The DOI matches its Crossref record; 93 of the 94 references it cites were found in a registry or an index.
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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“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
Citations
Cites
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The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
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Research works printed but not linked: 1
- Lassen, 2013, vol. 33, 1657
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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 770
“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 652
“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
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 287
“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 225
“Feedback control loops exist between mTORC1 and mTORC2 [105].”
Background
Metadata
- 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 › 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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