Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells

Zhou, Yuanfei; Ren, Jiao; Song, Tongxing; Peng, Jian; Wei, Hong

doi:10.3390/ijms17101684

Cited by 45 publications

(40 citation statements)

References 37 publications

(51 reference statements)

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“…It has, in fact, been proposed that the heterodimeric amino acid sensor T1R1/T1R3 can function as a regulator of autophagy through regulation of the mTOR complex 1 (Wauson et al, 2012). Thus, T1R1/T1R3 is believed to sense amino acid availability (Zheng et al, 2016;Zhou et al, 2016). One may hypothesize that GPR142 senses the production of essential aromatic amino acids generated from autophagy in the islet and, in turn, perhaps could function in an autocrine feedback loop to control autophagy.…”

Section: Islet Cell Communication Via Metabolitesmentioning

confidence: 99%

GPCR-Mediated Signaling of Metabolites

et al. 2017

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In addition to their bioenergetic intracellular function, several classical metabolites act as extracellular signaling molecules activating cell-surface G-protein-coupled receptors (GPCRs), similar to hormones and neurotransmitters. "Signaling metabolites" generated from nutrients or by gut microbiota target primarily enteroendocrine, neuronal, and immune cells in the lamina propria of the gut mucosa and the liver and, through these tissues, the rest of the body. In contrast, metabolites from the intermediary metabolism act mainly as metabolic stress-induced autocrine and paracrine signals in adipose tissue, the liver, and the endocrine pancreas. Importantly, distinct metabolite GPCRs act as efficient pro- and anti-inflammatory regulators of key immune cells, and signaling metabolites may thus function as important drivers of the low-grade inflammation associated with insulin resistance and obesity. The concept of key metabolites as ligands for specific GPCRs has broadened our understanding of metabolic signaling significantly and provides a number of novel potential drug targets.

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Section: Islet Cell Communication Via Metabolitesmentioning

confidence: 99%

GPCR-Mediated Signaling of Metabolites

et al. 2017

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“…T1R1/T1R3 receptor can mediate mTORC1 pathway in different cell types . To ascertain T1R1/T1R3‐mediate signal pathways in NK cells, CD49a + CD49b − NK cells were sorted from HCC mouse livers and incubated in amino acid‐free medium for 3 h. These NK cells were then incubated in amino acid‐containing medium for different time intervals.…”

Section: Resultsmentioning

confidence: 99%

Taste receptor T1R1/T1R3 promotes the tumoricidal activity of hepatic CD49a⁺CD49b⁻ natural killer cells

Liu

Zhu

et al. 2018

Eur J Immunol

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Natural Killer (NK) cell-based immunotherapy is a promising approach to treat hepatocellular carcinoma (HCC). The mechanisms underlying the regulation of NK cell activity are not completely understood. In this research, we identified the expression of taste receptor type 1 member 1 (T1R1) and taste receptor type 1 member 3 (T1R3) in a subset of hepatic NK cells in a mouse HCC model. T1R1 and T1R3 were selectively expressed in CD49a + CD49b − NK cells in livers with HCC. In the in vitro cytotoxicity assay, amino acids promoted the tumoricidal effect of CD49a + CD49b − NK cells through increasing the production of perforin, granzyme B and IFN-γ. Furthermore, using a lentivirus to induce the expression of exogenous T1R1 and T1R3 in normal hepatic NK cells, we found that amino acids enhanced NK cell-mediated cytotoxicity on tumor cells through the T1R1/T1R3 receptor, as demonstrated by more tumor cell lysis, up-regulation of perforin and granzyme B in comparison with control NK cells. In addition, amino acids activated Akt and mechanistic target of rapamycin complex 1 (mTORC1) signaling in NK cells through T1R1/T1R3 receptor. T-bet expression in NK cells was also increased by amino acid treatment. Therefore, T1R1/T1R3 receptor promotes the tumoricidal activity of hepatic CD49a + CD49b − NK cells.Keywords: Anti-tumor immunity r Cancer immunotherapy r Hepatocellular carcinoma r Natural Killer (NK) cells r Taste receptor T1R1/T1R3 Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…All these modifications contribute to chromatin architecture regulation and are directly correlated with the accessibility of the metabolites generated from the associated pathways: glycation with sugar glycolysis (30), citrullination with calcium homeostasis (12) and methylation with S-adenosyl methionine (SAM) metabolism (31), suggesting that this crosstalk is influenced by diet, metabolic state and the cellular microenvironment (32,33). The balance between MGO, Ca 2+ and SAM can be regulated through multiple processes including endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) and mTOR signalling, providing an additional potential link to changes in gene expression (34)(35)(36). Together with our previous identification of the interrelationship between glycation and methylation (9,10), this work suggests a three-way crosstalk (Figure 4) and new insights into the link between metabolism, epigenetics, and disease (37,38).…”

Section: Discussionmentioning

confidence: 99%

Protein Arginine Deiminase 4 Antagonizes Methylglyoxal-induced Histone Glycation

Zheng¹,

Osunsade

David

2019

Preprint

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Protein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of the core histones H3 and H4. While the precise epigenetic function of this modification has not been resolved, it was shown to associate with general chromatin decompaction and to compete with arginine methylation. Recently, we showed that histones are subjected to methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change chromatin architecture and the epigenetic landscape by competing with enzymatic modifications. Here we report that PAD4 antagonizes histone MGOglycation by protecting the reactive sites with oxygen substitution, as well as by converting already-glycated arginine residues into citrulline. Moreover, we show that similar to the deglycase DJ-1, PAD4 is overexpressed and histone citrullination is upregulated in breast cancer tumors, suggesting an additional mechanistic link to PAD4's oncogenic properties.Metabolic syndromes and diabetes increase the risk for certain diseases such as cancer. However, the mechanism behind this correlation is poorly understood. Methylglyoxal (MGO), a reactive dicarbonyl sugar metabolite found in cells under metabolic stress, can non-enzymatically modify arginine and lysine residues in histone proteins, making it a new epigenetic marker linking metabolism and disease. Histone MGO-glycation induces changes in chromatin architecture and the epigenetic landscape, and abrogates gene transcription. In this study, we found that protein arginine deiminase 4 (PAD4) exhibits dual functions to antagonize histone MGO-glycation: removing glycation adducts from arginines and converting the unmodified side chains into citrulline, which protects them from undergoing glycation. This unprecedented biochemical mechanism demonstrates a potential function of PAD4 in cancer cells.

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Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells

Cited by 45 publications

References 37 publications

GPCR-Mediated Signaling of Metabolites

GPCR-Mediated Signaling of Metabolites

Taste receptor T1R1/T1R3 promotes the tumoricidal activity of hepatic CD49a⁺CD49b⁻ natural killer cells

Protein Arginine Deiminase 4 Antagonizes Methylglyoxal-induced Histone Glycation

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Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells

Cited by 45 publications

References 37 publications

GPCR-Mediated Signaling of Metabolites

GPCR-Mediated Signaling of Metabolites

Taste receptor T1R1/T1R3 promotes the tumoricidal activity of hepatic CD49a+CD49b− natural killer cells

Protein Arginine Deiminase 4 Antagonizes Methylglyoxal-induced Histone Glycation

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Taste receptor T1R1/T1R3 promotes the tumoricidal activity of hepatic CD49a⁺CD49b⁻ natural killer cells