The Roles of Post-Translational Modifications on mTOR Signaling

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.

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Comparative Genome-wide Analysis and Expression Profiling of Histone Acetyltransferase (HAT) Gene Family in Response to Hormonal Applications, Metal and Abiotic Stresses in Cotton

International Journal of Molecular Sciences ◽

10.3390/ijms20215311 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5311 ◽

Cited By ~ 3

Author(s):

Muhammad Imran ◽

Sarfraz Shafiq ◽

Muhammad Ansar Farooq ◽

Muhammad Kashif Naeem ◽

Emilie Widemann ◽

...

Keyword(s):

Fiber Quality ◽

Purifying Selection ◽

Fiber Development ◽

Amino Acid Sequences ◽

Environmental Cues ◽

Post Translational Modifications ◽

Cellular Processes ◽

Genome Wide ◽

Selection Gene ◽

Almost All

Post-translational modifications are involved in regulating diverse developmental processes. Histone acetyltransferases (HATs) play vital roles in the regulation of chromation structure and activate the gene transcription implicated in various cellular processes. However, HATs in cotton, as well as their regulation in response to developmental and environmental cues, remain unidentified. In this study, 9 HATs were identified from Gossypium raimondi and Gossypium arboretum, while 18 HATs were identified from Gossypium hirsutum. Based on their amino acid sequences, Gossypium HATs were divided into three groups: CPB, GNAT, and TAFII250. Almost all the HATs within each subgroup share similar gene structure and conserved motifs. Gossypium HATs are unevenly distributed on the chromosomes, and duplication analysis suggests that Gossypium HATs are under strong purifying selection. Gene expression analysis showed that Gossypium HATs were differentially expressed in various vegetative tissues and at different stages of fiber development. Furthermore, all the HATs were differentially regulated in response to various stresses (salt, drought, cold, heavy metal and DNA damage) and hormones (abscisic acid (ABA) and auxin (NAA)). Finally, co-localization of HAT genes with reported quantitative trait loci (QTL) of fiber development were reported. Altogether, these results highlight the functional diversification of HATs in cotton growth and fiber development, as well as in response to different environmental cues. This study enhances our understanding of function of histone acetylation in cotton growth, fiber development, and stress adaptation, which will eventually lead to the long-term improvement of stress tolerance and fiber quality in cotton.

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mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21082718 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2718 ◽

Cited By ~ 2

Author(s):

Yasmine Lund-Ricard ◽

Patrick Cormier ◽

Julia Morales ◽

Agnès Boutet

Keyword(s):

Evolutionary Biology ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Human Diseases ◽

Whole Body ◽

Body Parts ◽

Animal Kingdom ◽

Structure Damage ◽

Wide Range

A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

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mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms20030755 ◽

2019 ◽

Vol 20 (3) ◽

pp. 755 ◽

Cited By ~ 93

Author(s):

Tian Tian ◽

Xiaoyi Li ◽

Jinhua Zhang

Keyword(s):

Mtor Inhibitors ◽

Genetic Alterations ◽

Mtor Pathway ◽

Mtor Signaling ◽

Genetic Changes ◽

Targeting Therapy ◽

Sequencing Technologies ◽

Innovative Therapies ◽

Cancer Types ◽

New Biomarkers

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.

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Role of mTOR Signaling in Tumor Microenvironment: An Overview

International Journal of Molecular Sciences ◽

10.3390/ijms19082453 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2453 ◽

Cited By ~ 46

Author(s):

Fabiana Conciatori ◽

Chiara Bazzichetto ◽

Italia Falcone ◽

Sara Pilotto ◽

Emilio Bria ◽

...

Keyword(s):

Tumor Microenvironment ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

New Combination ◽

Combination Therapies ◽

Cellular Processes ◽

Promising Target ◽

Exogenous Cues

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy.

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Mechanistic target of rapamycin signaling in mouse models of accelerated aging

The Journals of Gerontology Series A ◽

10.1093/gerona/glz059 ◽

2019 ◽

Vol 75 (1) ◽

pp. 64-72 ◽

Cited By ~ 4

Author(s):

Jin Young Lee ◽

Brian K Kennedy ◽

Chen-Yu Liao

Keyword(s):

Mouse Models ◽

Accelerated Aging ◽

Nutrient Sensing ◽

Mtor Signaling ◽

Human Diseases ◽

Target Of Rapamycin ◽

Cellular Processes ◽

Positive Effects ◽

Mechanistic Target Of Rapamycin ◽

Age Related

Abstract The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.

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Weighing In on mTOR Complex 2 Signaling: The Expanding Role in Cell Metabolism

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7838647 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 9

Author(s):

Yongting Luo ◽

Wenyi Xu ◽

Guannan Li ◽

Wei Cui

Keyword(s):

Structural Biology ◽

Metabolic Diseases ◽

Cell Metabolism ◽

Mtor Signaling ◽

Cellular Processes ◽

Mechanistic Target Of Rapamycin ◽

Signal Output ◽

Structure Regulation ◽

And Function ◽

Mtor Complex 1

In all eukaryotes, the mechanistic target of rapamycin (mTOR) signaling emerges as a master regulator of homeostasis, which integrates environmental inputs, including nutrients, energy, and growth factors, to regulate many fundamental cellular processes such as cell growth and metabolism. mTOR signaling functions through two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which correspond to two major branches of signal output. While mTORC1 is well characterized for its structure, regulation, and function in the last decade, information of mTORC2 signaling is only rapidly expanding in recent years, from structural biology, signaling network, to functional impact. Here we review the recent advances in many aspects of the mTORC2 signaling, with particular focus on its involvement in the control of cell metabolism and its physiological implications in metabolic diseases and aging.

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The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21124507 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4507 ◽

Cited By ~ 2

Author(s):

Boris Y. Shorning ◽

Manisha S. Dass ◽

Matthew J. Smalley ◽

Helen B. Pearson

Keyword(s):

Prostate Cancer ◽

Protein Kinase ◽

Wnt Signaling ◽

Genetic Alterations ◽

Signaling Network ◽

Mtor Pathway ◽

Mtor Signaling ◽

Signaling Cascades ◽

Prostate Tumorigenesis ◽

Frequent Event

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.

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The Role of mTOR Signaling as a Therapeutic Target in Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22041743 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1743

Author(s):

Nadezhda V. Popova ◽

Manfred Jücker

Keyword(s):

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Genetic Alterations ◽

Mtor Pathway ◽

Mtor Signaling ◽

Cell Processes ◽

And Function ◽

Available Information ◽

Mtor Complex 1

The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.

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Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

Current Medicinal Chemistry ◽

10.2174/0929867327666200504081503 ◽

2020 ◽

Vol 27 ◽

Author(s):

Naser-Aldin Lashgari ◽

Nazanin Momeni Roudsari ◽

Saeideh Momtaz ◽

Negar Ghanaatian ◽

Parichehr Kohansal ◽

...

Keyword(s):

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

In Vivo Studies ◽

Cochrane Library ◽

Mtor Signaling Pathway ◽

Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

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Mitochondrial Glucocorticoid Receptors and Their Actions

International Journal of Molecular Sciences ◽

10.3390/ijms22116054 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6054

Author(s):

Ioanna Kokkinopoulou ◽

Paraskevi Moutsatsou

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptors ◽

Mitochondrial Gene ◽

Cell Types ◽

Ros Generation ◽

Mitochondrial Gene Expression ◽

Mitochondrial Energy Metabolism ◽

Bcl2 Family ◽

Cellular Processes ◽

Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

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