Recent Advances in Understanding Amino Acid Sensing Mechanisms that Regulate mTORC1

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.

A sRNA in a reduced mutualistic symbiont genome regulates its own gene expression

“…The TOR signalling pathway is important in regulating cell growth in response to nutrients (Loewith & Hall, ). Increases in dietary arginine have been found to increase signalling of the TOR pathway, leading to increased cell growth (Zheng et al., ). Slimfast is an amino acid transporter that is found within the TOR signalling pathway, which can sense and transport arginine (Boudko et al., ; Colombani et al., ).…”

Preclinical Evaluation of 11C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer

“…The importance of the activity of SLC36 family amino acid (PAT) transporters in cell proliferation and cancer has only recently been fully recognized (22). Here, our data suggest that PAT-mediated sarcosine transport is key to 11 C-sarcosine uptake in prostate cancer.…”

“…Also, the mere addition of sarcosine to cultured benign prostate epithelial cells induced an invasive phenotype (4). Although the sarcosine metabolism is well-characterized, its metabolic functions in the human body are still poorly understood and are currently under active investigation (5,22).…”

Cyclase‐associated protein 1 is a key negative regulator of milk synthesis and proliferation of bovine mammary epithelial cells

“…CAP1 is a biological target of matrix metalloproteinase-9 (MMP-9). 32 Glycogen synthase kinase 3 (GSK3) phosphorylates CAP1 at Ser307 and Ser309 to regulate its association with cofilin and actin. 28 A number of publications have demonstrated that hormone receptors and G protein-coupled receptors (GPCRs) activate MMP-9.…”

“…[29][30][31] Recent research has also revealed that extracellular amino acids can be sensed by plasma membrane receptors, such as GPRC6A and GPCR T1R1/T1R3, and regulate mTOR. 32 Glycogen synthase kinase 3 (GSK3) phosphorylates CAP1 at Ser307 and Ser309 to regulate its association with cofilin and actin. 33 Oestrogen receptors and some GPCRs can promote phosphorylation, and thus, inhibit GSK3.…”