Glucagon-like peptide-2-stimulated protein synthesis through the PI 3-kinase-dependent Akt-mTOR signaling pathway

Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive neuropeptide that exerts diverse actions in the gastrointestinal tract, including enhancing mucosal cell survival and proliferation. GLP-2 stimulates mucosal growth in vivo with an increased rate of protein synthesis. However, it was unclear whether GLP-2 can directly stimulate protein synthesis. The objective was to test critically whether GLP-2 receptor (GLP-2R) activation directly stimulates protein synthesis through a PI 3-kinase-dependent Akt-mTOR signaling pathway. HEK 293 cells (transfected with human GLP-2R cDNA) were treated with human GLP-2 with/without pretreatment of PI 3-kinase inhibitor (LY-294002) or mTOR inhibitor (rapamycin). Results show that 1) GLP-2 specifically bound to GLP-2R overexpressed in the HEK cells with Ka = 0.22 nM and Bmax = 321 fmol/μg protein; 2) GLP-2-stimulated protein synthesis was dependent on the amount of GLP-2R cDNA and the dosage of GLP-2 and reached the plateau among 0.2–2 nM GLP-2; 3) GLP-2-stimulated protein synthesis was abolished by the PI 3-kinase inhibitor and mTOR inhibitor; and 4) GLP-2-mediated stimulation of phosphorylation on Akt and mTOR was dependent on the amount of GLP-2R cDNA transfected and the dosage of GLP-2. In addition, GLP-2-mediated action and signaling in regulation of protein synthesis were confirmed in mouse hippocampal neurons (expressing native GLP-2R). GLP-2 directly stimulated protein synthesis of primary cultured neurons in dosage-dependent, PI 3-kinase-dependent, and rapamycin-sensitive manners, which linked with activation of Akt-mTOR signaling pathway as well. We conclude that GLP-2R activation directly stimulates protein synthesis by activating the PI 3-kinase-dependent Akt-mTOR signaling pathway. GLP-2-stimulated protein synthesis may be physiologically relevant to maintaining neuronal long-term potentiation and providing secondary mediators (namely neuropeptides or growth factors).

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Roles of Glutamate Receptors and the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Activity-dependent Dendritic Protein Synthesis in Hippocampal Neurons

Journal of Biological Chemistry ◽

10.1074/jbc.m512524200 ◽

2006 ◽

Vol 281 (27) ◽

pp. 18802-18815 ◽

Cited By ~ 153

Author(s):

Ruomu Gong ◽

Chang Sin Park ◽

Nima Rezaei Abbassi ◽

Shao-Jun Tang

Keyword(s):

Protein Synthesis ◽

Glutamate Receptors ◽

Signaling Pathway ◽

Hippocampal Neurons ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mtor Signaling Pathway ◽

Dendritic Protein Synthesis ◽

Activity Dependent

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Leucine and histidine independently regulate milk protein synthesis in bovine mammary epithelial cells via mTOR signaling pathway

Journal of Zhejiang University SCIENCE B ◽

10.1631/jzus.b1400337 ◽

2015 ◽

Vol 16 (6) ◽

pp. 560-572 ◽

Cited By ~ 33

Author(s):

Hai-na Gao ◽

Han Hu ◽

Nan Zheng ◽

Jia-qi Wang

Keyword(s):

Protein Synthesis ◽

Epithelial Cells ◽

Signaling Pathway ◽

Milk Protein ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Bovine Mammary Epithelial Cells

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Valine supplementation during late pregnancy in gilts increases colostral protein synthesis through stimulating mTOR signaling pathway in mammary cells

Amino Acids ◽

10.1007/s00726-019-02790-7 ◽

2019 ◽

Vol 51 (10-12) ◽

pp. 1547-1559 ◽

Cited By ~ 1

Author(s):

Long Che ◽

Mengmeng Xu ◽

Kaiguo Gao ◽

Li Wang ◽

Xuefen Yang ◽

...

Keyword(s):

Protein Synthesis ◽

Signaling Pathway ◽

Late Pregnancy ◽

Mtor Signaling ◽

Mammary Cells ◽

Mtor Signaling Pathway

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l-Arginine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2011.06.012 ◽

2012 ◽

Vol 23 (9) ◽

pp. 1178-1183 ◽

Cited By ~ 91

Author(s):

Xiangfeng Kong ◽

Bie Tan ◽

Yulong Yin ◽

Haijun Gao ◽

Xilong Li ◽

...

Keyword(s):

Protein Synthesis ◽

Signaling Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Trophectoderm Cells

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52. Roles of the mTOR signaling pathway in hibernating ground squirrels, a differential suppression of active protein synthesis

Cryobiology ◽

10.1016/j.cryobiol.2013.02.058 ◽

2013 ◽

Vol 66 (3) ◽

pp. 356 ◽

Cited By ~ 1

Author(s):

Cheng-Wei Wu ◽

Kenneth B. Storey

Keyword(s):

Protein Synthesis ◽

Signaling Pathway ◽

Ground Squirrels ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Active Protein

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Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00068.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. E873-E881 ◽

Cited By ~ 16

Author(s):

Yu Chen ◽

Sumita Sood ◽

Kevin McIntire ◽

Richard Roth ◽

Ralph Rabkin

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Signaling Pathway ◽

Muscle Wasting ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Exercise Induced ◽

Rps6 Phosphorylation

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.

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Anger Emotional Stress Influences VEGF/VEGFR2 and Its Induced PI3K/AKT/mTOR Signaling Pathway

Neural Plasticity ◽

10.1155/2016/4129015 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 10

Author(s):

Peng Sun ◽

Sheng Wei ◽

Xia Wei ◽

Jieqiong Wang ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Emotional Stress ◽

Hippocampal Neurons ◽

Signal Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Open Field Behavior ◽

Abnormal Expression ◽

Behavioral Abnormalities ◽

Resident Intruder

Objective.We discuss the influence of anger emotional stress upon VEGF/VEGFR2 and its induced PI3K/AKT/mTOR signal pathway.Methods.We created a rat model of induced anger (anger-out and anger-in) emotional response using social isolation and resident-intruder paradigms and assessed changes in hippocampus’ VEGF content, neuroplasticity, and the PI3K/AKT/mTOR signaling pathway.Results.The resident-intruder method successfully generated anger-out and anger-in models that differed significantly in composite aggression score, aggression incubation, open field behavior, sucrose preference, and weight gain. Anger emotional stress decreased synaptic connections and VEGFR2 expression. Anger emotional stress led to abnormal expression of VEGF/VEGFR2 mRNA and protein and disorderly expression of key factors in the PI3K/AKT/mTOR signal pathway. Fluoxetine administration ameliorated behavioral abnormalities and damage to hippocampal neurons caused by anger emotional stress, as well as abnormal expression of some proteins in VEGF/VEGFR2 and its induced PI3K/AKT/mTOR signal pathway.Conclusion.This research provides a detailed classification of anger emotion and verifies its influence upon VEGF and the VEGF-induced signaling pathway, thus providing circumstantial evidence of mechanisms by which anger emotion damages neurogenesis. As VEGFR2 can promote neurogenesis and vasculogenesis in the hippocampus and frontal lobe, these results suggest that anger emotional stress can result in decreased neurogenesis.

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EPHA2 Promotes the Invasion and Migration of Human Tongue Squamous Cell Carcinoma Cal-27 Cells by Enhancing AKT/mTOR Signaling Pathway

BioMed Research International ◽

10.1155/2021/4219690 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Fengqin Wang ◽

Hanzhong Zhang ◽

Zhigang Cheng

Keyword(s):

Cell Cycle ◽

Signaling Pathway ◽

Mtor Inhibitor ◽

Mtor Signaling ◽

Biological Behavior ◽

Migration And Invasion ◽

Mtor Signaling Pathway ◽

Akt Inhibitor ◽

Invasion And Migration ◽

And Migration

EPHA2 is a member of the ephrin receptor tyrosine kinase family and is closely related to the malignant tumor progression. The effect of EPHA2 on OSCC is not clear. This study explored the role of EPHA2 and AKT/mTOR signaling pathways in Cal-27 cell invasion and migration. The expression of EPHA2 and EPHA4 in human OSCC and normal oral tissue was detected by immunohistochemistry. EPHA2-overexpressing and EPHA2-knockdown Cal-27 cells were established, and the cells were treated with an AKT inhibitor (MK2206) and mTOR inhibitor (RAD001). The expression of EPHA2 was detected by qRT-PCR, cell proliferation was evaluated by MTT assay, cell migration and invasion were examined by scratch and Transwell assay, and cell morphology and apoptosis were assessed by Hoechst 33258 staining. Western blot was performed to detect the expression of proteins related to AKT/mTOR signaling, cell cycle, and pseudopod invasion. EPHA2 and EPHA4 were highly expressed in clinical human OSCC. Overexpression of EPHA2 promoted the proliferation, migration, and invasion of Cal-27 cells, inhibited cell cycle blockage and apoptosis, and enhanced the activity of the AKT/mTOR signaling pathway. MK2206 (AKT inhibitor) and RAD001 (mTOR inhibitor) reversed the effect of EPHA2 overexpression on the biological behavior of Cal-27 cells. EPHA2 promotes the invasion and migration of Cal-27 human OSCC cells by enhancing the AKT/mTOR signaling pathway.

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Early leucine programming on protein utilization and mTOR signaling by DNA methylation in zebrafish (Danio rerio)

10.21203/rs.3.rs-40365/v1 ◽

2020 ◽

Author(s):

Qiang-Sheng Zhu ◽

Jie Wang ◽

shan he ◽

Xu-Fang Liang ◽

Shuang Xie ◽

...

Keyword(s):

Dna Methylation ◽

Protein Synthesis ◽

Amino Acid ◽

Signaling Pathway ◽

Danio Rerio ◽

Mtor Signaling ◽

Translation Initiation Factor ◽

Mtor Signaling Pathway ◽

Nutritional Programming ◽

Expression Of Genes

Abstract Background Early nutritional programming affects a series of metabolism, growth and development in mammals. Fish also exhibit the developmental plasticity by early nutritional programming. However, little is known about the effect of early amino acid programming on growth and metabolism. Methods In the present study, zebrafish (Danio rerio) was used as the experimental animal to study whether early leucine stimulation can programmatically affect the mechanistic target of rapamycin (mTOR) signaling pathway, growth and metabolism in the later life, and to undercover the mechanism of epigenetic regulation. Zebrafish larvas at 3 days post hatching (dph) were raised with 1.0% leucine from 3 to 13 dph during the critical developmental stage, then back to normal water for 70 days (83 dph). Results The growth performance and crude protein content of zebrafish in the early leucine programming group were increased, and consistent with the activation of the mTOR signaling pathway and the high expression of genes involved in the metabolism of amino acid and glycolipid. Furthermore, we compared the DNA methylation profiles between the control and leucine-stimulated zebrafish, and found that the methylation levels of CG-differentially methylated regions (DMGs) and CHH-DMGs of genes involved in mTOR signaling pathway were different between the two groups. With quantitative PCR analysis, the decreased methylation levels of CG type of Growth factor receptor-bound protein 10 (Grb10), eukaryotic translation initiation factor 4E (eIF4E) and mTOR genes of mTOR signaling pathway in the leucine programming group, might contribute to the enhanced gene expression. Conclusions The early leucine programming could improve the protein synthesis and growth, which might be attributed to the methylation of genes in mTOR pathway and the expression of genes involved in protein synthesis and glycolipid metabolism in zebrafish. These results could be beneficial for better understanding of the epigenetic regulatory mechanism of early nutritional programming.

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