mTORC2 Puts Its Shoulder to Krebs’ Wheel

Apelo, Sebastian I. Arriola; Lamming, Dudley W.

doi:10.1016/j.molcel.2016.08.016

Cited by 10 publications

(7 citation statements)

References 10 publications

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“…mTORC2 is stimulated by growth factors such as insulin, insulin like growth factor (IGF), and hormones, which signal to PI3K [ 47 ]. Although both mTORC1 and mTORC2 are activated by growth factors, including insulin, the signaling mechanism of mTORC2 activation is distinct from that of mTORC1 [ 8 ].…”

Section: Regulation Of Mtorc2mentioning

confidence: 99%

The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling

2017

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The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR). In addition, mTORC1 and mTORC2 regulate each other through a feedback loop to control cell growth. This review outlines the current understanding of mTOR regulation in insulin signaling in the context of whole body metabolism.

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Section: Regulation Of Mtorc2mentioning

confidence: 99%

The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling

2017

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“…It is also unclear what cellular signals mTORC2 might sense, or whether it is regulated through other mechanisms such as localization. Early studies indicated that mTORC2 activity is stimulated by growth factors [125–127], and more recently glucose [55, 128–130] and glutamine levels [131, 132]. In addition, lipid-derived signal also may control mTORC2 signaling [133, 134].…”

Section: Future Challengesmentioning

confidence: 99%

The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

Lee

Jung

Guertin

2017

Trends in Endocrinology & Metabolism

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Having healthy adipose tissue is essential for metabolic fitness. This is clear from the obesity epidemic, which is unveiling a myriad of comorbidities associated with excess adipose tissue including type 2 diabetes, cardiovascular disease, and cancer. Lipodystrophy also causes insulin resistance emphasizing the importance of having a balanced amount fat. In cells, the mammalian target of rapamycin (mTOR) complexes (mTORC1 and mTORC2) link nutrient and hormonal signaling with metabolism, and recent studies are shedding new light on their in vivo roles in adipocytes. Here, we discuss how recent advances in adipose tissue and mTOR biology are converging to reveal new mechanisms that maintain healthy adipose tissue, and discuss ongoing mysteries of mTOR signaling, particularly for the less understood complex mTORC2.

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“…This study not only provides a key link between one carbon metabolism and the mTORC1 pathway but raises the question of whether additional intermediate metabolites in amino acid catabolism are also sensed by mTORC1. For example, mTORC1 has been shown to sense α-ketoglutarate, a product of glutaminolysis 91,92 .…”

Section: Amino Acid Sensors From Hypothesis To Realitymentioning

confidence: 99%

“…However, both mTOR complexes also play a critical role in regulating catabolic processes. One recently discovered activity is that both mTORC2 and mTORC1 act to promote anaplerosis – the refilling of the citric acid cycle – by promoting the formation of α-ketoglutarate from glutamine 92 . Here, we will focus on the lysosomal pathways that lie downstream of the mTOR complexes.…”

Section: Lysosomal Functions Downstream Of Mtor Complexesmentioning

confidence: 99%

“…For example, mTORC1 has been shown to sense α-ketoglutarate, a product of glutaminolysis. 91,92 5 | RHEB AND TUBEROUS SCLEROSIS COMPLEX Recruitment of mTORC1 to the lysosome is a prerequisite for mTORC1 activation, because only at the lysosomal surface is mTORC1 able to interact with the Rheb-GTPase. A recent cryo-EM structure has revealed that Rheb-GTP binds to the mTOR protein kinase and allosterically realigns and activates kinase-site residues.…”

Section: Amino Acid Sensors From Hypothesis To Realitymentioning

confidence: 99%

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Lysosome: The metabolic signaling hub

Lamming

Bar-Peled

2018

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121

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For the past five decades the lysosome has been characterized as an unglamorous cellular recycling center. This notion has undergone a radical shift in the last ten years, with new research revealing that this organelle serves as a major hub for metabolic signaling pathways. The discovery that master growth regulators, including the protein kinase mTOR (mechanistic Target Of Rapamycin) make their home at the lysosomal surface has generated intense interest in the lysosome’s key role in nutrient sensing and cellular homeostasis. The transcriptional networks required for lysosomal maintenance and function are just being unraveled and their connection to lysosome-based signaling pathways revealed. The catabolic and anabolic pathways that converge on the lysosome connect this organelle with multiple facets of cellular function; when these pathways are deregulated they underlie multiple human diseases, and promote cellular and organismal aging. Thus, understanding how lysosome-based signaling pathways function will not only illuminate the fascinating biology of this organelle but will also be critical in unlocking its therapeutic potentials.

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mTORC2 Puts Its Shoulder to Krebs’ Wheel

Abstract: In this issue of Molecular Cell, Moloughney et al. (2016) find that mTORC2 responds to falling levels of glucose and glutamine catabolites, promoting glutaminolysis and preserving the TCA cycle and hexosamine biosynthesis.

Cited by 10 publications

References 10 publications

The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling

The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling

The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

Lysosome: The metabolic signaling hub

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