scholarly journals The lysosome: a crucial hub for AMPK and mTORC1 signalling

2017 ◽  
Vol 474 (9) ◽  
pp. 1453-1466 ◽  
Author(s):  
Bernadette Carroll ◽  
Elaine A. Dunlop
Keyword(s):  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Signalling Pathways ◽  
Initial Discovery ◽  
Multiple Levels ◽  
Energy Sensing ◽  
Amino Acid Sensing ◽  
Amp Activated Protein Kinase ◽  
Mtorc1 Activation

Much attention has recently been focussed on the lysosome as a signalling hub. Following the initial discovery that localisation of the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), to the lysosome was essential for mTORC1 activation, the field has rapidly expanded to reveal the role of the lysosome as a platform permitting the co-ordination of several homeostatic signalling pathways. Much is now understood about how the lysosome contributes to amino acid sensing by mTORC1, the involvement of the energy-sensing kinase, AMP-activated protein kinase (AMPK), at the lysosome and how both AMPK and mTORC1 signalling pathways feedback to lysosomal biogenesis and regeneration following autophagy. This review will cover the classical role of the lysosome in autophagy, the dynamic signalling interactions which take place on the lysosomal surface and the multiple levels of cross-talk which exist between lysosomes, AMPK and mTORC1.

scholarly journals Insights into the Interaction of Lysosomal Amino Acid Transporters SLC38A9 and SLC36A1 Involved in mTORC1 Signaling in C2C12 Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1314
Author(s):  
Dan Wang ◽  
Xuebin Wan ◽  
Xiaoli Du ◽  
Zhuxia Zhong ◽  
Jian Peng ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Skeletal Muscle Mass ◽  
Mammalian Target Of Rapamycin ◽  
C2c12 Cells ◽  
Amino Acid Transporters ◽  
Interacting Proteins ◽  
Mtorc1 Signaling ◽  
Amino Acid Sensing ◽  
Mtorc1 Activation

Amino acids are critical for mammalian target of rapamycin complex 1 (mTORC1) activation on the lysosomal surface. Amino acid transporters SLC38A9 and SLC36A1 are the members of the lysosomal amino acid sensing machinery that activates mTORC1. The current study aims to clarify the interaction of SLC38A9 and SLC36A1. Here, we discovered that leucine increased expressions of SLC38A9 and SLC36A1, leading to mTORC1 activation. SLC38A9 interacted with SLC36A1 and they enhanced each other’s expression levels and locations on the lysosomal surface. Additionally, the interacting proteins of SLC38A9 in C2C12 cells were identified to participate in amino acid sensing mechanism, mTORC1 signaling pathway, and protein synthesis, which provided a resource for future investigations of skeletal muscle mass.

scholarly journals Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between mTORC1 and CaSR-Gq signaling pathways

2021 ◽  
Author(s):  
Yulong Gong ◽  
Ding-Dong Zhang ◽  
Zihan Tang ◽  
Katie Coate ◽  
Walter Siv ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Calcium Sensing ◽  
Co Activation ◽  
Mouse Islets ◽  
Main Regulator ◽  
Necessary And Sufficient ◽  
Mtorc1 Activation

Abstract Glucagon has emerged as the main regulator of extracellular amino acid homeostasis. Insufficient glucagon signaling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Aside from mammalian target of rapamycin complex 1 (mTORC1), the role of other amino acid sensors in the α cell proliferation has not been described. Here, using gcgr-deficient zebrafish and cultured mouse islets, we show that α cell proliferation requires the calcium sensing receptor (CaSR) and downstream extracellular signalregulated protein kinase (ERK1/2). Inactivation of casr dampened α cell proliferation, which can be rescued by re-expression of CaSR or activation of the downstream Gq, but not Gi, signaling in α cells. CaSR was also unexpectedly necessary for mTORC1 activation in α cells. Furthermore, co-activation of Gq and mTORC1 induced α cell proliferation independent of hyperaminoacidemia. These results reveal another amino acid sensitive mediator, and identify major pathways necessary and sufficient for hyperaminoacidemia-induced α cell proliferation.

scholarly journals Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application

2021 ◽  
Vol 22 (21) ◽  
pp. 11427
Author(s):  
Chunchen Liu ◽  
Linbao Ji ◽  
Jinhua Hu ◽  
Ying Zhao ◽  
Lee J. Johnston ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Amino Acids ◽  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Comprehensive Overview ◽  
Related Disease ◽  
Signal Relay ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

Functional amino acids provide great potential for treating autophagy-related diseases by regulating autophagy. The purpose of the autophagy process is to remove unwanted cellular contents and to recycle nutrients, which is controlled by many factors. Disordered autophagy has been reported to be associated with various diseases, such as cancer, neurodegeneration, aging, and obesity. Autophagy cannot be directly controlled and dynamic amino acid levels are sufficient to regulate autophagy. To date, arginine, leucine, glutamine, and methionine are widely reported functional amino acids that regulate autophagy. As a signal relay station, mammalian target of rapamycin complex 1 (mTORC1) turns various amino acid signals into autophagy signaling pathways for functional amino acids. Deficiency or supplementation of functional amino acids can immediately regulate autophagy and is associated with autophagy-related disease. This review summarizes the mechanisms currently involved in autophagy and amino acid sensing, diverse signal transduction among functional amino acids and autophagy, and the therapeutic appeal of amino acids to autophagy-related diseases. We aim to provide a comprehensive overview of the mechanisms of amino acid regulation of autophagy and the role of functional amino acids in clinical autophagy-related diseases and to further convert these mechanisms into feasible therapeutic applications.

scholarly journals PAT2 regulates autophagy through vATPase assembly and lysosomal acidification in brown adipocytes

2020 ◽  
Author(s):  
Jiefu Wang ◽  
Martin Krueger ◽  
Stefanie M. Hauck ◽  
Siegfried Ussar
Keyword(s):  
Amino Acid ◽  
Brown Adipocyte ◽  
Amino Acid Transporters ◽  
Mitochondrial Uncoupling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Glucose And Lipid Homeostasis ◽  
Mtorc1 Activation ◽  
Lysosomal Acidification

Brown adipose tissue (BAT) plays a key role in maintaining body temperature as well as glucose and lipid homeostasis by its ability to dissipate energy through mitochondrial uncoupling. To facilitate these tasks BAT needs to adopt its thermogenic activity and substrate utilization to changes in nutrient availability, regulated by a complex network of neuronal, endocrine and nutritional inputs. Amongst this multitude of factors influencing BAT activity changes in the autophagic response of brown adipocytes are an important regulator of its thermogenic capacity and activity. Increasing evidence supports an important role of amino acid transporters in mTORC1 activation and the regulation of autophagy. However, a specific role of amino acid transporters in BAT regulating its function has not been described. Here we show that the brown adipocyte specific proton coupled amino acid transporter PAT2 rapidly translocates from the plasma membrane to the lysosome in response to amino acid withdrawal, where it facilitates the assembly of the lysosomal vATPase. Loss or overexpression of PAT2 therefore impair lysosomal acidification, autophagolysosome formation and starvation induced mTORC1 activation.

scholarly journals MicroRNA-126-3p Inhibits Angiogenic Function of Human Lung Microvascular Endothelial Cells via LAT1 (L-Type Amino Acid Transporter 1)-Mediated mTOR (Mammalian Target of Rapamycin) Signaling

2020 ◽  
Vol 40 (5) ◽  
pp. 1195-1206 ◽  
Author(s):  
Danting Cao ◽  
Andrew M. Mikosz ◽  
Alexandra J. Ringsby ◽  
Kelsey C. Anderson ◽  
Erica L. Beatman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Amino Acid ◽  
Cell Apoptosis ◽  
Human Lung ◽  
Mammalian Target Of Rapamycin ◽  
Tube Formation ◽  
Microvascular Endothelial Cells ◽  
Microvascular Endothelial

Objective: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. Conclusions: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.

scholarly journals Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 100 ◽  
Author(s):  
Yizhou Jiang ◽  
Fengxia Yan ◽  
Zhongping Feng ◽  
Philip Lazarovici ◽  
Wenhua Zheng
Keyword(s):  
Transcription Factors ◽  
Dietary Restriction ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Redox Balance ◽  
Energy Restriction ◽  
Health Span ◽  
Forkhead Box ◽  
Amp Activated Protein Kinase

Dietary restriction (DR), which is defined as a reduction of particular or total nutrient intake without causing malnutrition, has been proved to be a robust way to extend both lifespan and health-span in various species from yeast to mammal. However, the molecular mechanisms by which DR confers benefits on longevity were not yet fully elucidated. The forkhead box O transcription factors (FOXOs), identified as downstream regulators of the insulin/IGF-1 signaling pathway, control the expression of many genes regulating crucial biological processes such as metabolic homeostasis, redox balance, stress response and cell viability and proliferation. The activity of FOXOs is also mediated by AMP-activated protein kinase (AMPK), sirtuins and the mammalian target of rapamycin (mTOR). Therefore, the FOXO-related pathways form a complex network critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis and to support physiological aging. In this review, we will focus on the role of FOXOs in different DR interventions. As different DR regimens or calorie (energy) restriction mimetics (CRMs) can elicit both distinct and overlapped DR-related signaling pathways, the benefits of DR may be maximized by combining diverse forms of interventions. In addition, a better understanding of the precise role of FOXOs in different mechanistic aspects of DR response would provide clear cellular and molecular insights on DR-induced increase of lifespan and health-span.

scholarly journals Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis

2013 ◽  
Vol 24 (23) ◽  
pp. 3754-3763 ◽  
Author(s):  
Mee-Sup Yoon ◽  
Jie Chen
Keyword(s):  
Amino Acid ◽  
Growth Regulation ◽  
Myogenic Differentiation ◽  
Mammalian Target Of Rapamycin ◽  
Acid Activation ◽  
Class Iii ◽  
Independent Manner ◽  
Inhibitory Function ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase–independent manner. Our results uncover amino acid–sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling.

The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis

2013 ◽  
Vol 41 (4) ◽  
pp. 939-943 ◽  
Author(s):  
Elaine A. Dunlop ◽  
Andrew R. Tee
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Protein Kinases ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Status ◽  
Protein Translation ◽  
Cellular Growth ◽  
Target Of Rapamycin ◽  
Amp Activated Protein Kinase ◽  
Rate Limiting

In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as lipids and amino acids. Consequently, the energy and nutrient status of the cell is acutely monitored and carefully maintained. mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] is often considered to be the master regulator of cell growth that enhances cellular biomass through up-regulation of protein translation. In order for cells to control cellular homoeostasis during growth, there is close signalling interplay between mTORC1 and two other protein kinases, AMPK (AMP-activated protein kinase) and ULK1 (Unc-51-like kinase 1). This kinase triad collectively senses the energy and nutrient status of the cell and appropriately dictates whether the cell will actively favour energy- and amino-acid-consuming anabolic processes such as cellular growth, or energy- and amino-acid-generating catabolic processes such as autophagy. The present review discusses important feedback mechanisms between these three homoeostatic protein kinases that orchestrate cell growth and autophagy, with a particular focus on the mTORC1 component raptor (regulatory associated protein of mammalian target of rapamycin), as well as the autophagy-initiating kinase ULK1.

scholarly journals Amino acid sensing and mTOR regulation: inside or out?

2009 ◽  
Vol 37 (1) ◽  
pp. 248-252 ◽  
Author(s):  
Deborah C.I. Goberdhan ◽  
Margret H. Ögmundsdóttir ◽  
Shubana Kazi ◽  
Bruno Reynolds ◽  
Shivanthy M. Visvalingam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Environmental Conditions ◽  
Detection System ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Sensing ◽  
The Impact ◽  
Mtor Signalling

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

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