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

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
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.

scholarly journals DROSOPHILA MTOR COMPLEX 2 PRESERVES MITOCHONDRIAL AND CARDIAC FUNCTION UNDER HIGH FAT DIET TREATMENT

2021 ◽  
Author(s):  
Kai Chang ◽  
Guillermo A. Requejo Figueroa ◽  
Hua Bai
Keyword(s):  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Mitochondrial Morphology ◽  
Contractile Dysfunction ◽  
Wild Type ◽  
High Fat ◽  
Mitochondrial Homeostasis ◽  
Mechanistic Target Of Rapamycin ◽  
And Function ◽  
Mtor Complex 1

AbstractHigh fat diet (HFD)-associated lipotoxicity is one of the major causes of cardiovascular diseases. The mechanistic target of rapamycin (mTOR) pathway, especially mTOR complex 1 (mTORC1), has been previously implicated in HFD-induced heart dysfunction. In the present study, we find that unlike mTORC1, mTOR complex 2 (mTORC2) protects hearts from HFD-induced cardiomyopathy and mitochondrial dysfunction in Drosophila. We show that HFD feeding induces contractile dysfunction along with altered mitochondrial morphology and function. Upon HFD feeding, the mitochondria of cardiomyocytes exhibit fragmentation, loss of membrane potential, and calcium overload. Interestingly, HFD feeding also reduces the activity of cardiac mTORC2. In line with this finding, the flies with cardiac-specific knockdown of rictor, the key subunit of mTORC2, show cardiac and mitochondrial dysfunction similar to what is observed in HFD-fed wild-type flies. Conversely, cardiac-specific activation of mTORC2 by overexpressing rictor attenuates HFD-induced mitochondrial and cardiac dysfunction. Thus, our findings suggest that mTORC2 is a cardioprotective factor and regulates mitochondrial homeostasis upon HFD feeding.

scholarly journals Mechanistic target of rapamycin signaling in mouse models of accelerated aging

2019 ◽  
Vol 75 (1) ◽  
pp. 64-72 ◽  
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.

scholarly journals The Roles of Post-Translational Modifications on mTOR Signaling

2021 ◽  
Vol 22 (4) ◽  
pp. 1784
Author(s):  
Shasha Yin ◽  
Liu Liu ◽  
Wenjian Gan
Keyword(s):  
Metabolic Diseases ◽  
Lipid Synthesis ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Human Diseases ◽  
Post Translational Modifications ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Almost All

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.

scholarly journals Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1256
Author(s):  
Toufic Kassouf ◽  
Grzegorz Sumara
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Cell Metabolism ◽  
Extracellular Signal Regulated Kinase ◽  
Cellular Processes ◽  
Obesity And Diabetes ◽  
Extracellular Signal ◽  
Mediators Of Inflammation ◽  
Mitogen Activated Protein

The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.

scholarly journals mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review

Gerontology ◽  
2017 ◽  
Vol 64 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Thomas Weichhart
Keyword(s):  
Cellular Senescence ◽  
Cell Function ◽  
Individual Cell ◽  
Mtor Signaling ◽  
Model Organisms ◽  
Therapeutic Approaches ◽  
Mechanistic Target Of Rapamycin ◽  
Apoptosis And Inflammation ◽  
The Individual ◽  
Mtor Complex 1

The mechanistic target of rapamycin (mTOR) network is an evolutionary conserved signaling hub that senses and integrates environmental and intracellular nutrient and growth factor signals to coordinate basic cellular and organismal responses such as cell growth, proliferation, apoptosis, and inflammation depending on the individual cell and tissue. A growing list of evidence suggests that mTOR signaling influences longevity and aging. Inhibition of the mTOR complex 1 (mTORC1) with rapamycin is currently the only known pharmacological treatment that increases lifespan in all model organisms studied. This review discusses the potential mechanisms how mTOR signaling controls lifespan and influences aging-related processes such as cellular senescence, metabolism, and stem cell function. Understanding these processes might provide novel therapeutic approaches to influence longevity and aging-related diseases.

scholarly journals The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

2018 ◽  
Vol 19 (9) ◽  
pp. 2560 ◽  
Author(s):  
Abdullah Hoter ◽  
Marwan El-Sabban ◽  
Hassan Naim
Keyword(s):  
Potential Role ◽  
General Structure ◽  
Cell Cycle Control ◽  
Cellular Processes ◽  
Physiological Processes ◽  
Regulation Function ◽  
Health And Disease ◽  
Structure Regulation ◽  
And Function ◽  
Cellular Compartments

The mammalian HSP90 family of proteins is a cluster of highly conserved molecules that are involved in myriad cellular processes. Their distribution in various cellular compartments underlines their essential roles in cellular homeostasis. HSP90 and its co-chaperones orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis. Conversely, HSP90, and its secreted forms, contribute to the development and progress of serious pathologies, including cancer and neurodegenerative diseases. Therefore, targeting HSP90 is an attractive strategy for the treatment of neoplasms and other diseases. This manuscript will review the general structure, regulation and function of HSP90 family and their potential role in pathophysiology.

scholarly journals Chemical biology probes of mammalian GLUT structure and function

2018 ◽  
Vol 475 (22) ◽  
pp. 3511-3534 ◽  
Author(s):  
Geoffrey D. Holman
Keyword(s):  
Drug Targets ◽  
Chemical Biology ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Structure And Function ◽  
Research Groups ◽  
And Function ◽  
Diabetes And Obesity ◽  
Potential Drug Targets

The structure and function of glucose transporters of the mammalian GLUT family of proteins has been studied over many decades, and the proteins have fascinated numerous research groups over this time. This interest is related to the importance of the GLUTs as archetypical membrane transport facilitators, as key limiters of the supply of glucose to cell metabolism, as targets of cell insulin and exercise signalling and of regulated membrane traffic, and as potential drug targets to combat cancer and metabolic diseases such as type 2 diabetes and obesity. This review focusses on the use of chemical biology approaches and sugar analogue probes to study these important proteins.

scholarly journals The Role of mTOR Signaling as a Therapeutic Target in Cancer

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.

scholarly journals The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

2018 ◽  
Vol 10 (459) ◽  
pp. eaat9356 ◽  
Author(s):  
Fabiana Csukasi ◽  
Ivan Duran ◽  
Maya Barad ◽  
Tomas Barta ◽  
Iva Gudernova ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Skeletal Development ◽  
Mtor Signaling ◽  
Negative Regulator ◽  
Common Mechanism ◽  
Homozygous Mutation ◽  
Constitutive Activation ◽  
Mechanistic Target Of Rapamycin ◽  
Pthrp Receptor ◽  
Mtor Complex 1

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)–salt-inducible kinase 3 (SIK3)–mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

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