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https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#1
Jeffrey J Heard, Ivy Phung, Mark I Potes, Fuyuhiko Tamanoi
BACKGROUND: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29305496/determination-of-mtorc1-complex-structures-reveals-regulatory-mechanisms
#2
(no author information available yet)
RHEB promotes allosteric activation of mTOR whereas PRAS40 blocks substrate recruitment sites.
January 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29287199/trillium-tschonoskii-maxim-saponin-mitigates-d-galactose-induced-brain-aging-of-rats-through-rescuing-dysfunctional-autophagy-mediated-by-rheb-mtor-signal-pathway
#3
Lingjie Wang, Junlong Du, Fangyu Zhao, Zonghai Chen, Jingru Chang, Furong Qin, Zili Wang, Fengjie Wang, Xianbing Chen, Ning Chen
During the expansion of aging population, the study correlated with brain aging is one of the important research topics. Developing novel and effective strategies for delaying brain aging is highly desired. Brain aging is characteristics of impaired cognitive capacity due to dysfunctional autophagy regulated by Rheb-mTOR signal pathway in hippocampal tissues. In the present study, we have established a rat model with brain aging through subcutaneous injection of D-galactose (D-gal). Upon the intervention of Trillium tschonoskii Maxim (TTM) saponin, one of bioactive components from local natural herbs in China, the learning and memory capacity of D-gal-induced aging rats was evaluated through Morris water maze test, and the regulation of Rheb-mTOR signal pathway and functional status of autophagy in hippocampal tissues of D-gal-induced aging rats was explored by Western blot...
December 26, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29236692/mechanisms-of-mtorc1-activation-by-rheb-and-inhibition-by-pras40
#4
Haijuan Yang, Xiaolu Jiang, Buren Li, Hyo J Yang, Meredith Miller, Angela Yang, Ankita Dhar, Nikola P Pavletich
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1...
December 13, 2017: Nature
https://www.readbyqxmd.com/read/29222112/rheb-localized-on-the-golgi-membrane-activates-lysosome-localized-mtorc1-at-the-golgi-lysosome-contact-site
#5
Feike Hao, Kazuhiko Kondo, Takashi Itoh, Sumiko Ikari, Shigeyuki Nada, Masato Okada, Takeshi Noda
In response to amino acid supply, mTORC1, a master regulator of cell growth, is recruited to the lysosome and activated by a small GTPase, Rheb. However, the intracellular localization of Rheb is controversial. In this study, we showed that a significant portion of Rheb was localized on the Golgi but not on the lysosome. GFP-Rheb could activate mTORC1, even when forced to exclusively localize to the Golgi. Likewise, artificial recruitment of mTORC1 to the Golgi allowed its activation. Accordingly, the Golgi was in contact with the lysosome at the newly described Golgi lysosome contact site (GLCS)...
December 8, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29184052/notch-transactivates-rheb-to-maintain-the-multipotency-of-tsc-null-cells
#6
Jun-Hung Cho, Bhaumik Patel, Santosh Bonala, Sasikanth Manne, Yan Zhou, Surya K Vadrevu, Jalpa Patel, Marco Peronaci, Shanawaz Ghouse, Elizabeth P Henske, Fabrice Roegiers, Krinio Giannikou, David J Kwiatkowski, Hossein Mansouri, Maciej M Markiewski, Brandon White, Magdalena Karbowniczek
Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event...
November 29, 2017: Nature Communications
https://www.readbyqxmd.com/read/29180513/glucose-deprivation-induces-primary-cilium-formation-through-mtorc1-inactivation
#7
Kengo Takahashi, Tomoaki Nagai, Shuhei Chiba, Keiko Nakayama, Kensaku Mizuno
Primary cilia are antenna-like sensory organelles extending from the surface of many cell types and play critical roles in tissue development and homeostasis. Here, we examined the effect of nutrient status on primary cilium formation. Glucose deprivation significantly increased the number of ciliated cells under both serum-fed and -starved conditions. Glucose deprivation-induced ciliogenesis was suppressed by overexpression of Rheb, an activator of mammalian target of rapamycin complex-1 (mTORC1). Inactivation of mTORC1 by rapamycin treatment or Raptor knockdown significantly promoted ciliogenesis...
November 27, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29175333/distinct-roles-of-rheb-and-raptor-in-activating-mtor-complex-1-for-the-self-renewal-of-hematopoietic-stem-cells
#8
Hui Peng, Atsuo Kasada, Masaya Ueno, Takayuki Hoshii, Yuko Tadokoro, Naho Nomura, Chiaki Ito, Yusuke Takase, Ha Thi Vu, Masahiko Kobayashi, Bo Xiao, Paul F Worley, Atsushi Hirao
The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) senses a cell's energy status and environmental levels of nutrients and growth factors. In response, mTORC1 mediates signaling that controls protein translation and cellular metabolism. Although mTORC1 plays a critical role in hematopoiesis, it remains unclear which upstream stimuli regulate mTORC1 activity in the context of hematopoietic stem cells (HSC) maintenance in vivo. In this study, we investigated the function of Rheb, a critical regulator of mTORC1 activity controlled by the PI3K-AKT-TSC axis, both in HSC maintenance in mice at steady-state and in HSC-derived hematopoiesis post-transplantation...
November 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29150487/dynamin-inhibitors-block-mtorc1-activation-by-amino-acids-independently-of-dynamin
#9
Persaud Avinash, Cormerais Yann, Pouyssegur Jacques, Rotin Daniela
mTORC1 plays a critical role in protein synthesis and cell proliferation and growth. It is activated by growth factors and amino acids, including essential amino acid (EAA), such as Leu; Leu enters cells via the Leu transporter LAT1-4F2hc and potentially via endocytosis. 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 dynamin1/2/3. Our results show that LAT1 is the major route of Leu entry into cells and mTORC1 activation (∼70%), while dynamin-dependent endocytosis and macropinocytosis contribute minimally to both (5-15%)...
November 17, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29133930/plc%C3%AE-dependent-mtor-signalling-controls-il-7-mediated-early-b-cell-development
#10
Mei Yu, Yuhong Chen, Hu Zeng, Yongwei Zheng, Guoping Fu, Wen Zhu, Ulrich Broeckel, Praful Aggarwal, Amy Turner, Geoffrey Neale, Cliff Guy, Nan Zhu, Hongbo Chi, Renren Wen, Demin Wang
The precise molecular mechanism underlying the regulation of early B cell lymphopoiesis is unclear. The PLCγ signaling pathway is critical for antigen receptor-mediated lymphocyte activation, but its function in cytokine signaling is unknown. Here we show that PLCγ1/PLCγ2 double deficiency in mice blocks early B cell development at the pre-pro-B cell stage and renders B cell progenitors unresponsive to IL-7. PLCγ pathway inhibition blocks IL-7-induced activation of mTOR, but not Stat5. The PLCγ pathway activates mTOR through the DAG/PKC signaling branch, independent of the conventional Akt/TSC/Rheb signaling axis...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29119228/macropinocytosis-mtorc1-and-cellular-growth-control
#11
REVIEW
Sei Yoshida, Regina Pacitto, Ken Inoki, Joel Swanson
The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras...
November 8, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29104218/evolutionary-conservation-of-the-components-in-the-tor-signaling-pathways
#12
REVIEW
Hisashi Tatebe, Kazuhiro Shiozaki
Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that controls multiple cellular processes upon various intracellular and extracellular stimuli. Since its first discovery, extensive studies have been conducted both in yeast and animal species including humans. Those studies have revealed that TOR forms two structurally and physiologically distinct protein complexes; TOR complex 1 (TORC1) is ubiquitous among eukaryotes including animals, yeast, protozoa, and plants, while TOR complex 2 (TORC2) is conserved in diverse eukaryotic species other than plants...
November 1, 2017: Biomolecules
https://www.readbyqxmd.com/read/29091770/the-mtorc1-signaling-network-senses-changes-in-cellular-purine-nucleotide-levels
#13
Gerta Hoxhaj, James Hughes-Hallett, Rebecca C Timson, Erika Ilagan, Min Yuan, John M Asara, Issam Ben-Sahra, Brendan D Manning
Mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) integrates signals from growth factors and nutrients to control biosynthetic processes, including protein, lipid, and nucleic acid synthesis. We find that the mTORC1 pathway is responsive to changes in purine nucleotides in a manner analogous to its sensing of amino acids. Depletion of cellular purines, but not pyrimidines, inhibits mTORC1, and restoration of intracellular adenine nucleotides via addition of exogenous purine nucleobases or nucleosides acutely reactivates mTORC1...
October 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/29051493/variation-in-a-range-of-mtor-related-genes-associates-with-intracranial-volume-and-intellectual-disability
#14
M R F Reijnders, M Kousi, G M van Woerden, M Klein, J Bralten, G M S Mancini, T van Essen, M Proietti-Onori, E E J Smeets, M van Gastel, A P A Stegmann, S J C Stevens, S H Lelieveld, C Gilissen, R Pfundt, P L Tan, T Kleefstra, B Franke, Y Elgersma, N Katsanis, H G Brunner
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29050215/proteomics-analysis-of-bladder-cancer-invasion-targeting-eif3d-for-therapeutic-intervention
#15
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...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29017169/ox-ldl-induced-microrna-155-promotes-autophagy-in-human-endothelial-cells-via-repressing-the-rheb-mtor-pathway
#16
Jinlin Lv, Lixia Yang, Ruiwei Guo, Yankun Shi, Ziwei Zhang, Jinshan Ye
BACKGROUND/AIMS: Autophagy, an evolutionary conserved biological process, is activated in cells to cope with various types of stress. MicroRNAs control several activities related to autophagy. However, the role of autophagy-related microRNAs during atherosclerosis is far from known. MicroRNA-155 was identified to be a crucial regulator of atherosclerosis. The objectives of the study were to analyze the effect of microRNA-155 on autophagic signaling and explore its mechanism in human endothelial cells under ox-LDL stress...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28967557/combining-constitutively-active-rheb-expression-and-chondroitinase-promotes-functional-axonal-regeneration-after-cervical-spinal-cord-injury
#17
Di Wu, Michelle C Klaw, Theresa Connors, Nikolai Kholodilov, Robert E Burke, Marie-Pascale Côté, Veronica J Tom
After spinal cord injury (SCI), severed axons in the adult mammalian CNS are unable to mount a robust regenerative response. In addition, the glial scar at the lesion site further restricts the regenerative potential of axons. We hypothesized that a combinatorial approach coincidentally targeting these obstacles would promote axonal regeneration. We combined (1) transplantation of a growth-permissive peripheral nerve graft (PNG) into an incomplete, cervical lesion cavity; (2) transduction of neurons rostral to the SCI site to express constitutively active Rheb (caRheb; a Ras homolog enriched in brain), a GTPase that directly activates the growth-promoting pathway mammalian target of rapamycin (mTOR) via AAV-caRheb injection; and (3) digestion of growth-inhibitory chondroitin sulfate proteoglycans within the glial scar at the distal PNG interface using the bacterial enzyme chondroitinase ABC (ChABC)...
August 19, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28945203/mtorc1-loss-impairs-epidermal-adhesion-via-tgf-%C3%AE-rho-kinase-activation
#18
Kaushal Asrani, Akshay Sood, Alba Torres, Dan Georgess, Pornima Phatak, Harsimar Kaur, Amber Dubin, C Conover Talbot, Loubna Elhelu, Andrew J Ewald, Bo Xiao, Paul Worley, Tamara L Lotan
Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation...
September 25, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28808055/dynamin-dependent-amino-acid-endocytosis-activates-mechanistic-target-of-rapamycin-complex-1-mtorc1
#19
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)...
November 3, 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
#20
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...
September 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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