The mTOR Pathway in the Control of Protein Synthesis

Wang, Xuemin; Proud, Christopher G.

doi:10.1152/physiol.00024.2006

Cited by 616 publications

(553 citation statements)

References 55 publications

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“…Incubation with L‐Leu did not modify the phosphorylation status of PKB/Akt, a result in concordance with studies that propose a PKB/Akt independent activation of the anabolic actions of L‐Leu 2, 31, 32. In contrast, HMB significantly enhanced PKB/Akt phosphorylation, in agreement with previous studies 19, 21.…”

Section: Discussionsupporting

confidence: 91%

“…In contrast, HMB significantly enhanced PKB/Akt phosphorylation, in agreement with previous studies 19, 21. Therefore, under our experimental conditions, our results would support the idea that HMB acts mainly via the class I PI3K/Akt pathway,19 whereas it is described that L‐Leu exerts its action via the class III PI3K2, 31 that could mediate the activation of mTOR. In fact, it has been described that branched amino acids stimulate directly mTOR through a mechanism involving Rag GTPases 45.…”

Section: Discussionsupporting

confidence: 83%

“…The activation of mTOR, as a key element in protein synthesis, could be modulated by PI3K/Akt and MAPK/ERK1, 2, 3 signalling pathways. Therefore, we measured the effects of L‐Leu and HMB on protein synthesis in the presence of specific inhibitors of these pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of the kinase mechanistic target of rapamycin (mTOR) plays a central role in the regulation of protein synthesis 2. Mechanistic target of rapamycin is activated through protein kinase B (PKB/Akt)1 or extracellular signal‐regulated kinase (ERK1/2) pathways 3.…”

Section: Introductionmentioning

confidence: 99%

“…4E binding protein‐1 (4E‐BP1) and p70 S6 kinase (S6K1) are key regulatory proteins modulated by mTOR that are involved in the initiation of mRNA translation 4, 5. Once activated, mTOR phosphorylates 4E‐BP1, which accelerates the release of eukaryotic initiation factor 4E (eIF4E) from 4E‐BP1 or directly activates S6K1 1, 2…”

Section: Introductionmentioning

confidence: 99%

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Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundL‐Leu and its metabolite β‐hydroxy‐β‐methylbutyrate (HMB) stimulate muscle protein synthesis enhancing the phosphorylation of proteins that regulate anabolic signalling pathways. Alterations in these pathways are observed in many catabolic diseases, and HMB and L‐Leu have proven their anabolic effects in in vivo and in vitro models. The aim of this study was to compare the anabolic effects of L‐Leu and HMB in myotubes grown in the absence of any catabolic stimuli.MethodsStudies were conducted in vitro using rat L6 myotubes under normal growth conditions (non‐involving L‐Leu‐deprived conditions). Protein synthesis and mechanistic target of rapamycin signalling pathway were determined.ResultsOnly HMB was able to increase protein synthesis through a mechanism that involves the phosphorylation of the mechanistic target of rapamycin as well as its downstream elements, pS6 kinase, 4E binding protein‐1, and eIF4E. HMB was significantly more effective than L‐Leu in promoting these effects through an activation of protein kinase B/Akt. Because the conversion of L‐Leu to HMB is limited in muscle, L6 cells were transfected with a plasmid that codes for α‐keto isocaproate dioxygenase, the key enzyme involved in the catabolic conversion of α‐keto isocaproate into HMB. In these transfected cells, L‐Leu was able to promote protein synthesis and mechanistic target of rapamycin regulated pathway activation equally to HMB. Additionally, these effects of leucine were reverted to a normal state by mesotrione, a specific inhibitor of α‐keto isocaproate dioxygenase.ConclusionOur results suggest that HMB is an active L‐Leu metabolite able to maximize protein synthesis in skeletal muscle under conditions, in which no amino acid deprivation occurred. It may be proposed that supplementation with HMB may be very useful to stimulate protein synthesis in wasting conditions associated with chronic diseases, such as cancer or chronic heart failure.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

View full text Add to dashboard Cite

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UBE2T promotes β‐catenin nuclear translocation in hepatocellular carcinoma through MAPK/ERK‐dependent activation

et al. 2022

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Ubiquitin-conjugating enzyme E2T (UBE2T) has been implicated in many types of cancer including hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) process plays a fundamental role during tumor metastasis and progression. However, the molecular mechanisms underlying EMT in HCC in accordance with UBE2T still remain unknown. In this study, we showed that UBE2T overexpression augmented the oncogenic properties and specifically EMT in HCC cell lines, while its silencing attenuated them. UBE2T affected the activation of EMT-associated signaling pathways: MAPK/ERK, AKT/mTOR, and Wnt/b-catenin. In addition, we revealed that the epithelial protein complex of E-cadherin/b-catenin, a vital regulator of signal transduction in tumor initiation and progression, was totally disrupted at the cell membrane. In particular, we observed that UBE2T overexpression led to E-cadherin loss accompanied by a simultaneous elevation of both cytoplasmic and nuclear b-catenin, while its silencing resulted in a strong E-cadherin turnover at the cell membrane. Interestingly, chemical inhibition of the MAPK/ERK, AKT/mTOR, and Wnt/bcatenin signaling pathways demonstrated that the nuclear translocation of b-catenin and subsequent EMT was enhanced mainly by MAPK/ERK. Collectively, our findings demonstrate the UBE2T/MAPK-ERK/b-catenin axis as a critical regulator of cell state transition and EMT in HCC.

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Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells

et al. 2022

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Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors [e.g., synthesis of cytochrome c oxidase 2 (SCO2)] are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the insulin‐like growth factor 1 receptor (IGF1R)/AKT axis with paradoxical downregulation of mTOR signaling, which was accompanied by increased AMP‐activated kinase activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction.

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The mTOR Pathway in the Control of Protein Synthesis

Cited by 616 publications

References 55 publications

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

UBE2T promotes β‐catenin nuclear translocation in hepatocellular carcinoma through MAPK/ERK‐dependent activation

Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells

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