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https://www.readbyqxmd.com/read/28808055/dynamin-dependent-amino-acid-endocytosis-activates-mechanistic-target-of-rapamycin-complex-1-mtorc1
#1
Shusaku Shibutani, Hana Okazaki, Hiroyuki Iwata
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis and potential target for modifying cellular metabolism in various conditions, including cancer and aging. mTORC1 activity is tightly regulated by the availability of extracellular amino acids, and previous studies have revealed that amino acids in the extracellular fluid are transported to the lysosomal lumen. There, amino acids induce recruitment of cytoplasmic mTORC1 to the lysosome by the Rag GTPases, followed by mTORC1 activation by the small GTPase Ras homolog enriched in brain (Rheb)...
August 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28768723/lamtor1-is-critically-required-for-cd4-t-cell-proliferation-and-regulatory-t-cell-suppressive-function
#2
Takashi Hosokawa, Tetsuya Kimura, Shigeyuki Nada, Tatsusada Okuno, Daisuke Ito, Sujin Kang, Satoshi Nojima, Kazuya Yamashita, Takeshi Nakatani, Yoshitomo Hayama, Yasuhiro Kato, Yuhei Kinehara, Masayuki Nishide, Norihisa Mikami, Syohei Koyama, Hyota Takamatsu, Daisuke Okuzaki, Naganari Ohkura, Shimon Sakaguchi, Masato Okada, Atsushi Kumanogoh
Mechanistic target of rapamycin complex (mTORC)1 integrates intracellular sufficiency of nutrients and regulates various cellular functions. Previous studies using mice with conditional knockout of mTORC1 component proteins (i.e., mTOR, Raptor, and Rheb) gave conflicting results on the roles of mTORC1 in CD4(+) T cells. Lamtor1 is the protein that is required for amino acid sensing and activation of mTORC1; however, the roles of Lamtor1 in T cells have not been investigated. In this article, we show that Lamtor1-deficient CD4(+) T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes...
August 2, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28710231/tuberin-regulates-prostaglandin-receptor-mediated-viability-via-rheb-in-mtorc1-hyperactive-cells
#3
Chenggang Li, Xiaolei Liu, Yang Liu, Erik Zhang, Kantha Medepalli, Kohei Masuda, Na Li, Elizabeth J Kopras, David J Kwiatkowski, Michael T Borchers, Kathryn A Wikenheiser-Brokamp, Andrew Osterburg, Maxwell Mays, Yang Sun, David R Plas, Julia L Sun, David N Franz, Jamie K Capal, Anya Alayev, Marina K Holz, Darcy A Krueger, Brian J Siroky, Jane J Yu
Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2 resulting in hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulate that the action of excess PGE2 and its cognate receptors (EPs) contribute to cell survival...
July 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28694500/resistance-exercise-initiates-mechanistic-target-of-rapamycin-mtor-translocation-and-protein-complex-co-localisation-in-human-skeletal-muscle
#4
Zhe Song, Daniel R Moore, Nathan Hodson, Carl Ward, Jessica R Dent, Mary F O'Leary, Andrew M Shaw, D Lee Hamilton, Sovan Sarkar, Yann-Gaël Gangloff, Troy A Hornberger, Lawrence L Spriet, George J Heigenhauser, Andrew Philp
The mechanistic target of rapamycin (mTOR) is a central mediator of protein synthesis in skeletal muscle. We utilized immunofluorescence approaches to study mTOR cellular distribution and protein-protein co-localisation in human skeletal muscle in the basal state as well as immediately, 1 and 3 h after an acute bout of resistance exercise in a fed (FED; 20 g Protein/40 g carbohydrate/1 g fat) or energy-free control (CON) state. mTOR and the lysosomal protein LAMP2 were highly co-localised in basal samples...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28658616/purine-nucleotide-availability-regulates-mtorc1-activity-through-the-rheb-gtpase
#5
Natasha Emmanuel, Shoba Ragunathan, Qin Shan, Fang Wang, Andreas Giannakou, Nanni Huser, Guixian Jin, Jeremy Myers, Robert T Abraham, Keziban Unsal-Kacmaz
Pharmacologic agents that interfere with nucleotide metabolism constitute an important class of anticancer agents. Recent studies have demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. Here, we demonstrate that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools. Cellular treatment with AG2037, an inhibitor of the purine biosynthetic enzyme GARFT, profoundly inhibits mTORC1 activity via a reduction in the level of GTP-bound Rheb, an obligate upstream activator of mTORC1, because of a reduction in intracellular guanine nucleotides...
June 27, 2017: Cell Reports
https://www.readbyqxmd.com/read/28647319/in-vitro-stimulation-of-vitellogenin-expression-by-insulin-in-the-mud-crab-scylla-paramamosain-mediated-through-pi3k-akt-tor-pathway
#6
Xiaoshuai Huang, Biyun Feng, Huiyang Huang, Haihui Ye
Vitellogenin (vtg) synthesis, known as vitellogenesis, is one of most important processes in the ovarian development of oviparous animals. Recently, multiple insulin-like peptides (ILPs) have been reported in crustacean species due to the application of transcriptome sequencing. In this context, the present study reports that the addition of an exogenous ILP, bovine insulin, stimulates vtg (termed Sp-vtg) expression in hepatopancreatic explants from the mud crab, Scylla paramamosain, by in vitro experiments...
June 21, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28641977/a-novel-fluorescent-probe-reveals-starvation-controls-the-commitment-of-amyloid-precursor-protein-to-the-lysosome
#7
Leanne K Hein, Pirjo M Apaja, Kathryn Hattersley, Randall H Grose, Jianling Xie, Christopher G Proud, Timothy J Sargeant
Alzheimer's disease is the most important cause of dementia but there is no therapy that has been demonstrated to stop or slow disease progression. Amyloid precursor protein (APP) is the source of amyloid-β (Aβ), which aggregates in Alzheimer's disease to form toxic oligomeric species. The endo-lysosomal system can clear APP and Aβ from the cell if these molecular species are trafficked through to the lysosome. Currently, there are no easy methods available for the analysis of lysosomal APP trafficking. We therefore generated a fusion protein (tandem-fluorescent, or tf-APP) that allows detection of changes in APP trafficking using accessible techniques such as flow cytometry...
June 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28638431/erzhi-pill%C3%A2-repairs-experimental-liver-injury-via-tsc-mtor-signaling-pathway-inhibiting-excessive-apoptosis
#8
Bu-Gao Zhou, Hai-Mei Zhao, Xiu-Yun Lu, Xin Wang, Yong Zou, Rong Xu, Hai-Yang Yue, Yi Liu, Zheng-Yun Zuo, Duan-Yong Liu
The present study aimed to investigate the mechanism of hepatoprotective effect of Erzhi Pill (EZP) on the liver injury via observing TSC/mTOR signaling pathway activation. The experimental liver injury was induced by 2-acetylaminofluorene (2-AAF) treatment combined with partial hepatectomy (PH). EZP treated 2-AAF/PH-induced liver injury by the therapeutic and prophylactic administration. After the administration of EZP, the activities of aspartic transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP), and gamma-glutamyl transpeptidase (γ-GT) were decreased, followed by the decreased levels of hepatocyte apoptosis and caspase-3 expression...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28625796/the-characterization-of-rheb-gene-and-its-responses-to-hypoxia-and-thermal-stresses-in-the-small-abalone-haliotis-diversicolor
#9
Lianghua He, Xin Zhang, Ying Huang, Huiping Yang, Yilei Wang, Ziping Zhang
RHEB (Ras Homolog Enriched in Brain) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mechanistic target of rapamycin (mTOR) pathway, and regulates the cell cycle progression and growth. The goal of this study was to characterize the RHEB gene in the small abalone Haliotis diversicolor, and identify the responses of RHEB gene to stresses of hypoxia or/and thermal. The objectives were to: 1) clone the full-length cDNA RHEB gene in the H...
August 2017: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
https://www.readbyqxmd.com/read/28612328/antidepressant-actions-of-ketamine-mediated-by-the-mechanistic-target-of-rapamycin-nitric-oxide-and-rheb
#10
REVIEW
Maged M Harraz, Solomon H Snyder
The weeks/months it takes for traditional antidepressants to act pose an obstacle in the management of depression. Ketamine's prompt and sustained antidepressant effects constitute a major advance. Multiple studies implicate glutamatergic signaling to protein synthesis machinery and synapse formation in ketamine's antidepressant effects. Here we review evidence linking ketamine to glutamate receptor subtypes and protein homeostasis. We describe a signaling cascade wherein nitric oxide drives the formation of a ternary protein complex comprised of glyceraldehyde 3-phosphate dehydrogenase, seven in absentia homolog 1, and Ras homolog enriched in brain downstream of the glutamate N-methyl-D-aspartate receptor...
July 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/28610953/a-thirty-year-quest-for-a-role-of-r-ras-in-cancer-from-an-oncogene-to-a-multitasking-gtpase
#11
Wai Nam Liu, Mingfei Yan, Andrew M Chan
Since the identification of R-Ras, which is the first Ras-related GTPase isolated based on sequence similarity to the classical RAS oncogene, more than 160 members of the Ras superfamily of GTPases have been identified and classified into the Ras, Rho, Rap, Rab, Ran, Arf, Rheb, RGK, Rad, Rit, and Miro subfamilies. R-Ras belongs to the Ras subfamily of small G-proteins, which are frequently implicated in cell growth and differentiation. Although the roles of R-Ras in cellular transformation and integrin-mediated cell adhesion have been extensively studied, the physiological function of this enigmatic G-protein was only revealed when a mouse strain deficient in R-Ras was generated...
June 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28550454/oncogenic-roles-of-the-pi3k-akt-mtor-axis
#12
Masahiro Aoki, Teruaki Fujishita
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP...
May 28, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28488575/proteomics-analysis-of-bladder-cancer-invasion-targeting-eif3d-for-therapeutic-intervention
#13
Agnieszka Latosinska, Marika Mokou, Manousos Makridakis, William Mullen, Jerome Zoidakis, Vasiliki Lygirou, Maria Frantzi, Ioannis Katafigiotis, Konstantinos Stravodimos, Marie C Hupe, Maciej Dobrzynski, Walter Kolch, Axel S Merseburger, Harald Mischak, Maria G Roubelakis, Antonia Vlahou
Patients with advanced bladder cancer have poor outcomes, indicating a need for more efficient therapeutic approaches. This study characterizes proteomic changes underlying bladder cancer invasion aiming for the better understanding of disease pathophysiology and identification of drug targets. High resolution liquid chromatography coupled to tandem mass spectrometry analysis of tissue specimens from patients with non-muscle invasive (NMIBC, stage pTa) and muscle invasive bladder cancer (MIBC, stages pT2+) was conducted...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28475806/rapamycin-reduced-pulmonary-vascular-remodelling-by-inhibiting-cell-proliferation-via-akt-mtor-signalling-pathway-down-regulation-in-the-carotid-artery-jugular-vein-shunt-pulmonary-hypertension-rat-model
#14
Xiaofan Ma, Jianping Yao, Yuan Yue, Shangming Du, Han Qin, Jian Hou, Zhongkai Wu
OBJECTIVES: Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease. However, effective treatments for PAH are rare. This study aimed to investigate the inhibitory effects of rapamycin on PAH in the carotid artery-jugular vein (CA-JV) shunt PAH rat model as well as the mechanism underlying these effects. METHODS: Twenty-four Sprague-Dawley rats were randomized into the following 3 groups: a control group, a CA-JV shunt group and a treatment group...
May 4, 2017: Interactive Cardiovascular and Thoracic Surgery
https://www.readbyqxmd.com/read/28475102/the-small-gtpases-ras-and-rheb-studied-by-multidimensional-nmr-spectroscopy-structure-and-function
#15
REVIEW
Miriam Schöpel, Veena Nambiar Potheraveedu, Thuraya Al-Harthy, Raid Abdel-Jalil, Rolf Heumann, Raphael Stoll
Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDP-loaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human cancers...
May 1, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28475097/the-small-gtpases-ras-and-rheb-studied-by-multidimensional-nmr-spectroscopy-structure-and-function
#16
Miriam Schöpel, Veena Nambiar Potheraveedu, Thuraya Al-Harthy, Raid Abdel-Jalil, Rolf Heumann, Raphael Stoll
Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDPloaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one third of human cancers...
February 11, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28457749/an-fak-yap-mtor-signaling-axis-regulates-stem-cell-based-tissue-renewal-in-mice
#17
Jimmy Kuang-Hsien Hu, Wei Du, Samuel J Shelton, Michael C Oldham, C Michael DiPersio, Ophir D Klein
Tissue homeostasis requires the production of newly differentiated cells from resident adult stem cells. Central to this process is the expansion of undifferentiated intermediates known as transit-amplifying (TA) cells, but how stem cells are triggered to enter this proliferative TA state remains an important open question. Using the continuously growing mouse incisor as a model of stem cell-based tissue renewal, we found that the transcriptional cofactors YAP and TAZ are required both to maintain TA cell proliferation and to inhibit differentiation...
July 6, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28441755/role-of-rheb-in-regulating-differentiation-fate-of-mesenchymal-stem-cells-for-cartilage-and-bone-regeneration
#18
Sajjad Ashraf, In-Bo Han, Hansoo Park, Soo-Hong Lee
Advances in mesenchymal stem cells (MSCs) and cell replacement therapies are promising approaches to treat cartilage and bone defects since substantial differentiation capacities of MSCs match the demands of tissue regeneration. Our understanding of the dynamic process requiring indispensable differentiation of MSCs remains limited. Herein, we describe the role of RHEB (Ras homolog enriched in brain) regulating gene signature for differentiation of human adipose derived mesenchymal stem cells (ASCs) into chondrogenic, osteogenic, and adipogenic lineages...
April 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28424242/mtorc1-promotes-t-bet-phosphorylation-to-regulate-th1-differentiation
#19
Olesya Chornoguz, Robert S Hagan, Azeb Haile, Matthew L Arwood, Christopher J Gamper, Arnob Banerjee, Jonathan D Powell
CD4(+) T cells lacking the mTORC1 activator Rheb fail to secrete IFN-γ under Th1 polarizing conditions. We hypothesized that this phenotype is due to defects in regulation of the canonical Th1 transcription factor T-bet at the level of protein phosphorylation downstream of mTORC1. To test this hypothesis, we employed targeted mass-spectrometry proteomic analysis-multiple reaction monitoring mass spectrometry. We used this method to detect and quantify predicted phosphopeptides derived from T-bet. By analyzing activated murine wild-type and Rheb-deficient CD4(+) T cells, as well as murine CD4(+) T cells activated in the presence of rapamycin, a pharmacologic inhibitor of mTORC1, we were able to identify six T-bet phosphorylation sites...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28319048/amino-acid-insensitive-mtorc1-regulation-enables-nutritional-stress-resilience-in-hematopoietic-stem-cells
#20
Demetrios Kalaitzidis, Dongjun Lee, Alejo Efeyan, Youmna Kfoury, Naema Nayyar, David B Sykes, Francois E Mercier, Ani Papazian, Ninib Baryawno, Gabriel D Victora, Donna Neuberg, David M Sabatini, David T Scadden
The mTOR pathway is a critical determinant of cell persistence and growth wherein mTOR complex 1 (mTORC1) mediates a balance between growth factor stimuli and nutrient availability. Amino acids or glucose facilitates mTORC1 activation by inducing RagA GTPase recruitment of mTORC1 to the lysosomal outer surface, enabling activation of mTOR by the Ras homolog Rheb. Thereby, RagA alters mTORC1-driven growth in times of nutrient abundance or scarcity. Here, we have evaluated differential nutrient-sensing dependence through RagA and mTORC1 in hematopoietic progenitors, which dynamically drive mature cell production, and hematopoietic stem cells (HSC), which provide a quiescent cellular reserve...
April 3, 2017: Journal of Clinical Investigation
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