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Regulation of mTOR Signaling in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 8107

Special Issue Editor


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Guest Editor
Institut de Cancerologie Gustave Roussy, 94805 Villejuif, France
Interests: mTORC1 pathway; autophagy; mitochondria; cancer

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to our Special Issue, “Regulation of mTOR Signaling in Human Diseases”, which is a continuation of the series of reviews and original research on the same topic published by IJMS in 2019 and 2020.

https://www.mdpi.com/journal/ijms/special_issues/mTOR_human

https://www.mdpi.com/journal/ijms/special_issues/mTOR_human2

This Special issue aims to cover recent advances related to the role of mTORC1 and mTORC2 complexes as well as mTOR pathway in general in various human pathologies, including cancer, diabetes, neurological and metabolic disorders, cardio-vascular diseases and viral infections. Because the majority of these disorders are associated with hyperactivated mTOR signaling, we would also like to overview a research progress in the therapies with mTOR inhibitors.

If you are interested in contributing your work, including experimental studies, review articles and commentaries, please send a short abstract or tentative title to the Guest Editor or Editorial Office.

Dr. Svetlana Dokudovskaya
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mTOR pathway
  • cancer
  • neurodegenerative and neurodevelopmental disorders
  • metabolic diseases
  • mTOR inhibitors

Published Papers (5 papers)

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Research

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14 pages, 3120 KiB  
Article
GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1
by Maéline Muller, Jasmine Bélanger, Imane Hadj-Aissa, Conghao Zhang, Chantelle F. Sephton and Paul A. Dutchak
Int. J. Mol. Sci. 2024, 25(4), 2068; https://doi.org/10.3390/ijms25042068 - 08 Feb 2024
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Abstract
GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like [...] Read more.
GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like 2), NPRL3 (nitrogen permease regulator-like 3), and DEPDC5 (DEP domain containing 5), have been associated with epilepsy in humans; however, the specific effects of these mutations on GATOR1 function and mTORC1 regulation are not well understood. Herein, we report that epilepsy-linked mutations in the NPRL2 subunit of GATOR1, NPRL2-L105P, -T110S, and -D214H, increase basal mTORC1 signal transduction in cells. Notably, we show that NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation. Furthermore, our studies reveal that the GATOR1 complex is necessary for the rapid and robust inhibition of mTORC1 in response to growth factor withdrawal or pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids. Full article
(This article belongs to the Special Issue Regulation of mTOR Signaling in Human Diseases)
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21 pages, 3350 KiB  
Article
Activation of the PI3K/AKT/mTOR Pathway in Cajal–Retzius Cells Leads to Their Survival and Increases Susceptibility to Kainate-Induced Seizures
by Nasim Ramezanidoraki, Driss El Ouardi, Margaux Le, Stéphanie Moriceau, Mahboubeh Ahmadi, Elena Dossi, Danae Rolland, Philippe Bun, Gwenaëlle Le Pen, Guillaume Canaud, Nadia Bahi-Buisson, Nathalie Rouach, Rebecca Piskorowski, Alessandra Pierani and Pierre Billuart
Int. J. Mol. Sci. 2023, 24(6), 5376; https://doi.org/10.3390/ijms24065376 - 11 Mar 2023
Cited by 1 | Viewed by 1882
Abstract
Cajal–Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life [...] Read more.
Cajal–Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro–caudal and medio–lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the Pten model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype. Full article
(This article belongs to the Special Issue Regulation of mTOR Signaling in Human Diseases)
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Review

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18 pages, 2097 KiB  
Review
Signaling Pathways Leading to mTOR Activation Downstream Cytokine Receptors in Lymphocytes in Health and Disease
by Lucie Fallone, Thierry Walzer and Antoine Marçais
Int. J. Mol. Sci. 2023, 24(16), 12736; https://doi.org/10.3390/ijms241612736 - 13 Aug 2023
Cited by 1 | Viewed by 1837
Abstract
CD8+ T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. [...] Read more.
CD8+ T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. This integration is achieved by signaling hubs, such as the mechanistic target of rapamycin (mTOR). mTOR is a conserved protein kinase that controls cellular growth and metabolism in eukaryotic cells and, therefore, is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model for comprehending metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here, we review the signaling pathways leading to mTOR activation in CD8+ T and NK cells, focusing on activation by cytokines. We also discuss how this knowledge can contribute to immunotherapy development, particularly for cancer treatment. Full article
(This article belongs to the Special Issue Regulation of mTOR Signaling in Human Diseases)
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16 pages, 2444 KiB  
Review
The Role of mTORC1 Pathway and Autophagy in Resistance to Platinum-Based Chemotherapeutics
by Zhenrui Pan, Hanxiao Zhang and Svetlana Dokudovskaya
Int. J. Mol. Sci. 2023, 24(13), 10651; https://doi.org/10.3390/ijms241310651 - 26 Jun 2023
Cited by 2 | Viewed by 1371
Abstract
Cisplatin (cis-diamminedichloroplatinum I) is a platinum-based drug, the mainstay of anticancer treatment for numerous solid tumors. Since its approval by the FDA in 1978, the drug has continued to be used for the treatment of half of epithelial cancers. However, resistance [...] Read more.
Cisplatin (cis-diamminedichloroplatinum I) is a platinum-based drug, the mainstay of anticancer treatment for numerous solid tumors. Since its approval by the FDA in 1978, the drug has continued to be used for the treatment of half of epithelial cancers. However, resistance to cisplatin represents a major obstacle during anticancer therapy. Here, we review recent findings on how the mTORC1 pathway and autophagy can influence cisplatin sensitivity and resistance and how these data can be applicable for the development of new therapeutic strategies. Full article
(This article belongs to the Special Issue Regulation of mTOR Signaling in Human Diseases)
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18 pages, 1160 KiB  
Review
mTOR Signaling Pathway in Bone Diseases Associated with Hyperglycemia
by Shuangcheng Wang, Jiale Wang, Shuangwen Wang, Ran Tao, Jianru Yi, Miao Chen and Zhihe Zhao
Int. J. Mol. Sci. 2023, 24(11), 9198; https://doi.org/10.3390/ijms24119198 - 24 May 2023
Viewed by 1407
Abstract
The interplay between bone and glucose metabolism has highlighted hyperglycemia as a potential risk factor for bone diseases. With the increasing prevalence of diabetes mellitus worldwide and its subsequent socioeconomic burden, there is a pressing need to develop a better understanding of the [...] Read more.
The interplay between bone and glucose metabolism has highlighted hyperglycemia as a potential risk factor for bone diseases. With the increasing prevalence of diabetes mellitus worldwide and its subsequent socioeconomic burden, there is a pressing need to develop a better understanding of the molecular mechanisms involved in hyperglycemia-mediated bone metabolism. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that senses extracellular and intracellular signals to regulate numerous biological processes, including cell growth, proliferation, and differentiation. As mounting evidence suggests the involvement of mTOR in diabetic bone disease, we provide a comprehensive review of its effects on bone diseases associated with hyperglycemia. This review summarizes key findings from basic and clinical studies regarding mTOR’s roles in regulating bone formation, bone resorption, inflammatory responses, and bone vascularity in hyperglycemia. It also provides valuable insights into future research directions aimed at developing mTOR-targeted therapies for combating diabetic bone diseases. Full article
(This article belongs to the Special Issue Regulation of mTOR Signaling in Human Diseases)
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