Cited by 269PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerTuberous Sclerosis Complex Research

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Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship

Jhanwar-Uniyal, Meena, Wainwright, John V., Mohan, Avinash L., Tobias, Michael E., Murali, Raj, Gandhi, Chirag D., Schmidt, Meic H.·2019·Advances in Biological Regulation

DOI 10.1016/j.jbior.2019.03.003

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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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Background
Advances 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 41
Regulatory Mechanisms of Autophagy-Targeted Antimicrobial Therapeutics Against Mycobacterial Infection
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 35
“mTOR is a serine/threonine protein kinase consisting of mTORC1 andmTORC2 (Jhanwar-Uniyal et al., 2019), and regulates a variety”
Background
Targeting the mTOR pathway using novel ATP‑competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma
Amin, 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 36
“Molecular‐targeted therapy has garnered increasing attention in the treatment of GB (23,28,30).”
Background
GPX7 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
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
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 34
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
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 34
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
A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring
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 32
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 31
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 36
mTOR as a Potential Target for the Treatment of Microbial Infections, Inflammatory Bowel Diseases, and Colorectal Cancer
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 36
PAX7, a Key for Myogenesis Modulation in Muscular Dystrophies through Multiple Signaling Pathways: A Systematic Review
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
miR‐34a/c induce caprine endometrial epithelial cell apoptosis by regulating circ‐8073/CEP55 via the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways
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
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
“It serves as the core component of two multi-protein complexes (mTORC1 and mTORC2) that regulate different cell processes [reviewed in (17)].”
Background
Hepatoprotective effect of anemoside B4 against sepsis-induced acute liver injury through modulating the mTOR/p70S6K-mediated autophagy
Liang, P., & He, L. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109534 · Cited by 29
Trinity of inflammation, innate immune cells and cross-talk of signalling pathways in tumour microenvironment
Attiq, A., & Afzal, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1255727 · Cited by 31
“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).”
Background
mTOR 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
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
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
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
“The molecular details of the regulation of mTORC1 and mTORC2 complexes have been recently reviewed [37,38].”
Background
Structural analysis of a glucoglucuronan derived from laminarin and the mechanisms of its anti-lung cancer activity
Jin, 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
“Activation of mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerousmalignancies [44].”
Background
mTOR (Mammalian Target of Rapamycin): Hitting the Bull’s Eye for Enhancing Neurogenesis After Cerebral Ischemia?
Gao, J., Yao, M., Chang, D., & Liu, J. (2022) · Stroke · doi:10.1161/strokeaha.122.040376 · Cited by 26
Unveiling the genetic and epigenetic landscape of colorectal cancer: new insights into pathogenic pathways
Postwala, H., Shah, Y., Parekh, P. S., & Chorawala, M. R. (2023) · Medical Oncology · doi:10.1007/s12032-023-02201-8 · Cited by 26
“…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].”
Background
Discrete 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 26
“It is possible that mTOR activation is the major cause of GBM’s relentless growth and dissemination [79,80].”
Background
Mitochondrial dysfunction contributes to Rapamycin-induced apoptosis of Human Glioblastoma Cells - A synergistic effect with Temozolomide
Zimmerman, M. A., Wilkison, S. J., Qi, Q., Chen, G., & Li, P. A. (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.40159 · Cited by 25
“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].”
Background
HER2-Targeted Immunotherapy and Combined Protocols Showed Promising Antiproliferative Effects in Feline Mammary Carcinoma Cell-Based Models
Gameiro, A., Nascimento, C., Correia, J., & Ferreira, F. (2021) · Cancers · doi:10.3390/cancers13092007 · Cited by 28
“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].”
Background
mTOR 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 29
Phosphoinositides in cell proliferation and metabolism.
Hirsch, E., Gulluni, F., & Martini, M. (2020) · Advances in Biological Regulation · doi:10.1016/j.jbior.2020.100693 · Cited by 23
Amino Acid-Related Metabolic Signature in Obese Children and Adolescents
Polidori, N., Grasso, E. A., Chiarelli, F., & Giannini, C. (2022) · Nutrients · doi:10.3390/nu14071454 · Cited by 29
“, 4E-BP1 or EIF4E-BP1, S6K); meanwhile, mTORC2 regulates cytoskeletal remodeling and cells’ proliferation, migration and survival via PI3K and growth factor signaling [83].”
Background
Bioenergetic 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
Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome
Zaradzki, M., Mohr, F., Lont, S., Soethoff, J. P., Remes, A. K., Arif, R., Müller, O. J., Karck, M., Hecker, M., & Wagner, A. H. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115280 · Cited by 25
UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer
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
“With two distinct complexes called mTORC1 and mTORC2, the mTORC pathway contributes to diverse signaling pathways in physiological and pathological conditions [5].”
Background
Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma
Jhanwar‐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 21
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 25
Synergistic targeting strategies for prostate cancer
Li, X., Han, Z., & Ai, J. (2025) · Nature Reviews Urology · doi:10.1038/s41585-025-01042-6 · Cited by 22
“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…”
Resistance exercise: a mighty tool that adapts, destroys, rebuilds and modulates the molecular and structural environment of skeletal muscle
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
Compound essential oils relieve oxidative stress caused by PM2 .5 exposure by inhibiting autophagy through the AMPK / mTOR pathway
Ren, F., Xu, X., Xu, J., Mei, Y., Zhang, J., Wang, X., & Li, F. (2021) · Environmental Toxicology · doi:10.1002/tox.23297 · Cited by 20
“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.”
Background
Betulinic Acid Suppresses de novo Lipogenesis by Inhibiting Insulin and IGF1 Signaling as Upstream Effectors of the Nutrient-Sensing mTOR Pathway
Kim, 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
mTOR-Dependent Spine Dynamics in Autism
Chaudry, S., & Vasudevan, N. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.877609 · Cited by 23

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)
ORCID: Wainwright, John V.
Gandhi, Chirag D.
Schmidt, Meic H.
Venue: Advances in Biological Regulation
Publisher: Elsevier BV
Published: 2019-05
Volume: 72
Pages: 51-62
ISSN: 2212-4926 (ISSN-L)
DOI: 10.1016/j.jbior.2019.03.003
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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 › Genetics (clinical) › 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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Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship

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