scholarly journals Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids

2014 ◽  
Vol 15 (11) ◽  
pp. 20753-20769 ◽  
Author(s):  
Xu Zheng ◽  
Yan Liang ◽  
Qiburi He ◽  
Ruiyuan Yao ◽  
Wenlei Bao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Growth Factors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Mtorc1 Activation

Rheb and Rags come together at the lysosome to activate mTORC1

2013 ◽  
Vol 41 (4) ◽  
pp. 951-955 ◽  
Author(s):  
Marlous J. Groenewoud ◽  
Fried J.T. Zwartkruis
Keyword(s):  
Amino Acids ◽  
Growth Factors ◽  
Amino Acid ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Maturation Process ◽  
Phospholipase D1 ◽  
Strict Requirement ◽  
Mtorc1 Activation ◽  
Dependent Interaction

mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein complex regulating cell growth and metabolism via its kinase mTOR (mammalian target of rapamycin). The activity of mTOR is under the control of various GTPases, of which Rheb and the Rags play a central role. The presence of amino acids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to activate mTORC1. Rheb is responsive to growth factors, but, in conjunction with PLD1 (phospholipase D1), is also an integral part of the machinery that stimulates mTORC1 in response to amino acids. In the present article, we provide a brief overview of novel mechanisms by which amino acids affect the function of Rags. On the basis of existing literature, we postulate that Rheb is activated at the Golgi from where it will travel to lysosomes. Maturation of endosomes into lysosomes may be required to assure a continuous supply of GTP-bound Rheb for mTORC1 activation, which may help to drive the maturation process.

The mTOR Pathway in the Control of Protein Synthesis

Physiology ◽  
2006 ◽  
Vol 21 (5) ◽  
pp. 362-369 ◽  
Author(s):  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Cell Physiology ◽  
Elongation Factors ◽  
Energy Deficiency

Signaling through mammalian target of rapamycin (mTOR) is activated by amino acids, insulin, and growth factors, and impaired by nutrient or energy deficiency. mTOR plays key roles in cell physiology. mTOR regulates numerous components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves.

scholarly journals Amino acid regulation of TOR complex 1

2009 ◽  
Vol 296 (4) ◽  
pp. E592-E602 ◽  
Author(s):  
Joseph Avruch ◽  
Xiaomeng Long ◽  
Sara Ortiz-Vega ◽  
Joseph Rapley ◽  
Angela Papageorgiou ◽  
...  
Keyword(s):  
Amino Acids ◽  
Growth Factors ◽  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Energy Status ◽  
Phospholipase D1 ◽  
Direct Binding ◽  
Charged Form ◽  
Mtorc1 Activation

TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GβL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC1 kinase activity, with special emphasis on mTORC1 regulation by amino acids. The dominant positive regulator of mTORC1 is the GTP-charged form of the ras-like GTPase Rheb. Insulin, growth factors, and a variety of cellular stressors regulate mTORC1 by controlling Rheb GTP charging through modulating the activity of the tuberous sclerosis complex, the Rheb GTPase activating protein. In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Rheb binds directly to mTOR, an interaction that appears to be essential for mTORC1 activation. In addition, Rheb-GTP stimulates phospholipase D1 to generate phosphatidic acid, a positive effector of mTORC1 activation, and binds to the mTOR inhibitor FKBP38, to displace it from mTOR. The contribution of Rheb's regulation of PL-D1 and FKBP38 to mTORC1 activation, relative to Rheb's direct binding to mTOR, remains to be fully defined. The rag GTPases, functioning as obligatory heterodimers, are also required for amino acid regulation of mTORC1. As with amino acid deficiency, however, the inhibitory effect of rag depletion on mTORC1 can be overcome by Rheb overexpression, whereas Rheb depletion obviates rag's ability to activate mTORC1. The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb-containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1. The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3′OH-phosphatidylinositol, in this process is unclear.

scholarly journals Branched-Chain Amino Acids Enhance Premature Senescence through Mammalian Target of Rapamycin Complex I-Mediated Upregulation of p21 Protein

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e80411 ◽  
Author(s):  
Masayuki Nakano ◽  
Akio Nakashima ◽  
Taiki Nagano ◽  
Shintaro Ishikawa ◽  
Ushio Kikkawa ◽  
...  
Keyword(s):  
Amino Acids ◽  
Complex I ◽  
Mammalian Target Of Rapamycin ◽  
Branched Chain Amino Acids ◽  
Target Of Rapamycin ◽  
Premature Senescence ◽  
P21 Protein ◽  
Branched Chain

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

2014 ◽  
Vol 307 (9) ◽  
pp. F1023-F1032 ◽  
Author(s):  
Junhua Mao ◽  
Zhifeng Zeng ◽  
Zhuo Xu ◽  
Jiangzhong Li ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Target Of Rapamycin ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Mtorc1 Signaling ◽  
Cellular Crescent ◽  
Underlying Mechanisms ◽  
Mtorc1 Activation ◽  
Glomerular Tuft

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

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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