019), and regulates a variety”
BackgroundAmin, A. G., Eong, S., Gillick, J. L., Sursal, T., Murali, R., Gandhi, C. D., & Jhanwar‐Uniyal, M. (2021) · International Journal of Oncology · doi:10.3892/ijo.2021.5263 · Cited by 33 · see citing works
“Molecular‐targeted therapy has garnered increasing attention in the treatment of GB (23,28,30).”
BackgroundGPX7 Facilitates BMSCs Osteoblastogenesis via ER Stress and mTOR Pathway
Hu, X., Li, B., Wu, F., Liu, X., Liu, M., Wang, C., Shi, Y., & Ye, L. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16974 · Cited by 34 · see citing works
PI3K/AKT/mTOR and PD‑1/CTLA‑4/CD28 pathways as key targets of cancer immunotherapy (Review)
Wang, S., Liu, C., Yang, C., Jin, Y., Cui, Q., Wang, D., Ge, T., He, G., Li, W., Zhang, G., et al. (2024) · Oncology Letters · doi:10.3892/ol.2024.14700 · Cited by 35 · see citing works
Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment
Singh, S., Barik, D., Lawrie, K., Mohapatra, I., Prasad, S., Naqvi, A. R., Singh, A. R., & Singh, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914960 · Cited by 33 · see citing works
The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma
Jiang, Q., Xiao, J., Hsieh, Y.-C., Kumar, N., Han, L., Zou, Y., & Li, H. (2024) · Biomedicines · doi:10.3390/biomedicines12071610 · Cited by 32 · see citing works
Ras, PI3K and mTORC2 – three's a crowd?
Smith, S. F., Collins, S. E., & Charest, P. G. (2020) · Journal of Cell Science · doi:10.1242/jcs.234930 · Cited by 32 · see citing works
Therapeutic effect of metformin in the treatment of endometrial cancer (Review)
Mu, N., Xu, T., Gao, M., Dong, M., Tang, Q., Li, H., Wang, G., Li, Z., Wang, W., Yang, Y., et al. (2020) · Oncology Letters · doi:10.3892/ol.2020.12017 · Cited by 31 · see citing works
Vanderplow, A. M., Kermath, B. A., Bernhardt, C. R., Gums, K. T., Seablom, E. N., Radcliff, A. B., Ewald, A. C., Jones, M. V., Baker, T. L., Watters, J. J., et al. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001502 · Cited by 31 · see citing works
mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate
Fernandes, H., Moura, J., & Carvalho, E. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10131-z · Cited by 30 · see citing works
mTOR signaling: A pivotal player in Treg cell dysfunction in systemic lupus erythematosus
Zhao, X., Wang, S., Wang, S., Xie, J., & Cui, D. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109153 · Cited by 30 · see citing works
Afzal, O., Altamimi, A. S. A., Mubeen, B., Alzarea, S. I., Almalki, W. H., Al-Qahtani, S. D., Atiya, E. M., Al-Abbasi, F. A., Ali, F., Ullah, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012470 · Cited by 30 · see citing works
Rahman, N. I. A., Lam, C. L., Sulaiman, N. S., Abdullah, N. A. H., Nordin, F., Ariffin, S. H. Z., & Yazid, M. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713051 · Cited by 30 · see citing works
Liu, X., Zhang, L., Yang, L., Cui, J., Che, S., Liu, Y., Han, J., An, X., Cao, B., & Song, Y. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29821 · Cited by 29 · see citing works
Linking Immunoevasion and Metabolic Reprogramming in B-Cell–Derived Lymphomas
Böttcher, M., Baur, R., Stoll, A., Mackensen, A., & Mougiakakos, D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.594782 · Cited by 29 · see citing works
“It serves as the core component of two multi-protein complexes (mTORC1 and mTORC2) that regulate different cell processes [reviewed in (17)].”
BackgroundLiang, P., & He, L. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109534 · Cited by 29 · see citing works
Attiq, A., & Afzal, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1255727 · Cited by 30 · see citing works
“Due to a change in configuration, mTORC2 losses its rapamycin sensitivity but still retains its contribution to numerous cellular processes (Jhanwar-Uniyal et al., 2019).”
BackgroundmTOR Signaling in the Regulation of CD4+ T Cell Subsets in Periodontal Diseases
Jiang, Q., Huang, X., Yu, W., Huang, R., Zhao, X., & Chen, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.827461 · Cited by 28 · see citing works
FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19
Li, X., Zhang, Y., Su, L., Cai, L., Zhang, C., Zhang, J., Sun, J., Chai, M., Cai, M., Wu, Q., et al. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17318 · Cited by 28 · see citing works
Amplification of 8p11.23 in cancers and the role of amplicon genes
Voutsadakis, I. A. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118729 · Cited by 27 · see citing works
Therapeutic Potential for Targeting Autophagy in ER+ Breast Cancer
Finnegan, R., Elshazly, A. M., Schoenlein, P. V., & Gewirtz, D. A. (2022) · Cancers · doi:10.3390/cancers14174289 · Cited by 27 · see citing works
“The molecular details of the regulation of mTORC1 and mTORC2 complexes have been recently reviewed [37,38].”
BackgroundJin, W., He, X., Wu, W., Bao, Y., Wang, S., Cai, M., Zhang, W., Wang, C., Zhang, F., Linhardt, R. J., et al. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.07.069 · Cited by 26 · see citing works
“Activation of mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerousmalignancies [44].”
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Postwala, H., Shah, Y., Parekh, P. S., & Chorawala, M. R. (2023) · Medical Oncology · doi:10.1007/s12032-023-02201-8 · Cited by 26 · see citing works
“…ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), which regulate protein synthesis and translation. mTORC2, on the other hand, activates Akt and other downstream effectors involved in cell survival and cytoskeletal organization [132].”
BackgroundDiscrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets
Jhanwar‐Uniyal, M., Zeller, S. L., Spirollari, E., Das, M., Hanft, S. J., & Gandhi, C. D. (2024) · Cells · doi:10.3390/cells13050409 · Cited by 25 · see citing works
“It is possible that mTOR activation is the major cause of GBM’s relentless growth and dissemination [79,80].”
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“The mechanism of resistance is suggested to involve increased pro-survival AKT signaling through mTORC2 that is activated as a counterbalance to reduced mTOR levels via rapamycin’s inhibition of mTORC1 [19, 21].”
BackgroundGameiro, A., Nascimento, C., Correia, J., & Ferreira, F. (2021) · Cancers · doi:10.3390/cancers13092007 · Cited by 28 · see citing works
“Nowadays, the use of mAbs are widely common in HER2-positive breast cancer patients, decreasing its downstream pathways activation, such as AKT and mTOR, responsible for the antiapoptotic mechanisms [5], cell cycle progression and cell proliferation [14], important checkpoints in the carcinogenesis process [5].”
BackgroundmTOR Signaling in Macrophages: All Depends on the Context
Fedor, A., Bryniarski, K., & Nazimek, K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157598 · Cited by 26 · see citing works
Phosphoinositides in cell proliferation and metabolism.
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Amino Acid-Related Metabolic Signature in Obese Children and Adolescents
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“, 4E-BP1 or EIF4E-BP1, S6K); meanwhile, mTORC2 regulates cytoskeletal remodeling and cells’ proliferation, migration and survival via PI3K and growth factor signaling [83].”
BackgroundBioenergetic and inflammatory systemic phenotypes in Alzheimer’s disease APOE ε4‐carriers
Wilkins, H., Wang, X., Menta, B. W., Koppel, S. J., Bothwell, R. J., Becker, A. M., Anderson, H., Schwartz, E., Pei, D., Yellapu, N. K., et al. (2021) · Aging Cell · doi:10.1111/acel.13356 · Cited by 23 · see citing works
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Sane, S., Srinivasan, R., Potts, R. A., Eikanger, M. M., Zagirova, D., Freeling, J., Reihe, C. A., Antony, R. M., Gupta, B. K., Lynch, D. W., et al. (2023) · Oncogene · doi:10.1038/s41388-023-02686-7 · Cited by 23 · see citing works
“With two distinct complexes called mTORC1 and mTORC2, the mTORC pathway contributes to diverse signaling pathways in physiological and pathological conditions [5].”
BackgroundJhanwar‐Uniyal, M., Dominguez, J. F., MOHAN, A. L., Tobias, M. E., & Gandhi, C. D. (2021) · Advances in Biological Regulation · doi:10.1016/j.jbior.2021.100854 · Cited by 22 · see citing works
Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer
Schcolnik‐Cabrera, A., & Juárez-López, D. (2022) · Cellular Oncology · doi:10.1007/s13402-022-00706-4 · Cited by 22 · see citing works
Synergistic targeting strategies for prostate cancer
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“The main downstream effector of AKT, mTOR, forms two complexes (mTORC1 and mTORC2) by interacting with different proteins 237 . mTOR has been shown to be expressed at higher levels in prostate cancer than in benign samples 226,238 . mTOR inhibitors including mTORC1 (such as everolimus and…”
Bersiner, K., Park, S., Schaaf, K., Yang, W., Theis, C., Jacko, D., & Gehlert, S. (2023) · Physical Activity and Nutrition · doi:10.20463/pan.2023.0021 · Cited by 20 · see citing works
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“Notably, mTORC1 plays a more important role in autophagy.(18,19) When external conditions are not suitable for cells to survive, 50-adenosine monophosphate-activated protein kinase (AMPK) is initially activated, and then mTORC1 is inhibited.”
BackgroundKim, H. K., Park, Y., Shin, M., Kim, J., & Go, G. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c04797 · Cited by 20 · see citing works
mTOR-Dependent Spine Dynamics in Autism
Chaudry, S., & Vasudevan, N. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.877609 · Cited by 22 · see citing works
- Authors
- Jhanwar-Uniyal, M., Wainwright, J. V., Mohan, A. L., Tobias, M. E., Murali, R., Gandhi, C. D., & Schmidt, M. H.
- Affiliations
- Westchester Medical Center (US)
- Venue
- Advances in Biological Regulation
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 72
- Pages
- 51-62
- ISSN
- 2212-4926 (ISSN-L)
- OpenAlex
- W2939056166
- Cited by
- 268
- References
- 94
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 37 · 2023: 38 · 2022: 52 · 2021: 44 · 2020: 40 · 2019: 5
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-12-01)
- Open access
- closed
- Locations
- Advances in Biological Regulation (publishedVersion)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Funders
- Advanced Research Foundation
- 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 › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Keywords
- mTORC2, PI3K/Akt signaling, glioblastoma, PTEN loss, 4E-BP1, S6K, PRAS40, SIN-1, rapamycin, cancer stem cells, drug resistance, cell proliferation, cell motility, cell migration, cell invasion, cell adhesion
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Animals, Humans, Signal Transduction, Cell Proliferation, Proto-Oncogene Proteins c-akt
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