Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Frontiers in mTOR Signaling

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 53058

Share This Special Issue

Special Issue Editor

Dr. Antonios N. Gargalionis

E-Mail Website
Guest Editor

Assistant Professor of Clinical Biochemistry and Medical Chemistry, Department of Clinical Biochemistry, School of Medicine, National and Kapodistrian University of Athens, 115 28 Athens, Greece
Interests: signal transduction; mechanobiology; tumorigenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Mechanistic Target of Rapamycin (mTOR), previously known as the mammalian target of rapamycin, is a central protein kinase that mediates the dynamic crosstalk of notable signal transduction pathways in physiology and disease. The mTOR-associated signaling cascades have been extensively investigated in the past two decades. Their fundamental role has been highlighted in several physiological processes, including cell growth and protein synthesis, metabolism and homeostasis of macromolecules, autophagy, immune, and brain function. Furthermore, deregulation of mTOR signaling networks has been well-documented in molecular mechanisms which drive carcinogenesis, diabetes, and aging. Recent findings also demonstrate that aberrant mTOR signaling is implicated in disorders of the central nervous system, including autism and Alzheimer's disease, as well as in systemic autoimmune diseases. Novel insights further suggest that mTOR regulates alterations in gut microbiota but also mediates viral survival and replication, and therefore, it plays a substantial role in regulating the host metabolic and immune functions. Regarding therapy, the mTOR inhibitors are a class of drugs that has been established as major immunosuppressants against transplant rejection, and they have been extensively tested as anticancer agents in the past with limited clinical activity. However, second-generation agents hold promise for potential efficacy in various disease entities.

In this Special Issue, we invite investigators to submit original research or review articles on the many facets in the regulation of mTOR signaling.

Dr. Antonios N. Gargalionis
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 signaling in cancer
mTOR inhibitors
mTOR signaling in metabolism
Alzheimer’s disease and mTOR signaling
mTOR and autophagy
mTOR and gut microbiota
mTOR and viral pathogenesis
mTOR and autoimmune diseases

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (11 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

9 pages, 1533 KiB

Open AccessArticle

Tadalafil Treatment of Mice with Fetal Growth Restriction and Preeclampsia Improves Placental mTOR Signaling

by Kayo Tanaka, Hiroaki Tanaka, Ryota Tachibana, Kento Yoshikawa, Takuya Kawamura, Sho Takakura, Hiroki Takeuchi and Tomoaki Ikeda

Int. J. Mol. Sci. 2022, 23(3), 1474; https://doi.org/10.3390/ijms23031474 - 27 Jan 2022

Cited by 3 | Viewed by 2553

Abstract

Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no effective intrauterine treatment method has been established. This study aimed to use tadalafil, a phosphodiesterase 5 inhibitor (PDE5) inhibitor, as a novel intrauterine treatment and conducted several basic and clinical studies. The study investigated the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR on 13 days post coitum (d.p.c.) but recovered to the same level as that of the control on 17 d.p.c. following tadalafil treatment. The results were similar for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) protein, which act downstream in the mTOR signaling pathway. We demonstrate that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and thus would be helpful for future clinical studies on FGR. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

21 pages, 47746 KiB

Open AccessArticle

The Energy Sensor AMPKα1 Is Critical in Rapamycin-Inhibition of mTORC1-S6K-Induced T-cell Memory

by Anjuman Ara, Aizhang Xu, Khawaja Ashfaque Ahmed, Scot C. Leary, Md. Fahmid Islam, Zhaojia Wu, Rajni Chibbar and Jim Xiang

Int. J. Mol. Sci. 2022, 23(1), 37; https://doi.org/10.3390/ijms23010037 - 21 Dec 2021

Cited by 9 | Viewed by 3588

Abstract

Energy sensors mTORC1 and AMPKα1 regulate T-cell metabolism and differentiation, while rapamycin (Rapa)-inhibition of mTORC1 (RIM) promotes T-cell memory. However, the underlying pathway and the role of AMPKα1 in Rapa-induced T-cell memory remain elusive. Using genetic and pharmaceutical tools, we demonstrate that Rapa promotes T-cell memory in mice in vivo post Listeria monocytogenesis rLmOVA infection and in vitro transition of effector T (T_E) to memory T (T_M) cells. IL-2- and IL-2+Rapa-stimulated T [IL-2/T and IL-2(Rapa+)/T] cells, when transferred into mice, differentiate into short-term IL-7R⁻CD62L⁻KLRG1⁺ T_E and long-lived IL-7R⁺CD62L⁺KLRG1⁻ T_M cells, respectively. To assess the underlying pathways, we performed Western blotting, confocal microscopy and Seahorse-assay analyses using IL-2/T and IL-2(Rapa+)/T-cells. We determined that IL-2(Rapa+)/T-cells activate transcription FOXO1, TCF1 and Eomes and metabolic pAMPKα1(T₁₇₂), pULK1(S₅₅₅) and ATG7 molecules and promote mitochondrial biogenesis and fatty-acid oxidation (FAO). We found that rapamycin-treated AMPKα-deficient AMPKα1-KO IL-2(Rapa+)/T_M cells up-regulate transcription factor HIF-1α and induce a metabolic switch from FAO to glycolysis. Interestingly, despite the rapamycin treatment, AMPKα-deficient T_M cells lost their cell survival capacity. Taken together, our data indicate that rapamycin promotes T-cell memory via transcriptional FOXO1-TCF1-Eomes programs and AMPKα1-ULK1-ATG7 metabolic axis, and that AMPKα1 plays a critical role in RIM-induced T-cell memory. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

Review

Jump to: Research

17 pages, 1216 KiB

Open AccessReview

mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity

by Natalia Mota-Martorell, Mariona Jové and Reinald Pamplona

Int. J. Mol. Sci. 2022, 23(15), 8747; https://doi.org/10.3390/ijms23158747 - 6 Aug 2022

Cited by 8 | Viewed by 3634

Abstract

Decreased content and activity of the mechanistic target of rapamycin (mTOR) signalling pathway, as well as the mTOR complex 1 (mTORC1) itself, are key traits for animal species and human longevity. Since mTORC1 acts as a master regulator of intracellular metabolism, it is responsible, at least in part, for the longevous phenotype. Conversely, increased content and activity of mTOR signalling and mTORC1 are hallmarks of ageing. Additionally, constitutive and aberrant activity of mTORC1 is also found in age-related diseases such as Alzheimer’s disease (AD) and cancer. The downstream processes regulated through this network are diverse, and depend upon nutrient availability. Hence, multiple nutritional strategies capable of regulating mTORC1 activity and, consequently, delaying the ageing process and the development of age-related diseases, are under continuous study. Among these, the restriction of calories is still the most studied and robust intervention capable of downregulating mTOR signalling and feasible for application in the human population. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

17 pages, 1035 KiB

Open AccessReview

The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data

by Aigli G. Vakrakou, Anastasia Alexaki, Maria-Evgenia Brinia, Maria Anagnostouli, Leonidas Stefanis and Panos Stathopoulos

Int. J. Mol. Sci. 2022, 23(15), 8077; https://doi.org/10.3390/ijms23158077 - 22 Jul 2022

Cited by 20 | Viewed by 4345

Abstract

This article recapitulates the evidence on the role of mammalian targets of rapamycin (mTOR) complex pathways in multiple sclerosis (MS). Key biological processes that intersect with mTOR signaling cascades include autophagy, inflammasome activation, innate (e.g., microglial) and adaptive (B and T cell) immune responses, and axonal and neuronal toxicity/degeneration. There is robust evidence that mTOR inhibitors, such as rapamycin, ameliorate the clinical course of the animal model of MS, experimental autoimmune encephalomyelitis (EAE). New, evolving data unravel mechanisms underlying the therapeutic effect on EAE, which include balance among T-effector and T-regulatory cells, and mTOR effects on myeloid cell function, polarization, and antigen presentation, with relevance to MS pathogenesis. Radiologic and preliminary clinical data from a phase 2 randomized, controlled trial of temsirolimus (a rapamycin analogue) in MS show moderate efficacy, with significant adverse effects. Large clinical trials of indirect mTOR inhibitors (metformin) in MS are lacking; however, a smaller prospective, non-randomized study shows some potentially promising radiological results in combination with ex vivo beneficial effects on immune cells that might warrant further investigation. Importantly, the study of mTOR pathway contributions to autoimmune inflammatory demyelination and multiple sclerosis illustrates the difficulties in the clinical application of animal model results. Nevertheless, it is not inconceivable that targeting metabolism in the future with cell-selective mTOR inhibitors (compared to the broad inhibitors tried to date) could be developed to improve efficacy and reduce side effects. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

15 pages, 1639 KiB

Open AccessReview

Medical Aspects of mTOR Inhibition in Kidney Transplantation

by Elena Cuadrado-Payán, Fritz Diekmann and David Cucchiari

Int. J. Mol. Sci. 2022, 23(14), 7707; https://doi.org/10.3390/ijms23147707 - 12 Jul 2022

Cited by 6 | Viewed by 2789

Abstract

The advances in transplant immunosuppression have reduced substantially the incidence of kidney graft rejection. In recent years, the focus has moved from preventing rejection to preventing the long-term consequences of long-standing immunosuppression, including nephrotoxicity induced by calcineurin inhibitors (CNI), as well as infectious and neoplastic complications. Since the appearance in the late 1990s of mTOR inhibitors (mTORi), these unmet needs in immunosuppression management could be addressed thanks to their benefits (reduced rate of viral infections and cancer). However, management of side effects can be troublesome and hands-on experience is needed. Here, we review all the available information about them. Thanks to all the basic, translational and clinical research achieved in the last twenty years, we now use mTORi as de novo immunosuppression in association with CNI. Another possibility is represented by the conversion of either CNI or mycophenolate (MPA) to an mTORi later on after transplantation in low-risk kidney transplant recipients. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

15 pages, 979 KiB

Open AccessReview

The Role of mTOR and eIF Signaling in Benign Endometrial Diseases

by Tatiana S. Driva, Christoph Schatz, Monika Sobočan and Johannes Haybaeck

Int. J. Mol. Sci. 2022, 23(7), 3416; https://doi.org/10.3390/ijms23073416 - 22 Mar 2022

Cited by 14 | Viewed by 4053

Abstract

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

24 pages, 3035 KiB

Open AccessReview

Dysregulation of mTOR Signaling after Brain Ischemia

by Mario Villa-González, Gerardo Martín-López and María José Pérez-Álvarez

Int. J. Mol. Sci. 2022, 23(5), 2814; https://doi.org/10.3390/ijms23052814 - 4 Mar 2022

Cited by 18 | Viewed by 4417

Abstract

In this review, we provide recent data on the role of mTOR kinase in the brain under physiological conditions and after damage, with a particular focus on cerebral ischemia. We cover the upstream and downstream pathways that regulate the activation state of mTOR complexes. Furthermore, we summarize recent advances in our understanding of mTORC1 and mTORC2 status in ischemia–hypoxia at tissue and cellular levels and analyze the existing evidence related to two types of neural cells, namely glia and neurons. Finally, we discuss the potential use of mTORC1 and mTORC2 as therapeutic targets after stroke. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

16 pages, 12113 KiB

Open AccessReview

mTOR Signaling and Potential Therapeutic Targeting in Meningioma

by Benjamin Pinker and Anna-Maria Barciszewska

Int. J. Mol. Sci. 2022, 23(4), 1978; https://doi.org/10.3390/ijms23041978 - 10 Feb 2022

Cited by 9 | Viewed by 3585

Abstract

Meningiomas are the most frequent primary tumors arising in the central nervous system. They typically follow a benign course, with an excellent prognosis for grade I lesions through surgical intervention. Although radiotherapy is a good option for recurrent, progressive, or inoperable tumors, alternative treatments are very limited. mTOR is a protein complex with increasing therapeutical potential as a target in cancer. The current understanding of the mTOR pathway heavily involves it in the development of meningioma. Its activation is strongly dependent on PI3K/Akt signaling and the merlin protein. Both factors are commonly defective in meningioma cells, which indicates their likely function in tumor growth. Furthermore, regarding molecular tumorigenesis, the kinase activity of the mTORC1 complex inhibits many components of the autophagosome, such as the ULK1 or Beclin complexes. mTOR contributes to redox homeostasis, a vital component of neoplasia. Recent clinical trials have investigated novel chemotherapeutic agents for mTOR inhibition, showing promising results in resistant or recurrent meningiomas. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

16 pages, 1105 KiB

Open AccessReview

mTOR Signaling Components in Tumor Mechanobiology

by Antonios N. Gargalionis, Kostas A. Papavassiliou, Efthimia K. Basdra and Athanasios G. Papavassiliou

Int. J. Mol. Sci. 2022, 23(3), 1825; https://doi.org/10.3390/ijms23031825 - 5 Feb 2022

Cited by 19 | Viewed by 4531

Abstract

Mechanistic target of rapamycin (mTOR) is a central signaling hub that integrates networks of nutrient availability, cellular metabolism, and autophagy in eukaryotic cells. mTOR kinase, along with its upstream regulators and downstream substrates, is upregulated in most human malignancies. At the same time, mechanical forces from the tumor microenvironment and mechanotransduction promote cancer cells’ proliferation, motility, and invasion. mTOR signaling pathway has been recently found on the crossroads of mechanoresponsive-induced signaling cascades to regulate cell growth, invasion, and metastasis in cancer cells. In this review, we examine the emerging association of mTOR signaling components with certain protein tools of tumor mechanobiology. Thereby, we highlight novel mechanisms of mechanotransduction, which regulate tumor progression and invasion, as well as mechanisms related to the therapeutic efficacy of antitumor drugs. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

20 pages, 9568 KiB

Open AccessReview

Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential

by Fani Karagianni, Antreas Pavlidis, Lina S. Malakou, Christina Piperi and Evangelia Papadavid

Int. J. Mol. Sci. 2022, 23(3), 1693; https://doi.org/10.3390/ijms23031693 - 1 Feb 2022

Cited by 36 | Viewed by 11938

Abstract

The serine/threonine kinase mechanistic target of rapamycin (mTOR) plays a pivotal role in the regulation of cell proliferation, survival, and motility in response to availability of energy and nutrients as well as mitogens. The mTOR signaling axis regulates important biological processes, including cellular growth, metabolism, and survival in many tissues. In the skin, dysregulation of PI3K/AKT/mTOR pathway may lead to severe pathological conditions characterized by uncontrolled proliferation and inflammation, including skin hyperproliferative as well as malignant diseases. Herein, we provide an update on the current knowledge regarding the pathogenic implication of the mTOR pathway in skin diseases with inflammatory features (such as psoriasis, atopic dermatitis, pemphigus, and acne) and malignant characteristics (such as cutaneous T cell lymphoma and melanoma) while we critically discuss current and future perspectives for therapeutic targeting of mTOR axis in clinical practice. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Figure 1

19 pages, 2023 KiB

Open AccessReview

Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis

by Wei Shern Lee, Sara Baldassari, Sarah E. M. Stephenson, Paul J. Lockhart, Stéphanie Baulac and Richard J. Leventer

Int. J. Mol. Sci. 2022, 23(3), 1344; https://doi.org/10.3390/ijms23031344 - 25 Jan 2022

Cited by 20 | Viewed by 6087

Abstract

Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development. Full article

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

► Show Figures

Journal Menu

Journal Browser

Frontiers in mTOR Signaling

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (11 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI