Abstract
The mammalian target of rapamycin (mTOR) is the central regulator of mammalian cell growth, and is essential for the formation of two structurally and functionally distinct complexes: mTORC1 and mTORC2. mTORC1 can sense multiple cues such as nutrients, energy status, growth factors and hormones to control cell growth and proliferation, angiogenesis, autophagy, and metabolism. As one of the key environmental stimuli, amino acids (AAs), especially leucine, glutamine and arginine, play a crucial role in mTORC1 activation, but where and how AAs are sensed and signal to mTORC1 are not fully understood. Classically, AAs activate mTORC1 by Rag GTPases which recruit mTORC1 to lysosomes, where AA signaling initiates. Plasma membrane transceptor L amino acid transporter 1 (LAT1)-4F2hc has dual transporter-receptor function that can sense extracellular AA availability upstream of mTORC1. The lysosomal AA sensors (PAT1 and SLC38A9) and cytoplasmic AA sensors (LRS, Sestrin2 and CASTOR1) also participate in regulating mTORC1 activation. Importantly, AAs can be sensed by plasma membrane receptors, like G protein-coupled receptor (GPCR) T1R1/T1R3, and regulate mTORC1 without being transported into the cells. Furthermore, AA-dependent mTORC1 activation also initiates within Golgi, which is regulated by Golgi-localized AA transporter PAT4. This review provides an overview of the research progress of the AA sensing mechanisms that regulate mTORC1 activity.
Highlights
Mammalian target of rapamycin is an evolutionary conserved serine/threonine protein kinase, which shares significant homology with phosphatidylinositol kinase
amino acids (AAs) deprivation causes a dramatic decline in the phosphorylation of S6 kinase (S6K) and 4E-BP1, which cannot be compensated by other stimuli such as growth factors or energy [11,16], indicating that AAs are required for mTOR complex 1 (mTORC1) activation
These facts indicate that AA transporters responsible for the transport of leucine, arginine and glutamine may play an important role in the regulation of mTORC1
Summary
Mammalian target of rapamycin (mTOR) is an evolutionary conserved serine/threonine protein kinase, which shares significant homology with phosphatidylinositol kinase. Raptor plays an important signaling, in which it functions as a scaffolding protein to recruit mTORC1 substrates [7]. AMPK serves as a negative regulator of mTORC1 through direct phosphorylation of TSC2 and Raptor, inhibiting cell growth and preserving energy [15]. Amino acids (AAs) act as substrates for protein synthesis and intermediates in lipid and adenosine triphosphate synthesis, and directly initiate a signaling cascade leading to the activation of mTORC1. AA deprivation causes a dramatic decline in the phosphorylation of S6K and 4E-BP1, which cannot be compensated by other stimuli such as growth factors or energy [11,16], indicating that AAs are required for mTORC1 activation. The mechanisms by which growth factors and energy stimulate mTORC1 activity have been extensively studied. The objective of this article is to review recent advances in the studies about the AA sensing mechanisms that regulate mTORC1
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