PMID-sentid Pub_year Sent_text comp_official_name comp_offsetprotein_name organism prot_offset 33910001-0 2021 Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 58-64 34016143-9 2021 Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. Leucine 59-66 CREB regulated transcription coactivator 1 Mus musculus 124-130 33910001-1 2021 Leucyl-tRNA synthetase 1 (LARS1) mediates activation of leucine-dependent mechanistic target of rapamycin complex 1 (mTORC1) as well as ligation of leucine to its cognate tRNAs, yet its mechanism of leucine sensing is poorly understood. Leucine 56-63 CREB regulated transcription coactivator 1 Mus musculus 117-123 33910001-3 2021 We determine different crystal structures of LARS1 complexed with leucine, ATP, and a reaction intermediate analog, leucyl-sulfamoyl-adenylate (Leu-AMS), and find two distinct functional states of LARS1 for mTORC1 activation. Leucine 66-73 CREB regulated transcription coactivator 1 Mus musculus 207-213 33910001-6 2021 Thus, this work unveils the structural basis for leucine-dependent long-range communication between the catalytic and RagD-binding domains of LARS1 for mTORC1 activation. Leucine 49-56 CREB regulated transcription coactivator 1 Mus musculus 152-158 33883257-8 2021 Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Leucine 39-46 CREB regulated transcription coactivator 1 Mus musculus 136-142 33979735-2 2021 Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 18-24 33863987-2 2021 LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Leucine 54-61 CREB regulated transcription coactivator 1 Mus musculus 124-130 33883257-8 2021 Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Leucine 48-51 CREB regulated transcription coactivator 1 Mus musculus 136-142 33883257-11 2021 The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway. Leucine 42-45 CREB regulated transcription coactivator 1 Mus musculus 58-64 33222863-18 2020 In addition, the AA responsible for the bulk of mTORC1 activation in MAC-T are limited to Leu, Met, Ile, Arg, and Thr. Leucine 90-93 CREB regulated transcription coactivator 1 Mus musculus 48-54 33127851-2 2020 The family of cAMP-response element binding (CREB)-regulated transcription coactivators (CRTC)1-3 activate transcription by targeting the basic leucine zipper domain of CREB. Leucine 144-151 CREB regulated transcription coactivator 1 Mus musculus 14-97 33285244-4 2021 We used leucine and rapamycin to modulate mTORC1 activation and evaluate this effect on circadian rhythms. Leucine 8-15 CREB regulated transcription coactivator 1 Mus musculus 42-48 33285244-5 2021 In the liver, mTORC1 was inhibited by leucine. Leucine 38-45 CREB regulated transcription coactivator 1 Mus musculus 14-20 33285244-6 2021 REV-ERBalpha overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Leucine 150-157 CREB regulated transcription coactivator 1 Mus musculus 42-48 33285244-6 2021 REV-ERBalpha overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Leucine 150-157 CREB regulated transcription coactivator 1 Mus musculus 99-105 33285244-6 2021 REV-ERBalpha overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Leucine 150-157 CREB regulated transcription coactivator 1 Mus musculus 99-105 33285244-9 2021 Inhibition of liver mTORC1 by leucine or rapamycin led to low-amplitude circadian rhythms. Leucine 30-37 CREB regulated transcription coactivator 1 Mus musculus 20-26 33285244-10 2021 In summary, our study shows that leucine inhibits liver mTORC1 pathway leading to dampened circadian rhythms. Leucine 33-40 CREB regulated transcription coactivator 1 Mus musculus 56-62 32561715-0 2020 Leucine regulates autophagy via acetylation of the mTORC1 component raptor. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 51-57 32799865-4 2020 The discovery of Rag GTPases has greatly expanded our understanding of the regulation of mTORC1 activity by amino acids, especially leucine and arginine. Leucine 132-139 CREB regulated transcription coactivator 1 Mus musculus 89-95 32620110-6 2020 First, we show that mTORC1 activity increases during muscle cell differentiation and in response to leucine stimulation in different subcellular compartments such as the cytosol and at the surface of the lysosome, the nucleus, and near the mitochondria. Leucine 100-107 CREB regulated transcription coactivator 1 Mus musculus 20-26 32561715-3 2020 While leucine (Leu) is a critical mTORC1 regulator under AA-starved conditions, how Leu regulates autophagy is poorly understood. Leucine 6-13 CREB regulated transcription coactivator 1 Mus musculus 34-40 32561715-3 2020 While leucine (Leu) is a critical mTORC1 regulator under AA-starved conditions, how Leu regulates autophagy is poorly understood. Leucine 15-18 CREB regulated transcription coactivator 1 Mus musculus 34-40 32561715-7 2020 Thus, in most cell types we examined, Leu regulates autophagy via the impact of its metabolite AcCoA on mTORC1, suggesting that AcCoA and EP300 play pivotal roles in cell anabolism and catabolism. Leucine 38-41 CREB regulated transcription coactivator 1 Mus musculus 104-110 32297642-0 2020 Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 114-120 32232361-4 2020 Beyond its role in translation, hcLRS has an important moonlight function as a leucine sensor in the rapamycin complex 1 (mTORC1) pathway. Leucine 79-86 CREB regulated transcription coactivator 1 Mus musculus 122-128 32019866-3 2020 Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 44-50 31924757-3 2020 PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. Leucine 62-69 CREB regulated transcription coactivator 1 Mus musculus 29-35 31924757-4 2020 The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Leucine 171-178 CREB regulated transcription coactivator 1 Mus musculus 31-37 31924757-8 2020 In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity. Leucine 58-65 CREB regulated transcription coactivator 1 Mus musculus 39-45 30092695-3 2019 In certain types of cell, it is known that mTORC1 activation depends on influx of l-leucine through an amino acid transporter, Slc7a5. Leucine 82-91 CREB regulated transcription coactivator 1 Mus musculus 43-49 31668641-3 2019 mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Leucine 70-77 CREB regulated transcription coactivator 1 Mus musculus 0-6 30092695-10 2019 Conclusion: l-leucine influx through Slc7a5 critically regulates mTORC1 activity and the immunological responses of human B cells. Leucine 12-21 CREB regulated transcription coactivator 1 Mus musculus 65-71 31134526-0 2019 ATP6V0d2 mediates leucine-induced mTORC1 activation and polarization of macrophages. Leucine 18-25 CREB regulated transcription coactivator 1 Mus musculus 34-40 31345230-2 2019 This pathway relies on mTORC1 sensing sufficient levels of intracellular amino acids, such as leucine, which are required for mTORC1 activation. Leucine 94-101 CREB regulated transcription coactivator 1 Mus musculus 23-29 31345230-2 2019 This pathway relies on mTORC1 sensing sufficient levels of intracellular amino acids, such as leucine, which are required for mTORC1 activation. Leucine 94-101 CREB regulated transcription coactivator 1 Mus musculus 126-132 30197302-0 2019 Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 19-25 31067471-1 2019 mTORC1 regulates cellular growth and is activated by growth factors and by essential amino acids such as Leu. Leucine 105-108 CREB regulated transcription coactivator 1 Mus musculus 0-6 30990795-2 2019 This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Leucine 104-111 CREB regulated transcription coactivator 1 Mus musculus 129-135 31107245-2 2019 In this issue of the JCI, Kato and colleagues reported that administration of NV-5138, a recently developed synthetic leucine analog, has a rapid and sustained antidepressant action in rat models via activation of mTORC1 signaling. Leucine 118-125 CREB regulated transcription coactivator 1 Mus musculus 214-220 30835510-0 2019 Evidence for a role for Sestrin1 in mediating leucine-induced activation of mTORC1 in skeletal muscle. Leucine 46-53 CREB regulated transcription coactivator 1 Mus musculus 76-82 30835510-1 2019 Previous studies established that leucine stimulates protein synthesis in skeletal muscle to the same extent as a complete mixture of amino acids, and the effect occurs through activation of the mechanistic target of rapamycin in complex 1 (mTORC1). Leucine 34-41 CREB regulated transcription coactivator 1 Mus musculus 241-247 30835510-2 2019 Recent studies using cells in culture showed that the Sestrins bind leucine and are required for leucine-dependent activation of mTORC1. Leucine 68-75 CREB regulated transcription coactivator 1 Mus musculus 129-135 30835510-2 2019 Recent studies using cells in culture showed that the Sestrins bind leucine and are required for leucine-dependent activation of mTORC1. Leucine 97-104 CREB regulated transcription coactivator 1 Mus musculus 129-135 30835510-4 2019 The goal of the present study was to compare expression of the Sestrins in skeletal muscle to other tissues and to assess their relative role in mediating activation of mTORC1 by leucine. Leucine 179-186 CREB regulated transcription coactivator 1 Mus musculus 169-175 30835510-8 2019 Overall, the results presented herein are consistent with a model in which leucine-induced activation of mTORC1 in skeletal muscle in vivo occurs primarily through release of Sestrin1 from GATOR2. Leucine 75-82 CREB regulated transcription coactivator 1 Mus musculus 105-111 30696773-5 2019 Notably, treatment of IL-18-stimulated NK cells with leucine activates the metabolic sensor mTORC1, indicating that the high expression of amino acid transporters induces amino acid-driven mTORC1 activation. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 92-98 30696773-5 2019 Notably, treatment of IL-18-stimulated NK cells with leucine activates the metabolic sensor mTORC1, indicating that the high expression of amino acid transporters induces amino acid-driven mTORC1 activation. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 189-195 30696773-6 2019 Inhibition of the amino acid transporter CD98/LAT1 abrogated the leucine-driven mTORC1 activation and reduced NK cell effector function. Leucine 65-72 CREB regulated transcription coactivator 1 Mus musculus 80-86 30858438-5 2019 NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. Leucine 13-20 CREB regulated transcription coactivator 1 Mus musculus 43-49 30844724-2 2019 Amino acids, especially leucine, arginine and glutamine, signal to mTORC1 activation. Leucine 24-31 CREB regulated transcription coactivator 1 Mus musculus 67-73 30197302-2 2019 Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 24-30 30197302-2 2019 Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Leucine 0-3 CREB regulated transcription coactivator 1 Mus musculus 24-30 30197302-2 2019 Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Leucine 9-12 CREB regulated transcription coactivator 1 Mus musculus 24-30 30197302-3 2019 Here we describe that the Leu metabolite acetyl-coenzyme A (AcCoA) positively regulates mTORC1 activity by EP300-mediated acetylation of the mTORC1 regulator, Raptor, at K1097. Leucine 26-29 CREB regulated transcription coactivator 1 Mus musculus 88-94 30197302-3 2019 Here we describe that the Leu metabolite acetyl-coenzyme A (AcCoA) positively regulates mTORC1 activity by EP300-mediated acetylation of the mTORC1 regulator, Raptor, at K1097. Leucine 26-29 CREB regulated transcription coactivator 1 Mus musculus 141-147 30197302-4 2019 Leu metabolism and consequent mTORC1 activity are regulated by intermediary enzymes. Leucine 0-3 CREB regulated transcription coactivator 1 Mus musculus 30-36 30197302-8 2019 These results provide a direct mechanism for mTORC1 regulation by Leu metabolism. Leucine 66-69 CREB regulated transcription coactivator 1 Mus musculus 45-51 30282607-6 2018 Cell growth, casein synthesis and mTORC1 signaling pathway were decreased in response to Leu absence, but these decreases were partially restored by GNG12 overexpression, and those effects were partially reversed by inhibiting GNG12. Leucine 89-92 CREB regulated transcription coactivator 1 Mus musculus 34-40 31379141-5 2019 Recently, several sensors of leucine, arginine, and S-adenosylmethionine for the amino acid-stimulated mTORC1 pathway have been coming to light. Leucine 29-36 CREB regulated transcription coactivator 1 Mus musculus 103-109 30282607-0 2018 Proteomic analyses reveal GNG12 regulates cell growth and casein synthesis by activating the Leu-mediated mTORC1 signaling pathway. Leucine 93-96 CREB regulated transcription coactivator 1 Mus musculus 106-112 30282607-8 2018 Taken together, these results suggest that GNG12 is a positive regulator of the Leu-mediated mTORC1 signaling pathway in CMECs that promotes cell growth and casein synthesis. Leucine 80-83 CREB regulated transcription coactivator 1 Mus musculus 93-99 29278758-8 2018 Results showed that Leu supplementation decreased cell proliferation by 40% through mechanisms not related to cell necrosis, apoptosis, oxidative stress, autophagy or inhibition of the mTORC1 pathway. Leucine 20-23 CREB regulated transcription coactivator 1 Mus musculus 185-191 29728917-1 2018 The objective of this study was to determine if enteral leucine or branched-chain amino acid (BCAA) supplementation increases muscle protein synthesis in neonates who consume less than their protein and energy requirements, and whether this increase is mediated via the upregulation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway or the decrease in muscle protein degradation signaling. Leucine 56-63 CREB regulated transcription coactivator 1 Mus musculus 333-339 29784813-1 2018 A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. Leucine 70-77 CREB regulated transcription coactivator 1 Mus musculus 136-142 29784813-5 2018 The GTP-GDP cycle of the RagD-RagB pair, rather than the RagC-RagA pair, is critical for leucine-induced mTORC1 activation. Leucine 89-96 CREB regulated transcription coactivator 1 Mus musculus 105-111 30175263-0 2018 L-leucine stimulates glutamate dehydrogenase activity and glutamate synthesis by regulating mTORC1/SIRT4 pathway in pig liver. Leucine 0-9 CREB regulated transcription coactivator 1 Mus musculus 92-98 30175263-7 2018 Leucine could also activate mammalian target of rapamycin complex 1 (mTORC1) signaling (P < 0.05), as evidenced by the increased phosphorylation levels of ribosomal protein S6 kinase 1 (S6K1) and ribosomal protein S6 (S6). Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 69-75 30175263-12 2018 In conclusion, L-leucine increases GDH activity and stimulates glutamate synthesis from different nitrogen sources by regulating mTORC1/SIRT4 pathway in the liver of pigs. Leucine 15-24 CREB regulated transcription coactivator 1 Mus musculus 129-135 30041947-1 2018 According to recent studies, leucyl-tRNA synthetase (LRS) acts as a leucine sensor and modulates the activation of the mammalian target of rapamycin complex 1 (mTORC1) activation. Leucine 68-75 CREB regulated transcription coactivator 1 Mus musculus 160-166 30029003-4 2018 Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation leads to loss of tRNA charging and ribosome pausing. Leucine 102-109 CREB regulated transcription coactivator 1 Mus musculus 37-43 29574525-3 2018 Of this family, Sestrin2 is a putative leucine sensor implicated in mTORC1 and AMP-dependent protein kinase (AMPK) regulation. Leucine 39-46 CREB regulated transcription coactivator 1 Mus musculus 68-74 29844341-8 2018 Furthermore, treatment with leucine and glutamine, for both proximal and distal fin stumps, led to an up-regulation in cell proliferation via mTORC1 activation, indicating that leucine/glutamine signaling possesses the ability to change the position-dependent regeneration. Leucine 28-35 CREB regulated transcription coactivator 1 Mus musculus 142-148 29844341-8 2018 Furthermore, treatment with leucine and glutamine, for both proximal and distal fin stumps, led to an up-regulation in cell proliferation via mTORC1 activation, indicating that leucine/glutamine signaling possesses the ability to change the position-dependent regeneration. Leucine 177-184 CREB regulated transcription coactivator 1 Mus musculus 142-148 29422900-4 2018 We provide evidence that SLC7A5-mediated leucine influx contributes to pro-inflammatory cytokine production via mTOR complex 1 (mTORC1)-induced glycolytic reprograming in activated human monocytes/macrophages. Leucine 41-48 CREB regulated transcription coactivator 1 Mus musculus 128-134 29150487-3 2018 Here, we investigated the contribution of the different routes of Leu entry into cells to mTORC1 activation using pharmacological inhibitors and cells that lack LAT1 or dynamin-1, -2 and -3. Leucine 66-69 CREB regulated transcription coactivator 1 Mus musculus 90-96 28409828-2 2017 We utilized a tissue engineering approach in order to test whether supplementing culture medium with leucine could enhance mTORC1 signaling, myotube growth, and muscle function. Leucine 101-108 CREB regulated transcription coactivator 1 Mus musculus 123-129 29053970-4 2017 SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. Leucine 124-131 CREB regulated transcription coactivator 1 Mus musculus 139-145 29053970-5 2017 SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Leucine 25-32 CREB regulated transcription coactivator 1 Mus musculus 100-106 29283439-10 2018 Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine. Leucine 164-171 CREB regulated transcription coactivator 1 Mus musculus 147-153 28882589-10 2017 The results showed a decrease in autophagy on addition of leucine, demonstrating crosstalk between leucine sensing, LRS translocation, RagD interaction, and mTORC1 activation. Leucine 58-65 CREB regulated transcription coactivator 1 Mus musculus 157-163 29296509-4 2017 Multiple studies have focused on how leucine and arginine activate mTORC1 through the Rag GTPases, with mechanistic details slowly emerging. Leucine 37-44 CREB regulated transcription coactivator 1 Mus musculus 67-73 28963468-1 2017 Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 116-122 28963468-3 2017 Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. Leucine 30-37 CREB regulated transcription coactivator 1 Mus musculus 58-64 28963468-7 2017 These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Leucine 203-210 CREB regulated transcription coactivator 1 Mus musculus 225-231 28963468-8 2017 Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition. Leucine 143-150 CREB regulated transcription coactivator 1 Mus musculus 198-204 28731988-10 2017 In primary preterm rat skeletal muscle satellite cells, MAP4K3 knockdown resulted in significantly weaker, but not entirely blunted, leucine-induced mTORC1 signaling. Leucine 133-140 CREB regulated transcription coactivator 1 Mus musculus 149-155 28731988-12 2017 MAP4K3 may play a role in mTORC1 full activation in response to leucine. Leucine 64-71 CREB regulated transcription coactivator 1 Mus musculus 26-32 28626421-7 2017 Recent studies have highlighted that mitochondrial proteins such as glutamate dehydrogenase and the human branched chain aminotransferase protein, through metabolism of leucine and glutamate, differentially regulate mTORC1 and autophagy. Leucine 169-176 CREB regulated transcription coactivator 1 Mus musculus 216-222 27933890-1 2016 Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. Leucine 46-53 CREB regulated transcription coactivator 1 Mus musculus 69-75 27934653-5 2016 Leucine acts as a signaling molecule directly at the muscle level via the activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1). Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 141-147 28588499-10 2017 In vitro, we confirmed that ketone bodies potentiate the increase in mTORC1 activation and protein synthesis in leucine-stimulated myotubes. Leucine 112-119 CREB regulated transcription coactivator 1 Mus musculus 69-75 27988363-5 2017 AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. Leucine 87-94 CREB regulated transcription coactivator 1 Mus musculus 70-76 27988363-5 2017 AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. Leucine 87-94 CREB regulated transcription coactivator 1 Mus musculus 128-134 27649739-1 2016 Sestrin2 is a GATOR2-interacting protein that directly binds leucine and is required for the inhibition of mTORC1 under leucine deprivation, indicating that it is a leucine sensor for the mTORC1 pathway. Leucine 120-127 CREB regulated transcription coactivator 1 Mus musculus 107-113 27690010-3 2016 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. Leucine 71-78 CREB regulated transcription coactivator 1 Mus musculus 127-133 27649739-1 2016 Sestrin2 is a GATOR2-interacting protein that directly binds leucine and is required for the inhibition of mTORC1 under leucine deprivation, indicating that it is a leucine sensor for the mTORC1 pathway. Leucine 120-127 CREB regulated transcription coactivator 1 Mus musculus 107-113 27649739-2 2016 We recently reported the structure of Sestrin2 in complex with leucine [Protein Data Bank (PDB) ID, 5DJ4] and demonstrated that mutations in the leucine-binding pocket that alter the affinity of Sestrin2 for leucine result in a corresponding change in the leucine sensitivity of mTORC1 in cells. Leucine 145-152 CREB regulated transcription coactivator 1 Mus musculus 279-285 27649739-2 2016 We recently reported the structure of Sestrin2 in complex with leucine [Protein Data Bank (PDB) ID, 5DJ4] and demonstrated that mutations in the leucine-binding pocket that alter the affinity of Sestrin2 for leucine result in a corresponding change in the leucine sensitivity of mTORC1 in cells. Leucine 145-152 CREB regulated transcription coactivator 1 Mus musculus 279-285 27649739-2 2016 We recently reported the structure of Sestrin2 in complex with leucine [Protein Data Bank (PDB) ID, 5DJ4] and demonstrated that mutations in the leucine-binding pocket that alter the affinity of Sestrin2 for leucine result in a corresponding change in the leucine sensitivity of mTORC1 in cells. Leucine 145-152 CREB regulated transcription coactivator 1 Mus musculus 279-285 27477288-3 2016 Here, we identify leucyl-tRNA synthetase (LRS) as a leucine sensor for the activation of Vps34-PLD1 upstream of mTORC1. Leucine 52-59 CREB regulated transcription coactivator 1 Mus musculus 112-118 27010498-10 2016 Overall, the results support a model in which leucine selectively promotes dephosphorylation of Sestrin2, causing it to dissociate from and thereby activate GATOR2, leading to activation of mTORC1. Leucine 46-53 CREB regulated transcription coactivator 1 Mus musculus 190-196 27010498-0 2016 Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 55-61 27010498-1 2016 The studies described herein were designed to explore the role of Sestrin2 in mediating the selective action of leucine to activate mTORC1. Leucine 112-119 CREB regulated transcription coactivator 1 Mus musculus 132-138 27010498-3 2016 Moreover, leucine availability-induced alterations in Sestrin2 phosphorylation correlated temporally and dose dependently with the activation state of mTORC1, there being a reciprocal relationship between the degree of phosphorylation of Sestrin2 and the extent of repression of mTORC1. Leucine 10-17 CREB regulated transcription coactivator 1 Mus musculus 151-157 27010498-3 2016 Moreover, leucine availability-induced alterations in Sestrin2 phosphorylation correlated temporally and dose dependently with the activation state of mTORC1, there being a reciprocal relationship between the degree of phosphorylation of Sestrin2 and the extent of repression of mTORC1. Leucine 10-17 CREB regulated transcription coactivator 1 Mus musculus 279-285 27010498-5 2016 Notably, in cells lacking the protein kinase ULK1, the activation state of mTORC1 was elevated in leucine-deficient medium, such that the effect of re-addition of the amino acid was blunted. Leucine 98-105 CREB regulated transcription coactivator 1 Mus musculus 75-81 27422517-3 2016 Leucine has been described as an important essential amino acid and a nutrient signal that activates complex 1 of the mammalian target of rapamycin (mTORC1), which is a critical regulator of T cell proliferation, differentiation, and function. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 149-155 27245337-6 2016 Signaling through mTORC1, as reflected in p70S6 kinase phosphorylation, was stimulated to a greater extent by the EAA and BCAA than the leucine or placebo supplements. Leucine 136-143 CREB regulated transcription coactivator 1 Mus musculus 18-24 27209231-3 2016 Compound 5 inhibited downstream phosphorylation of mTORC1 by blocking leucine-sensing ability of LRS, without affecting the catalytic activity of LRS. Leucine 70-77 CREB regulated transcription coactivator 1 Mus musculus 51-57 27280402-0 2016 FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1. Leucine 19-26 CREB regulated transcription coactivator 1 Mus musculus 58-64 27297692-0 2016 GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism. Leucine 41-48 CREB regulated transcription coactivator 1 Mus musculus 20-26 27297692-5 2016 Our data establish that GCN2 is involved in the inhibition of mTORC1 upon leucine or arginine deprivation. Leucine 74-81 CREB regulated transcription coactivator 1 Mus musculus 62-68 26836250-6 2016 Further, L-leucine supplementation resulted in higher embryonic expression of genes involved in cell cycle (cyclin D1; CCND1), translation initiation (eukaryotic translation initiation factor 4E; EIF4E), amino acid transport (large neutral amino acid transporter 2; Lat2: gene SLC7A8) and proliferation (proliferating cell nuclear antigen; PCNA) in a mTORC1-dependent manner. Leucine 9-18 CREB regulated transcription coactivator 1 Mus musculus 351-357 27053525-0 2016 Activation of mTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exercise. Leucine 24-31 CREB regulated transcription coactivator 1 Mus musculus 14-20 27053525-2 2016 Moreover, activation of mammalian target of rapamycin complex 1 (mTORC1) signaling by leucine is potentiated by the presence of other essential amino acids (EAA). Leucine 86-93 CREB regulated transcription coactivator 1 Mus musculus 65-71 26836250-5 2016 High levels of L-leucine and glucose lead to higher phosphorylation of mTORC1 and its downstream target ribosomal S6 kinase 1 (S6K1) in these embryos. Leucine 15-24 CREB regulated transcription coactivator 1 Mus musculus 71-77 26884386-4 2016 Fractional protein synthesis rates in longissimus dorsi, gastrocnemius, and soleus muscles were ~30% higher in CON + LEU compared with CON + ALA and were associated with decreased Deptor abundance and increased mTORC1, mTORC2, 4E-BP1, and S6K1 phosphorylation, SNAT2 abundance, and association of eIF4E with eIF4G and RagC with mTOR. Leucine 117-120 CREB regulated transcription coactivator 1 Mus musculus 211-217 26884386-6 2016 Our results demonstrate that pulsatile delivery of a leucine supplement during 21 days of continuous enteral feeding enhances lean growth by stimulating the mTORC1-dependent translation initiation pathway, leading to protein synthesis in skeletal muscle of neonates. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 157-163 26645537-9 2016 The p-mTORC1 levels were higher in the LEU, SD, and LEU + SD groups vs. the CTL group. Leucine 39-42 CREB regulated transcription coactivator 1 Mus musculus 6-12 26724922-1 2016 Among amino acids, leucine is a potential signaling molecule to regulate cell growth and metabolism by activating mechanistic target of rapamycin complex 1 (mTORC1). Leucine 19-26 CREB regulated transcription coactivator 1 Mus musculus 157-163 26724922-2 2016 To reveal the critical structures of leucine molecule to activate mTORC1, we examined the structure-activity relationships of leucine derivatives in HeLa S3 cells for cellular uptake and for the induction of phosphorylation of p70 ribosomal S6 kinase 1 (p70S6K), a downstream effector of mTORC1. Leucine 37-44 CREB regulated transcription coactivator 1 Mus musculus 66-72 26724922-2 2016 To reveal the critical structures of leucine molecule to activate mTORC1, we examined the structure-activity relationships of leucine derivatives in HeLa S3 cells for cellular uptake and for the induction of phosphorylation of p70 ribosomal S6 kinase 1 (p70S6K), a downstream effector of mTORC1. Leucine 37-44 CREB regulated transcription coactivator 1 Mus musculus 288-294 26724922-2 2016 To reveal the critical structures of leucine molecule to activate mTORC1, we examined the structure-activity relationships of leucine derivatives in HeLa S3 cells for cellular uptake and for the induction of phosphorylation of p70 ribosomal S6 kinase 1 (p70S6K), a downstream effector of mTORC1. Leucine 126-133 CREB regulated transcription coactivator 1 Mus musculus 66-72 26724922-3 2016 The activation of mTORC1 by leucine and its derivatives was the consequence of two successive events: the cellular uptake by L-type amino acid transporter 1 (LAT1) responsible for leucine uptake in HeLa S3 cells and the activation of mTORC1 following the transport. Leucine 28-35 CREB regulated transcription coactivator 1 Mus musculus 18-24 26724922-3 2016 The activation of mTORC1 by leucine and its derivatives was the consequence of two successive events: the cellular uptake by L-type amino acid transporter 1 (LAT1) responsible for leucine uptake in HeLa S3 cells and the activation of mTORC1 following the transport. Leucine 28-35 CREB regulated transcription coactivator 1 Mus musculus 234-240 26724922-3 2016 The activation of mTORC1 by leucine and its derivatives was the consequence of two successive events: the cellular uptake by L-type amino acid transporter 1 (LAT1) responsible for leucine uptake in HeLa S3 cells and the activation of mTORC1 following the transport. Leucine 180-187 CREB regulated transcription coactivator 1 Mus musculus 18-24 26645537-9 2016 The p-mTORC1 levels were higher in the LEU, SD, and LEU + SD groups vs. the CTL group. Leucine 52-55 CREB regulated transcription coactivator 1 Mus musculus 6-12 26449471-5 2016 The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. Leucine 4-11 CREB regulated transcription coactivator 1 Mus musculus 77-83 26959180-2 2016 Recent reports by Sabatini and coworkers (Saxton et al., 2016; Wolfson et al., 2016) characterize a cytoplasmic amino acid receptor that couples the binding of leucine to the activation of mTORC1. Leucine 160-167 CREB regulated transcription coactivator 1 Mus musculus 189-195 26729373-5 2016 L-leucine treatment partially rescued translational efficiency of ribosomal subunits, translation initiation factors, snoRNA production, and mitochondrial function in RBS cells, consistent with these processes being mTORC1 controlled. Leucine 0-9 CREB regulated transcription coactivator 1 Mus musculus 216-222 26729373-9 2016 This study reveals the dramatic rescue effects of L-leucine stimulation of mTORC1 in RBS cells and supports that normal gene expression and translation requires ESCO2 function. Leucine 50-59 CREB regulated transcription coactivator 1 Mus musculus 75-81 26449471-0 2016 Sestrin2 is a leucine sensor for the mTORC1 pathway. Leucine 14-21 CREB regulated transcription coactivator 1 Mus musculus 37-43 26449471-1 2016 Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 142-148 26449471-4 2016 We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. Leucine 13-20 CREB regulated transcription coactivator 1 Mus musculus 216-222 26449471-5 2016 The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. Leucine 57-64 CREB regulated transcription coactivator 1 Mus musculus 77-83 26449471-6 2016 These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway. Leucine 42-49 CREB regulated transcription coactivator 1 Mus musculus 65-71 26586190-0 2016 Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Leucine 21-28 CREB regulated transcription coactivator 1 Mus musculus 53-59 26586190-7 2016 A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. Leucine 72-79 CREB regulated transcription coactivator 1 Mus musculus 154-160 26586190-7 2016 A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. Leucine 119-126 CREB regulated transcription coactivator 1 Mus musculus 154-160 26169935-9 2015 Leucine alone stimulates mTORC1 signaling, although this response is enhanced by other EAAs and does not appear to be caused by alterations in mTORC1 assembly. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 25-31 26169935-1 2015 We examined how the stimulatory effect of leucine on the mechanistic target of rapamycin complex 1 (mTORC1) pathway is affected by the presence of the remaining essential amino acids (EAAs). Leucine 42-49 CREB regulated transcription coactivator 1 Mus musculus 100-106 25774780-8 2015 Interestingly, the acute orexigenic effect of the mTORC1 inhibitor rapamycin was preserved in HF-fed mice, supporting the assertion that HF-induced increase in baseline cmNTS mTORC1 activity underlies the defect in L-leucine sensing. Leucine 215-224 CREB regulated transcription coactivator 1 Mus musculus 50-56 25998567-1 2015 Mammalian target of rapamycin 1 (mTORC1), a master regulator of cellular growth, is activated downstream of growth factors, energy signalling and intracellular essential amino acids (EAAs) such as Leu. Leucine 197-200 CREB regulated transcription coactivator 1 Mus musculus 33-39 25998567-5 2015 We show that LAPTM4b recruits LAT1-4F2hc to lysosomes, leading to uptake of Leu into lysosomes, and is required for mTORC1 activation via V-ATPase following EAA or Leu stimulation. Leucine 164-167 CREB regulated transcription coactivator 1 Mus musculus 116-122 26007333-11 2015 We have shown that leucine promoted the differentiation of myotubes in part through the mTORC1-MyoD signal pathway. Leucine 19-26 CREB regulated transcription coactivator 1 Mus musculus 88-94 25872869-0 2015 The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability. Leucine 64-73 CREB regulated transcription coactivator 1 Mus musculus 4-10 25872869-6 2015 These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine. Leucine 237-246 CREB regulated transcription coactivator 1 Mus musculus 93-99 24806638-5 2014 The inhibitor of mammalian target of rapamycin complex 1 (mTORC1), rapamycin, had no effect on the insulin-stimulated glucose uptake, but eliminated the facilitating effect of leucine in the insulin-stimulated glucose uptake and AKT phosphorylation. Leucine 176-183 CREB regulated transcription coactivator 1 Mus musculus 58-64 25567907-4 2015 We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Leucine 15-22 CREB regulated transcription coactivator 1 Mus musculus 47-53 25231351-0 2014 Suppression of mTORC1 activation in acid-alpha-glucosidase-deficient cells and mice is ameliorated by leucine supplementation. Leucine 102-109 CREB regulated transcription coactivator 1 Mus musculus 15-21 25231351-4 2014 Treatment with the cell-permeable leucine analog L-leucyl-L-leucine methyl ester restored mTORC1 activation. Leucine 34-41 CREB regulated transcription coactivator 1 Mus musculus 90-96 25231351-5 2014 In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 72-78 25231351-6 2014 Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine 8-15 CREB regulated transcription coactivator 1 Mus musculus 62-68 25231351-6 2014 Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine 43-50 CREB regulated transcription coactivator 1 Mus musculus 62-68 25231351-9 2014 Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model. Leucine 40-47 CREB regulated transcription coactivator 1 Mus musculus 10-16 24806638-0 2014 Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: involving mTORC1 and mTORC2. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 116-122 27021048-5 2015 Recent studies have shown that activity of the hypothalamic mTORC1 pathway varies according to cell and stimulus types, and that this signaling cascade regulates food intake and body weight in response to nutrients, such as leucine, and hormones like leptin, ghrelin and triiodothyronine. Leucine 224-231 CREB regulated transcription coactivator 1 Mus musculus 60-66 25444557-3 2014 In skeletal muscle, it has been clearly demonstrated that of all the amino acids, leucine is the most potent stimulator of mTORC1 and protein synthesis in vitro and in vivo. Leucine 82-89 CREB regulated transcription coactivator 1 Mus musculus 123-129 24793303-3 2014 Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. Leucine 31-38 CREB regulated transcription coactivator 1 Mus musculus 82-88 24793303-7 2014 In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. Leucine 15-22 CREB regulated transcription coactivator 1 Mus musculus 32-38 24793303-8 2014 In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Leucine 94-101 CREB regulated transcription coactivator 1 Mus musculus 139-145 24806638-7 2014 Together, these findings show that leucine can facilitate the insulin-induced insulin signaling and glucose uptake in skeletal muscle cells through both mTORC1 and mTORC2, implicating the potential importance of this amino acid in glucose homeostasis and providing new mechanistic insights. Leucine 35-42 CREB regulated transcription coactivator 1 Mus musculus 153-159 24847056-4 2014 Leu is a known activator of the mammalian target of rapamycin complex 1 (mTORC1). Leucine 0-3 CREB regulated transcription coactivator 1 Mus musculus 73-79 24476474-0 2014 Absence of leucine in an essential amino acid supplement reduces activation of mTORC1 signalling following resistance exercise in young females. Leucine 11-18 CREB regulated transcription coactivator 1 Mus musculus 79-85 24762008-2 2014 Leucine is not only important as a building block for proteins, but plays a critical role in mTORC1 signaling leading to protein translation. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 93-99 24762008-7 2014 We further show in LNCaP prostate cancer cells that ESK246 is a potent (IC50 = 8.12 muM) inhibitor of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Leucine 102-109 CREB regulated transcription coactivator 1 Mus musculus 137-143 24740400-0 2014 Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome. Leucine 22-29 CREB regulated transcription coactivator 1 Mus musculus 41-47 24740400-3 2014 Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. Leucine 30-37 CREB regulated transcription coactivator 1 Mus musculus 107-113 24722568-1 2014 The role of LeuRS, an aminoacyl-tRNA synthetase, as an intracellular l-leucine sensor for the mTORC1 pathway has been the subject of much research recently. Leucine 69-78 CREB regulated transcription coactivator 1 Mus musculus 94-100 24476474-1 2014 The purpose of the study was to investigate the specific effect of leucine on mTORC1 signalling and amino acid metabolism in connection with resistance exercise. Leucine 67-74 CREB regulated transcription coactivator 1 Mus musculus 78-84 24476474-10 2014 In conclusion, the presence of leucine in the supplement enhances the stimulatory effect on mTORC1 signalling and reduces the level of tyrosine and the sum of the EAA in muscle and plasma, suggesting a stimulation of protein synthesis and (or) inhibition of breakdown, leading to improvement in net protein balance. Leucine 31-38 CREB regulated transcription coactivator 1 Mus musculus 92-98 22442136-14 2012 Collectively, our results indicate that EtOH inhibits the anabolic effects that Leu has on protein synthesis and mTORC1 activity by modulating both Rag GTPase function and AMPK/TSC2/Rheb signaling. Leucine 80-83 CREB regulated transcription coactivator 1 Mus musculus 113-119 24284439-5 2014 AA transporters at the cell surface, particularly those for large neutral AAs such as leucine, interact functionally with intracellular nutrient-signaling pathways that regulate metabolism: for example, the mammalian target of rapamycin complex 1 (mTORC1) pathway, which promotes cell growth, and the general control non-derepressible (GCN) pathway, which is activated by AA starvation. Leucine 86-93 CREB regulated transcription coactivator 1 Mus musculus 248-254 22898570-1 2013 The regulation of cell growth and protein biosynthesis is triggered by the mammalian target of rapamycin complex 1 (mTORC1) responding to amino acids, especially leucine. Leucine 162-169 CREB regulated transcription coactivator 1 Mus musculus 116-122 23529682-4 2013 mTORC1, the central hub of protein- and lipid biosynthesis, cell growth and proliferation, is activated by insulin, IGF-1 and branched-chain essential amino acids, especially leucine. Leucine 175-182 CREB regulated transcription coactivator 1 Mus musculus 0-6 22160257-12 2012 LEU and CIT administration differently stimulated the mTORC1 pathway (LEU > CIT). Leucine 0-3 CREB regulated transcription coactivator 1 Mus musculus 54-60 22160257-12 2012 LEU and CIT administration differently stimulated the mTORC1 pathway (LEU > CIT). Leucine 70-73 CREB regulated transcription coactivator 1 Mus musculus 54-60 22160257-15 2012 LEU, CIT and NEAA may have different actions on MPS in this model as they share different mTORC1 regulation capacities. Leucine 0-3 CREB regulated transcription coactivator 1 Mus musculus 90-96 22898570-3 2013 We analyzed whether the free intracellular leucine availability, a metabolite of leucine catabolism or the process of leucine oxidation activates mTORC1 signaling. Leucine 43-50 CREB regulated transcription coactivator 1 Mus musculus 146-152 22898570-4 2013 We further investigated whether mTORC1 signaling is subject to altered regulation in disturbed leucine metabolism. Leucine 95-102 CREB regulated transcription coactivator 1 Mus musculus 32-38 22898570-10 2013 Our data provide evidence that mechanisms determining intracellular leucine availability and the amino acid sensor MAP4K3 are key upstream modulators of nutrient-sensitive mTORC1 signaling, whereas specific leucine metabolites or leucine oxidation rates do not play a role. Leucine 68-75 CREB regulated transcription coactivator 1 Mus musculus 172-178 23525088-5 2013 The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Leucine 110-117 CREB regulated transcription coactivator 1 Mus musculus 172-178 23404499-3 2013 The leucine-facilitated insulin-induced phosphorylation of Akt at residue 473 was not affected by knocking down the key component of mTORC1 or -2 complexes but was blocked by inhibition of c-Src (PP2), PI3K (LY294002), Galphai protein (pertussis toxin or siRNA against Galphai1 gene, or beta-arrestin 2 (siRNA)). Leucine 4-11 CREB regulated transcription coactivator 1 Mus musculus 133-139 22985970-0 2013 Upregulation of amino acid transporter expression induced by L-leucine availability in L6 myotubes is associated with ATF4 signaling through mTORC1-dependent mechanism. Leucine 61-70 CREB regulated transcription coactivator 1 Mus musculus 141-147 22985970-1 2013 OBJECTIVE: Essential amino acids, especially l-leucine, initiate the signaling of the mammalian target of rapamycin complex-1 (mTORC1) and protein synthesis in skeletal muscle. Leucine 45-54 CREB regulated transcription coactivator 1 Mus musculus 127-133 22985970-3 2013 The objectives of this study were to determine whether an increase in leucine availability upregulates the gene transcription and translation of amino acid transporters and other amino acid members in an mTORC1-dependent pathway that control amino acid use (general control non-repressed-2 and activating transcription factor-4) and to measure the factors related to protein synthesis and proteolysis. Leucine 70-77 CREB regulated transcription coactivator 1 Mus musculus 204-210 22985970-4 2013 METHODS: L6 skeletal muscle cells that had been treated with l-leucine (0.105 g/L) were incubated for 30 min to stimulate the transcription of L-type amino acid transporter-1, CD98, and sodium-coupled neutral amino acid transporter-2 and increase activating transcription factor-4 protein, which is dependent on the mTORC1 signaling pathway. Leucine 61-70 CREB regulated transcription coactivator 1 Mus musculus 316-322 22749528-5 2012 We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and alpha-ketoglutarate production. Leucine 50-57 CREB regulated transcription coactivator 1 Mus musculus 85-91 22749528-10 2012 Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and alpha-ketoglutarate production upstream of Rag. Leucine 54-61 CREB regulated transcription coactivator 1 Mus musculus 6-12 22523661-8 2012 Exaggerated leucine-mediated mTORC1-S6K1 signalling induced by infant formulas may thus explain increased adipogenesis and generation of lifelong elevated adipocyte numbers. Leucine 12-19 CREB regulated transcription coactivator 1 Mus musculus 29-35 22258093-7 2012 Hence, we establish a novel cell-free assay recapitulating leucine-mediated autophagy inhibition in an mTORC1-dependent manner; this assay will help us to dissect the regulation of amino acids in autophagy and related human metabolic diseases. Leucine 59-66 CREB regulated transcription coactivator 1 Mus musculus 103-109 22870349-3 2012 Metabolic signals of Western diet are sensed by the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), which integrates signals of cellular energy, growth factors (insulin, IGF-1) and protein-derived signals, predominantly leucine, provided in high amounts by milk proteins and meat. Leucine 249-256 CREB regulated transcription coactivator 1 Mus musculus 120-126 22870349-5 2012 Leucine stimulates mTORC1-SREBP signaling and leucine is directly converted by sebocytes into fatty acids and sterols for sebaceous lipid synthesis. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 19-25 22424946-0 2012 Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Leucine 43-50 CREB regulated transcription coactivator 1 Mus musculus 66-72 22424946-3 2012 Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Leucine 134-141 CREB regulated transcription coactivator 1 Mus musculus 91-97 22424946-4 2012 Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. Leucine 50-57 CREB regulated transcription coactivator 1 Mus musculus 78-84 22442749-2 2012 This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). Leucine 62-69 CREB regulated transcription coactivator 1 Mus musculus 221-227 22442749-2 2012 This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). Leucine 144-151 CREB regulated transcription coactivator 1 Mus musculus 221-227 22442749-9 2012 In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Leucine 58-65 CREB regulated transcription coactivator 1 Mus musculus 75-81 22675606-4 2012 To evaluate the mode of action of leucine, we used rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) complex-1 (mTORC1). Leucine 34-41 CREB regulated transcription coactivator 1 Mus musculus 126-132 22675606-7 2012 The leucine-induced stimulation of protein synthesis and S6K1 and 4E-BP1 phosphorylation were completely blocked by rapamycin, suggesting that leucine action is by an mTORC1-dependent mechanism. Leucine 4-11 CREB regulated transcription coactivator 1 Mus musculus 167-173 22675606-7 2012 The leucine-induced stimulation of protein synthesis and S6K1 and 4E-BP1 phosphorylation were completely blocked by rapamycin, suggesting that leucine action is by an mTORC1-dependent mechanism. Leucine 143-150 CREB regulated transcription coactivator 1 Mus musculus 167-173 22056783-6 2012 Both arginine and leucine act individually and additively to propagate signals that are dependent on the activity of the mammalian target of rapamycin complex 1 (mTORC1). Leucine 18-25 CREB regulated transcription coactivator 1 Mus musculus 162-168 22523661-9 2012 Attenuation of mTORC1 signalling of infant formula by leucine restriction to physiologic lower levels of human milk offers a great chance for the prevention of childhood obesity and obesity-related metabolic diseases. Leucine 54-61 CREB regulated transcription coactivator 1 Mus musculus 15-21 21289294-6 2011 The results also suggest that leucine-induced stimulation of mTORC1 signaling occurs through a mechanism distinct from TSC2 and the Akt and ERK signaling pathways. Leucine 30-37 CREB regulated transcription coactivator 1 Mus musculus 61-67 22007000-2 2011 Here, we report that prostate cancer cells coordinate the expression of LAT1 and LAT3 to maintain sufficient levels of leucine needed for mTORC1 signaling and cell growth. Leucine 119-126 CREB regulated transcription coactivator 1 Mus musculus 138-144 21575862-3 2011 Hyperactivation of the RAS-MEK pathway, which is common in melanoma, prevents leucine deprivation from inhibiting mTORC1, the main repressor of autophagy under nutrient-rich conditions. Leucine 78-85 CREB regulated transcription coactivator 1 Mus musculus 114-120 21239491-7 2011 The studies were extended to a cell culture model in which mTORC1 activity was repressed by deprivation of leucine and serum, and resupplementation with the amino acid and insulin acted in an additive manner to restore mTORC1 activation. Leucine 107-114 CREB regulated transcription coactivator 1 Mus musculus 59-65 20851890-9 2010 Taken together, our studies reveal that RSV inhibits leucine-stimulated mTORC1 activation by promoting mTOR/DEPTOR interaction and thus uncover a novel mechanism by which RSV negatively regulates mTOR activity. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 72-78 20427710-8 2010 Overall, the results demonstrate that leucine and PA signal through parallel pathways to activate mTORC1 and that PA mediates its effect through the ERK pathway, rather than through direct binding to mTOR. Leucine 38-45 CREB regulated transcription coactivator 1 Mus musculus 98-104 18765678-5 2009 In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Leucine 37-44 CREB regulated transcription coactivator 1 Mus musculus 55-61 18765678-5 2009 In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Leucine 37-44 CREB regulated transcription coactivator 1 Mus musculus 113-119 19203575-3 2009 (2009) describe a mechanism by which glutamine facilitates the uptake of leucine, leading to mTORC1 activation. Leucine 73-80 CREB regulated transcription coactivator 1 Mus musculus 93-99 19150856-1 2009 In this review we discuss current findings in the human skeletal muscle literature describing the acute influence of nutrients (leucine-enriched essential amino acids in particular) and resistance exercise on muscle protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling. Leucine 128-135 CREB regulated transcription coactivator 1 Mus musculus 279-285 18676370-15 2008 Leucine deprivation markedly inhibited mTORC1 signaling in these cells, but shifting the cells to the nonpermissive temperature for the synthetase did not. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 39-45 18682538-9 2008 Together, these in vivo data suggest that leucine stimulates muscle protein synthesis in neonates by enhancing mTORC1 activation and its downstream effectors. Leucine 42-49 CREB regulated transcription coactivator 1 Mus musculus 111-117 34610328-4 2021 We discovered a leucine-derived monomethyl branched-chain fatty acid and its downstream metabolite, glycosphingolipid, which critically mediates the overall amino acid sensing by intestinal and neuronal mTORC1, which in turn regulates postembryonic development at least partly by controlling protein translation and ribosomal biogenesis. Leucine 16-23 CREB regulated transcription coactivator 1 Mus musculus 203-209 34714145-4 2022 A body of evidence shows that, acting through the highly conserved nutrient sensor pathway mTORc1, the branch chain amino acid leucine can trigger and enhance MPS in older adults, and thus has a role in the medical management of sarcopenia. Leucine 127-134 CREB regulated transcription coactivator 1 Mus musculus 91-97 17724476-4 2008 In some cell-types, rapamycin does not affect cyclin D1 levels, whereas the starvation for leucine (which impairs mTORC1 signaling more profoundly than rapamycin) does. Leucine 91-98 CREB regulated transcription coactivator 1 Mus musculus 114-120 34862201-2 2022 In beta-cells mTORC1 is inhibited while fasting, and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Leucine 116-123 CREB regulated transcription coactivator 1 Mus musculus 14-20 34862201-7 2022 Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyperinsulinemia by inhibiting autophagy. Leucine 48-55 CREB regulated transcription coactivator 1 Mus musculus 29-35 34343656-10 2021 In parallel, the inhibitory effect of Dioscin on M1 polarization was mitigated by the mTORC1 agonist L-leucine. Leucine 103-110 CREB regulated transcription coactivator 1 Mus musculus 86-92 34126555-2 2021 Sestrin2, the function of which is regulated by leucine, has been reported to attenuate the activity of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) that stimulates protein synthesis. Leucine 48-55 CREB regulated transcription coactivator 1 Mus musculus 158-164 34323596-1 2021 Leucine is regarded as an anabolic trigger for the mTORC1 pathway and the stimulation muscle protein synthesis rates. Leucine 0-7 CREB regulated transcription coactivator 1 Mus musculus 51-57 34126555-15 2021 CONCLUSIONS: IGF-I and leucine cooperatively increased mTORC1 activity in C2C12 cells. Leucine 23-30 CREB regulated transcription coactivator 1 Mus musculus 55-61 34126555-17 2021 Sestrin2 siRNA experiments showed that Sestrin2 was involved in the effect of leucine and IGF-I on mTORC1 activity in C2C12 and L6 cells, and suggested that increased Sestrin2 by IGF-I pretreatment might play a role in enhancing the effect of leucine on mTORC1. Leucine 78-85 CREB regulated transcription coactivator 1 Mus musculus 99-105 34126555-17 2021 Sestrin2 siRNA experiments showed that Sestrin2 was involved in the effect of leucine and IGF-I on mTORC1 activity in C2C12 and L6 cells, and suggested that increased Sestrin2 by IGF-I pretreatment might play a role in enhancing the effect of leucine on mTORC1. Leucine 78-85 CREB regulated transcription coactivator 1 Mus musculus 254-260 34126555-17 2021 Sestrin2 siRNA experiments showed that Sestrin2 was involved in the effect of leucine and IGF-I on mTORC1 activity in C2C12 and L6 cells, and suggested that increased Sestrin2 by IGF-I pretreatment might play a role in enhancing the effect of leucine on mTORC1. Leucine 243-250 CREB regulated transcription coactivator 1 Mus musculus 99-105 34126555-17 2021 Sestrin2 siRNA experiments showed that Sestrin2 was involved in the effect of leucine and IGF-I on mTORC1 activity in C2C12 and L6 cells, and suggested that increased Sestrin2 by IGF-I pretreatment might play a role in enhancing the effect of leucine on mTORC1. Leucine 243-250 CREB regulated transcription coactivator 1 Mus musculus 254-260 34325132-4 2021 Here, we demonstrate that leucine is required for cell proliferation through the activation of leucyl-tRNA synthetase (LARS1)-mTORC1 pathway in TSC-null cells. Leucine 26-33 CREB regulated transcription coactivator 1 Mus musculus 126-132 34572527-4 2021 Here, we discovered that leucine increased expressions of SLC38A9 and SLC36A1, leading to mTORC1 activation. Leucine 25-32 CREB regulated transcription coactivator 1 Mus musculus 90-96 34503187-2 2021 Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 116-122 34290409-0 2021 SAR1B senses leucine levels to regulate mTORC1 signalling. Leucine 13-20 CREB regulated transcription coactivator 1 Mus musculus 40-46 34290409-2 2021 Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Leucine 26-33 CREB regulated transcription coactivator 1 Mus musculus 56-62 34290409-2 2021 Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Leucine 113-120 CREB regulated transcription coactivator 1 Mus musculus 56-62 34290409-4 2021 In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. Leucine 17-24 CREB regulated transcription coactivator 1 Mus musculus 142-148 34290409-4 2021 In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. Leucine 53-60 CREB regulated transcription coactivator 1 Mus musculus 142-148 34075648-6 2021 As another indicator of mTORC1 activation, colocalization of MTOR and a lysosomal marker was increased in embryos cultured with 3.75 or 10 mM GlutaMAX in the absence of leucine. Leucine 169-176 CREB regulated transcription coactivator 1 Mus musculus 24-30 34258600-1 2021 Leucyl-tRNA synthetase 1 (LARS1) synthesizes Leu-tRNALeu for protein synthesis and plays an important role in mTORC1 activation by sensing intracellular leucine concentrations. Leucine 153-160 CREB regulated transcription coactivator 1 Mus musculus 110-116 35614056-0 2022 O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine. Leucine 61-68 CREB regulated transcription coactivator 1 Mus musculus 106-112 34198993-2 2021 Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Leucine 24-31 CREB regulated transcription coactivator 1 Mus musculus 86-92 34198993-2 2021 Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Leucine 24-31 CREB regulated transcription coactivator 1 Mus musculus 135-141 34198993-2 2021 Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Leucine 24-31 CREB regulated transcription coactivator 1 Mus musculus 149-155 34118944-7 2021 In contrast, in C2C12 cells, 1 mM leucine increased mTORC1 and S6K1 phosphorylation (P < 0.05), which was inhibited by 2 mg/ml chloroquine. Leucine 34-41 CREB regulated transcription coactivator 1 Mus musculus 52-58 35614056-0 2022 O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine. Leucine 139-146 CREB regulated transcription coactivator 1 Mus musculus 106-112 35614056-3 2022 Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Leucine 109-116 CREB regulated transcription coactivator 1 Mus musculus 80-86 35614056-5 2022 This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. Leucine 151-158 CREB regulated transcription coactivator 1 Mus musculus 224-230 35614056-6 2022 The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. Leucine 99-106 CREB regulated transcription coactivator 1 Mus musculus 59-65 35614056-6 2022 The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. Leucine 146-153 CREB regulated transcription coactivator 1 Mus musculus 59-65 35614056-7 2022 This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine. Leucine 45-52 CREB regulated transcription coactivator 1 Mus musculus 90-96 35457142-4 2022 BCAAs-in particular leucine-activate the rapamycin complex1 mTORC1, which regulates cell growth and metabolism, glucose metabolism and several more essential physiological processes. Leucine 20-27 CREB regulated transcription coactivator 1 Mus musculus 60-66 35577075-0 2022 Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1. Leucine 37-44 CREB regulated transcription coactivator 1 Mus musculus 88-94 35577075-2 2022 mTORC1 activity is regulated by growth factors and amino acids which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. Leucine 240-247 CREB regulated transcription coactivator 1 Mus musculus 0-6 35577075-2 2022 mTORC1 activity is regulated by growth factors and amino acids which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. Leucine 240-247 CREB regulated transcription coactivator 1 Mus musculus 281-287 35577075-3 2022 While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Leucine 59-66 CREB regulated transcription coactivator 1 Mus musculus 94-100 35577075-4 2022 Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Leucine 67-74 CREB regulated transcription coactivator 1 Mus musculus 100-106 35114100-2 2022 Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. Leucine 44-51 CREB regulated transcription coactivator 1 Mus musculus 100-106 35114100-2 2022 Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. Leucine 74-81 CREB regulated transcription coactivator 1 Mus musculus 100-106 35334826-8 2022 Mild endurance exercise during fasting did not increase prefrontal cortex BHB levels nor was BDNF activated, whereas increased leucine levels were associated with Akt-independent increased phosphorylation of the mTORC1 target P70S6K. Leucine 127-134 CREB regulated transcription coactivator 1 Mus musculus 212-218 35022234-5 2022 GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Leucine 107-114 CREB regulated transcription coactivator 1 Mus musculus 40-46