scholarly journals Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability

2003 ◽  
Vol 372 (2) ◽  
pp. 555-566 ◽  
Author(s):  
Anne BEUGNET ◽  
Andrew R. TEE ◽  
Peter M. TAYLOR ◽  
Christopher G. PROUD
Keyword(s):  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Availability ◽  
Intracellular Amino Acid

scholarly journals Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin

2001 ◽  
Vol 21 (15) ◽  
pp. 5050-5062 ◽  
Author(s):  
Atsuko Takano ◽  
Isao Usui ◽  
Tetsuro Haruta ◽  
Junko Kawahara ◽  
Tatsuhito Uno ◽  
...  
Keyword(s):  
Amino Acid ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Mammalian Target Of Rapamycin ◽  
Proteasomal Degradation ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Amino Acid Deprivation ◽  
Insulin Receptor Substrate 1 ◽  
Amino Acid Availability

ABSTRACT A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM) to the cytosol. After prolonged insulin stimulation, inhibition of the redistribution of IRS-1 by rapamycin resulted in increased levels of IRS-1 and the associated phosphatidylinositol (PI) 3-kinase in both the LDM and cytosol, whereas the proteasome inhibitor lactacystin increased the levels only in the cytosol. Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associated PI 3-kinase localized at the LDM was suggested to be important in the regulation of glucose transport. The amino acid deprivation attenuated and the amino acid excess enhanced insulin-induced Ser/Thr phosphorylation and subcellular redistribution and degradation of IRS-1 in parallel with the effects on phosphorylation of p70 S6 kinase and 4E-BP1. Accordingly, the amino acid deprivation increased and the amino acid excess decreased insulin-stimulated activation of Akt and 2-DOG uptake. Furthermore, 2-DOG uptake was affected by amino acid availability even when the degradation of IRS-1 was inhibited by lactacystin. We propose that subcellular redistribution of IRS-1, regulated by the mTOR-dependent pathway, facilitates proteasomal degradation of IRS-1, thereby down-regulating Akt, and that the pathway also negatively regulates insulin-stimulated glucose transport, probably through the redistribution of IRS-1. This work identifies a novel function of mTOR that integrates nutritional signals and metabolic signals of insulin.

Leucine and mTORC1: a complex relationship

2012 ◽  
Vol 302 (11) ◽  
pp. E1329-E1342 ◽  
Author(s):  
Kayleigh M. Dodd ◽  
Andrew R. Tee
Keyword(s):  
Signal Transduction ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Protein Turnover ◽  
Muscle Growth ◽  
Protein Translation ◽  
Amino Acid Availability ◽  
Intracellular Amino Acid ◽  
System L ◽  
Mtorc1 Signaling

Amino acid availability is a rate-limiting factor in the regulation of protein synthesis. When amino acid supplies become restricted, mammalian cells employ homeostatic mechanisms to rapidly inhibit processes such as protein synthesis, which demands high levels of amino acids. Muscle cells in particular are subject to high protein turnover rates to maintain amino acid homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved multiprotein complex that coordinates a network of signaling cascades and functions as a key mediator of protein translation, gene transcription, and autophagy. Signal transduction through mTORC1, which is centrally involved in muscle growth through enhanced protein translation, is governed by intracellular amino acid supply. The branched-chain amino acid leucine is critical for muscle growth and acts in part through activation of mTORC1. Recent research has revealed that mTORC1 signaling is coordinated primarily at the lysosomal membranes. This discovery has sparked a wealth of research in this field, revealing several different signaling molecules involved in transducing the amino acid signal to mTORC1, including the Rag GTPases, MAP4K3, and Vps34/ULK1. This review evaluates the current knowledge regarding cellular mechanisms that control and sense the intracellular amino acid pool. We discuss the role of leucine and mTORC1 in the regulation of amino acid transport via the system L and system A transporters such as LAT1 and SNAT2, as well as protein degradation via autophagic and proteasomal pathways. We also describe the complexities of energy homeostasis via AMPK and cell receptor-mediated growth signals that also converge on mTORC1. Leucine is a particularly potent regulator of protein turnover, to the extent where leucine stimulation alone is sufficient to stimulate mTORC1 signal transduction. The significance of leucine in this context is not yet known; however, recent advancements in this area will also be covered within this review.

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.

Deletion of the amino acid transporter Slc6a14 suppresses tumour growth in spontaneous mouse models of breast cancer

2015 ◽  
Vol 469 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Ellappan Babu ◽  
Yangzom D. Bhutia ◽  
Sabarish Ramachandran ◽  
Jaya P. Gnanaprakasam ◽  
Puttur D. Prasad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Amino Acid ◽  
Mouse Models ◽  
Therapeutic Target ◽  
Tumour Growth ◽  
Mammalian Target Of Rapamycin ◽  
Amino Acid Transporter ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Acid Transporter

Deletion of the amino acid transporter Slc6a14 in mice suppresses tumour growth in spontaneous models of breast cancer via interference with mammalian target of rapamycin (mTOR) pathway; this indicates an obligatory role for SLC6A14 in breast cancer, highlighting its potential as a therapeutic target.

scholarly journals Rag proteins regulate amino-acid-induced mTORC1 signalling

2009 ◽  
Vol 37 (1) ◽  
pp. 289-290 ◽  
Author(s):  
Yasemin Sancak ◽  
David M. Sabatini
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Master Regulator ◽  
Growth And Survival ◽  
Field Identification ◽  
Rag Proteins ◽  
Cell Growth And Survival

The serum- and nutrient-sensitive protein kinase mTOR (mammalian target of rapamycin) is a master regulator of cell growth and survival. The mechanisms through which nutrients regulate mTOR have been one of the major unanswered questions in the mTOR field. Identification of the Rag (Ras-related GTPase) family of GTPases as mediators of amino acid signalling to mTOR is an important step towards our understanding of this mechanism.

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 Up-Regulation of the Excitatory Amino Acid Transporters EAAT1 and EAAT2 by Mammalian Target of Rapamycin

2016 ◽  
Vol 39 (6) ◽  
pp. 2492-2500 ◽  
Author(s):  
Abeer Abousaab ◽  
Nestor Luis Uzcategui ◽  
Bhaeldin Elsir ◽  
Florian Lang
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Synaptic Cleft ◽  
Target Of Rapamycin ◽  
Amino Acid Transporters ◽  
Protein Abundance ◽  
Excitatory Amino Acid Transporters ◽  
Neuronal Excitation ◽  
Electrode Voltage

Background: The excitatory amino-acid transporters EAAT1 and EAAT2 clear glutamate from the synaptic cleft and thus terminate neuronal excitation. The carriers are subject to regulation by various kinases. The EAAT3 isoform is regulated by mammalian target of rapamycin (mTOR). The present study thus explored whether mTOR influences transport by EAAT1 and/or EAAT2. Methods: cRNA encoding wild type EAAT1 (SLC1A3) or EAAT2 (SLC1A2) was injected into Xenopus oocytes without or with additional injection of cRNA encoding mTOR. Dual electrode voltage clamp was performed in order to determine electrogenic glutamate transport (IEAAT). EAAT2 protein abundance was determined utilizing chemiluminescence. Results: Appreciable IEAAT was observed in EAAT1 or EAAT2 expressing but not in water injected oocytes. IEAAT was significantly increased by coexpression of mTOR. Coexpression of mTOR increased significantly the maximal IEAAT in EAAT1 or EAAT2 expressing oocytes, without significantly modifying affinity of the carriers. Moreover, coexpression of mTOR increased significantly EAAT2 protein abundance in the cell membrane. Conclusions: The kinase mTOR up-regulates the excitatory amino acid transporters EAAT1 and EAAT2.

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