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203. Proteomic Landscape of Aldosterone-Producing Adenoma

Author

Swierczynska, Marta M., primary, Betz, Matthias J., additional, Colombi, Marco, additional, Dazert, Eva, additional, Jenö, Paul, additional, Moes, Suzette, additional, Pfaff, Cécile, additional, Glatz, Katharina, additional, Reincke, Martin, additional, Beuschlein, Felix, additional, Donath, Marc Y., additional, and Hall, Michael N., additional

Published
2019
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206. Abstract 702: IMLEC: A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1

Author

Tang, Fei, primary, Zhang, Peng, additional, Ye, Peiying, additional, Lazarski, Christopher A., additional, Wu, Qi, additional, Bergin, Ingrid L., additional, Bender, Timothy P., additional, Hall, Michael N., additional, Cui, Ya, additional, Zhang, Liguo, additional, Jiang, Taijiao, additional, Liu, Yang, additional, and Zheng, Pan, additional

Published
2018
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207. CLIP and cohibin separate rDNA from nucleolar proteins destined for degradation by nucleophagy

Author

Mostofa, Md. Golam, primary, Rahman, Muhammad Arifur, additional, Koike, Naoki, additional, Yeasmin, Akter MST, additional, Islam, Nafisa, additional, Waliullah, Talukdar Muhammad, additional, Hosoyamada, Shun, additional, Shimobayashi, Mitsugu, additional, Kobayashi, Takehiko, additional, Hall, Michael N., additional, and Ushimaru, Takashi, additional

Published
2018
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210. NGS-pipe: a flexible, easily extendable, and highly configurable framework for NGS analysis

Author

Singer, Jochen, Ruscheweyh, Hans-Joachim, Hofmann, Ariane L, Thurnherr, Thomas, Singer, Franziska, Toussaint, Nora C, Ng, Charlotte K Y, Piscuoglio, Salvatore, Beisel, Christian, Christofori, Gerhard, Dummer, Reinhard, Hall, Michael N, Krek, Wilhelm, Levesque, Mitchell P; https://orcid.org/0000-0001-5902-9420, Manz, Markus G, Moch, Holger, Papassotiropoulos, Andreas, Stekhoven, Daniel J, Wild, Peter, Wüst, Thomas, Rinn, Bernd, Beerenwinkel, Niko, Singer, Jochen, Ruscheweyh, Hans-Joachim, Hofmann, Ariane L, Thurnherr, Thomas, Singer, Franziska, Toussaint, Nora C, Ng, Charlotte K Y, Piscuoglio, Salvatore, Beisel, Christian, Christofori, Gerhard, Dummer, Reinhard, Hall, Michael N, Krek, Wilhelm, Levesque, Mitchell P; https://orcid.org/0000-0001-5902-9420, Manz, Markus G, Moch, Holger, Papassotiropoulos, Andreas, Stekhoven, Daniel J, Wild, Peter, Wüst, Thomas, Rinn, Bernd, and Beerenwinkel, Niko

Abstract

Motivation: Next-generation sequencing is now an established method in genomics, and massive amounts of sequencing data are being generated on a regular basis. Analysis of the sequencing data is typically performed by lab-specific in-house solutions, but the agreement of results from different facilities is often small. General standards for quality control, reproducibility, and documentation are missing. Results: We developed NGS-pipe, a flexible, transparent, and easy-to-use framework for the design of pipelines to analyze whole-exome, whole-genome, and transcriptome sequencing data. NGS-pipe facilitates the harmonization of genomic data analysis by supporting quality control, documentation, reproducibility, parallelization, and easy adaptation to other NGS experiments.

Published
2018

211. Indirect monitoring of TORC1 signalling pathway reveals molecular diversity among different yeast strains

Author

Consejo Superior de Investigaciones Científicas (España), Kessi-Pérez, Eduardo I., Salinas, Francisco, Molinet, Jennifer, González, Asier, Muñiz Calvo, Sara, Guillamón, José Manuel, Hall, Michael N., Larrondo, Luis F., Martínez, Claudio, Consejo Superior de Investigaciones Científicas (España), Kessi-Pérez, Eduardo I., Salinas, Francisco, Molinet, Jennifer, González, Asier, Muñiz Calvo, Sara, Guillamón, José Manuel, Hall, Michael N., Larrondo, Luis F., and Martínez, Claudio

Abstract

Saccharomyces cerevisiae is the main species responsible for the alcoholic fermentation in wine production. One of the main problems in this process is the deficiency of nitrogen sources in the grape must, which can lead to stuck or sluggish fermentations. Currently, yeast nitrogen consumption and metabolism are under active inquiry, with emphasis on the study of the TORC1 signalling pathway, given its central role responding to nitrogen availability and influencing growth and cell metabolism. However, the mechanism by which different nitrogen sources activates TORC1 is not completely understood. Existing methods to evaluate TORC1 activation by nitrogen sources are time‐consuming, making difficult the analyses of large numbers of strains. In this work, a new indirect method for monitoring TORC1 pathway was developed on the basis of the luciferase reporter gene controlled by the promoter region of RPL26A gene, a gene known to be expressed upon TORC1 activation. The method was tested in strains representative of the clean lineages described so far in S. cerevisiae. The activation of the TORC1 pathway by a proline‐to‐glutamine upshift was indirectly evaluated using our system and the traditional direct methods based on immunoblot (Sch9 and Rps6 phosphorylation). Regardless of the different molecular readouts obtained with both methodologies, the general results showed a wide phenotypic variation between the representative strains analysed. Altogether, this easy‐to‐use assay opens the possibility to study the molecular basis for the differential TORC1 pathway activation, allowing to interrogate a larger number of strains in the context of nitrogen metabolism phenotypic differences.

Published
2018

212. Basal m diurnal variation in mouse perivascular adipose tissue TORC2 activity and expression of its components display

Author

Drägert, Katja, Bhattacharya, Indranil, Hall, Michael N, Humar, Rok, Battegay, Edouard, Haas, Elvira, University of Zurich, and Haas, Elvira

Subjects
1307 Cell Biology, 11178 Center of Competence Multimorbidity, 1303 Biochemistry, 10076 Center for Integrative Human Physiology, 1312 Molecular Biology, Biophysics, 610 Medicine & health, UFSP13-4 Dynamics of Healthy Aging, Cell Biology, 10029 Clinic and Policlinic for Internal Medicine, Biochemistry, Molecular Biology, 1304 Biophysics
Published
2016

215. Architecture of the human mTORC2 core complex

Author

Stuttfeld, Edward, primary, Aylett, Christopher HS, additional, Imseng, Stefan, additional, Boehringer, Daniel, additional, Scaiola, Alain, additional, Sauer, Evelyn, additional, Hall, Michael N, additional, Maier, Timm, additional, and Ban, Nenad, additional

Published
2018
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219. A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice

Author

Tang, Fei, primary, Zhang, Peng, additional, Ye, Peiying, additional, Lazarski, Christopher A, additional, Wu, Qi, additional, Bergin, Ingrid L, additional, Bender, Timothy P, additional, Hall, Michael N, additional, Cui, Ya, additional, Zhang, Liguo, additional, Jiang, Taijiao, additional, Liu, Yang, additional, and Zheng, Pan, additional

Published
2017
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220. Author response: A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice

Author

Tang, Fei, primary, Zhang, Peng, additional, Ye, Peiying, additional, Lazarski, Christopher A, additional, Wu, Qi, additional, Bergin, Ingrid L, additional, Bender, Timothy P, additional, Hall, Michael N, additional, Cui, Ya, additional, Zhang, Liguo, additional, Jiang, Taijiao, additional, Liu, Yang, additional, and Zheng, Pan, additional

Published
2017
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221. NGS-pipe: a flexible, easily extendable and highly configurable framework for NGS analysis

Author

Singer, Jochen, primary, Ruscheweyh, Hans-Joachim, additional, Hofmann, Ariane L, additional, Thurnherr, Thomas, additional, Singer, Franziska, additional, Toussaint, Nora C, additional, Ng, Charlotte K Y, additional, Piscuoglio, Salvatore, additional, Beisel, Christian, additional, Christofori, Gerhard, additional, Dummer, Reinhard, additional, Hall, Michael N, additional, Krek, Wilhelm, additional, Levesque, Mitchell P, additional, Manz, Markus G, additional, Moch, Holger, additional, Papassotiropoulos, Andreas, additional, Stekhoven, Daniel J, additional, Wild, Peter, additional, Wüst, Thomas, additional, Rinn, Bernd, additional, and Beerenwinkel, Niko, additional

Published
2017
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222. Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Author

Blandino-Rosano, Manuel, primary, Barbaresso, Rebecca, additional, Jimenez-Palomares, Margarita, additional, Bozadjieva, Nadejda, additional, Werneck-de-Castro, Joao Pedro, additional, Hatanaka, Masayuki, additional, Mirmira, Raghavendra G., additional, Sonenberg, Nahum, additional, Liu, Ming, additional, Rüegg, Markus A., additional, Hall, Michael N., additional, and Bernal-Mizrachi, Ernesto, additional

Published
2017
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223. mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation

Author

Fitter, Stephen, primary, Matthews, Mary P., additional, Martin, Sally K., additional, Xie, Jianling, additional, Ooi, Soo Siang, additional, Walkley, Carl R., additional, Codrington, John D., additional, Ruegg, Markus A., additional, Hall, Michael N., additional, Proud, Christopher G., additional, Gronthos, Stan, additional, and Zannettino, Andrew C. W., additional

Published
2017
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224. Deletion of rictor in brain and fat alters peripheral clock gene expression and increases blood pressure

Author

Drägert, Katja, Bhattacharya, Indranil, Pellegrini, Giovanni, Seebeck, Petra, Azzi, Abdelhalim, Brown, Steven A, Georgiopoulou, Stavroula, Held, Ulrike, Blyszczuk, Przemyslaw, Arras, Margarete, Humar, Rok, Hall, Michael N, Battegay, Edouard, Haas, Elvira, University of Zurich, and Haas, Elvira

Subjects
11178 Center of Competence Multimorbidity, 2724 Internal Medicine, 10076 Center for Integrative Human Physiology, 10050 Institute of Pharmacology and Toxicology, 10184 Institute of Veterinary Pathology, 610 Medicine & health, UFSP13-4 Dynamics of Healthy Aging, 10029 Clinic and Policlinic for Internal Medicine
Published
2015
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227. Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae

Author

Crespo, Jose L. and Hall, Michael N.

Subjects
Microbiology -- Research, Molecular biology -- Research, Rapamycin -- Physiological aspects, Brewer's yeast -- Genetic aspects, Brewer's yeast -- Physiological aspects, Biological sciences
Abstract

The authors review the publications on target of rapamycin signaling and rapamycin action. The topics of interest include target of rapamycin inlower and higher eukaryotes and target of rapamycin in yeasts and higher eukaryotes.

Published
2002

228. Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors

Author

Carr, Theresa D., Feehan, Robert P., Hall, Michael N., Rüegg, Markus A., Shantz, Lisa M., Carr, Theresa D., Feehan, Robert P., Hall, Michael N., Rüegg, Markus A., and Shantz, Lisa M.

Abstract

These studies show for the first time that mTORC2 is essential for skin tumor development and maintenance of established tumors, but is dispensable for normal keratinocyte proliferation. They further suggest that mTORC2 controls pro-survival pathways in vitro and in tumors

Published
2017

229. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD)

Author

Wahl, Patricia R., Serra, Andreas L., Le Hir, Michel, Molle, Klaus D., Hall, Michael N., Wüthrich, Rudolf P., Wahl, Patricia R., Serra, Andreas L., Le Hir, Michel, Molle, Klaus D., Hall, Michael N., and Wüthrich, Rudolf P.

Abstract

Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the formation of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the effect of the mTOR inhibitor sirolimus (rapamycin) on renal functional loss and cyst progression in the Han:SPRD rat model of ADPKD. Methods. Five-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) rats were administered sirolimus (2 mg/kg/day) orally through the drinking water for 3 months. The renal function was monitored throughout the treatment phase, and rats were sacrificed thereafter. Kidneys were analysed histomorphometrically, and for the expression and phosphorylation of S6K, a well-characterized target of mTOR in the regulation of cell growth. Results. The steady increase in BUN and creatinine in Cy/+ rats was reduced by 39 and 34%, respectively with sirolimus after 3 months treatment. Kidney weight and 2-kidney/total body weight (2K/TBW) ratios were reduced by 34 and 26% in sirolimus-treated Cy/+ rats. Cyst volume density was also reduced by 18%. Of importance, Cy/+ rats displayed enhanced levels of total and phosphorylated S6K. Sirolimus effectively reduced total and phosphorylated levels of S6K. Conclusion. We conclude that oral sirolimus markedly delays the loss of renal function and retards cyst development in Han:SPRD rats with ADPKD. Our data also suggest that activation of the S6K signalling pathway plays an important role in the pathogenesis of PKD. Sirolimus could be a useful drug to retard progressive renal failure in patients with ADPKD

Published
2017

230. mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation

Author

Ding, Xiaolei, Bloch, Wilhelm, Iden, Sandra, Ruegg, Markus A., Hall, Michael N., Leptin, Maria, Partridge, Linda, Eming, Sabine A., Ding, Xiaolei, Bloch, Wilhelm, Iden, Sandra, Ruegg, Markus A., Hall, Michael N., Leptin, Maria, Partridge, Linda, and Eming, Sabine A.

Abstract

Mammalian target of rapamycin (mTOR), a regulator of growth in many tissues, mediates its activity through two multiprotein complexes, mTORC1 or mTORC2. The role of mTOR signalling in skin morphogenesis and epidermal development is unknown. Here we identify mTOR as an essential regulator in skin morphogenesis by epidermis-specific deletion of Mtor in mice (mTOR(EKO)). mTOR(EKO) mutants are viable, but die shortly after birth due to deficits primarily during the early epidermal differentiation programme and lack of a protective barrier development. Epidermis-specific loss of Raptor, which encodes an essential component of mTORC1, confers the same skin phenotype as seen in mTOR(EKO) mutants. In contrast, newborns with an epidermal deficiency of Rictor, an essential component of mTORC2, survive despite a hypoplastic epidermis and disruption in late stage terminal differentiation. These findings highlight a fundamental role for mTOR in epidermal morphogenesis that is regulated by distinct functions for mTORC1 and mTORC2.

Published
2016

231. Syrosingopine sensitizes cancer cells to killing by metformin

Author

Benjamin, Don, primary, Colombi, Marco, additional, Hindupur, Sravanth K., additional, Betz, Charles, additional, Lane, Heidi A., additional, El-Shemerly, Mahmoud Y. M., additional, Lu, Min, additional, Quagliata, Luca, additional, Terracciano, Luigi, additional, Moes, Suzette, additional, Sharpe, Timothy, additional, Wodnar-Filipowicz, Aleksandra, additional, Moroni, Christoph, additional, and Hall, Michael N., additional

Published
2016
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232. mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer

Author

Driscoll, David R., primary, Karim, Saadia A, additional, Sano, Makoto, additional, Gay, David M., additional, Jacob, Wright, additional, Yu, Jun, additional, Mizukami, Yusuke, additional, Gopinathan, Aarthi, additional, Jodrell, Duncan I., additional, Evans, T.R. Jeffry, additional, Bardeesy, Nabeel, additional, Hall, Michael N., additional, Quattrochi, Brian J., additional, Klimstra, David S., additional, Barry, Simon T., additional, Sansom, Owen J., additional, Lewis, Brian C., additional, and Morton, Jennifer P., additional

Published
2016
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237. Indirect monitoring of TORC1 signalling pathway reveals molecular diversity among different yeast strains.

Author

Kessi‐Pérez, Eduardo I., Salinas, Francisco, Molinet, Jennifer, González, Asier, Muñiz, Sara, Guillamón, José M., Hall, Michael N., Larrondo, Luis F., and Martínez, Claudio

Abstract

Saccharomyces cerevisiae is the main species responsible for the alcoholic fermentation in wine production. One of the main problems in this process is the deficiency of nitrogen sources in the grape must, which can lead to stuck or sluggish fermentations. Currently, yeast nitrogen consumption and metabolism are under active inquiry, with emphasis on the study of the TORC1 signalling pathway, given its central role responding to nitrogen availability and influencing growth and cell metabolism. However, the mechanism by which different nitrogen sources activates TORC1 is not completely understood. Existing methods to evaluate TORC1 activation by nitrogen sources are time‐consuming, making difficult the analyses of large numbers of strains. In this work, a new indirect method for monitoring TORC1 pathway was developed on the basis of the luciferase reporter gene controlled by the promoter region of RPL26A gene, a gene known to be expressed upon TORC1 activation. The method was tested in strains representative of the clean lineages described so far in S. cerevisiae. The activation of the TORC1 pathway by a proline‐to‐glutamine upshift was indirectly evaluated using our system and the traditional direct methods based on immunoblot (Sch9 and Rps6 phosphorylation). Regardless of the different molecular readouts obtained with both methodologies, the general results showed a wide phenotypic variation between the representative strains analysed. Altogether, this easy‐to‐use assay opens the possibility to study the molecular basis for the differential TORC1 pathway activation, allowing to interrogate a larger number of strains in the context of nitrogen metabolism phenotypic differences. [ABSTRACT FROM AUTHOR]

Published
2019
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238. Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells (vol 154, pg 859, 2013)

Author

Thedieck, Kathrin, Holzwarth, Birgit, Prentzell, Mirja Tamara, Boehlke, Christopher, Klaesener, Kathrin, Ruf, Stefanie, Sonntag, Annika Gwendolin, Maerz, Lars, Grellscheid, Sushma-Nagaraja, Kremmer, Elisabeth, Nitschke, Roland, Kuehn, E. Wolfgang, Jonker, Johan W., Groen, Albert K., Reth, Michael, Hall, Michael N., Baumeister, Ralf, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)

Published
2013

239. Talks about TORCs: recent advancesin target of rapamycin signalling. On mTOR nomenclature

Author

Hall Michael N

Subjects
TOR Serine-Threonine Kinases, Terminology as Topic, Signal Transduction
Abstract

In the present article, I discuss recent developments in the naming of the TOR (target of rapamycin) protein. In particular, I address the issue of mammalian target of rapamycin (mTOR) versus the newer mechanistic target of rapamycin (MTOR). mTOR is the name given by the TOR community almost two decades ago and widely used ever since. MTOR is a name recently imposed on the TOR community by database curators and used mainly by newcomers. I argue that MTOR is causing needless confusion in the field, and conclude that one should use the name mTOR.

Published
2013

240. Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology

Author

Betz, Charles, Stracka, Daniele, Prescianotto-Baschong, Cristina, Frieden, Maud, Demaurex, Nicolas, and Hall, Michael N

Subjects
Membrane Potential, Mitochondrial, Mice, Knockout, TOR Serine-Threonine Kinases, Feature Article, Membrane Proteins, Intracellular Membranes, Mechanistic Target of Rapamycin Complex 2, Endoplasmic Reticulum, Mitochondria, Mice, Hexokinase, Multiprotein Complexes, Animals, Humans, Inositol 1,4,5-Trisphosphate Receptors, HSP70 Heat-Shock Proteins, ddc:612, Proto-Oncogene Proteins c-akt, HeLa Cells, Signal Transduction
Abstract

The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75-voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism.

Published
2013

241. The protein histidine phosphatase LHPP is a tumour suppressor.

Author

Hindupur, Sravanth K., Colombi, Marco, Fuhs, Stephen R., Matter, Matthias S., Guri, Yakir, Adam, Kevin, Cornu, Marion, Piscuoglio, Salvatore, Ng, Charlotte K. Y., Betz, Charles, Liko, Dritan, Quagliata, Luca, Moes, Suzette, Jenoe, Paul, Terracciano, Luigi M., Heim, Markus H., Hunter, Tony, and Hall, Michael N.

Abstract

Histidine phosphorylation, the so-called hidden phosphoproteome, is a poorly characterized post-translational modification of proteins. Here we describe a role of histidine phosphorylation in tumorigenesis. Proteomic analysis of 12 tumours from an mTOR-driven hepatocellular carcinoma mouse model revealed that NME1 and NME2, the only known mammalian histidine kinases, were upregulated. Conversely, expression of the putative histidine phosphatase LHPP was downregulated specifically in the tumours. We demonstrate that LHPP is indeed a protein histidine phosphatase. Consistent with these observations, global histidine phosphorylation was significantly upregulated in the liver tumours. Sustained, hepatic expression of LHPP in the hepatocellular carcinoma mouse model reduced tumour burden and prevented the loss of liver function. Finally, in patients with hepatocellular carcinoma, low expression of LHPP correlated with increased tumour severity and reduced overall survival. Thus, LHPP is a protein histidine phosphatase and tumour suppressor, suggesting that deregulated histidine phosphorylation is oncogenic. [ABSTRACT FROM AUTHOR]

Published
2018
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242. Raptor levels are critical for β-cell adaptation to a high-fat diet in male mice.

Author

Blandino-Rosano, Manuel, Louzada, Ruy Andrade, Werneck-De-Castro, Joao Pedro, Lubaczeuski, Camila, Almaça, Joana, Rüegg, Markus A., Hall, Michael N., Leibowitz, Gil, and Bernal-Mizrachi, Ernesto

Abstract

The essential role of raptor/mTORC1 signaling in β-cell survival and insulin processing has been recently demonstrated using raptor knock-out models. Our aim was to evaluate the role of mTORC1 function in adaptation of β-cells to insulin resistant state. Here, we use mice with heterozygous deletion of raptor in β-cells (βra Het ) to assess whether reduced mTORC1 function is critical for β-cell function in normal conditions or during β-cell adaptation to high-fat diet (HFD). Deletion of a raptor allele in β-cells showed no differences at the metabolic level, islets morphology, or β-cell function in mice fed regular chow. Surprisingly, deletion of only one allele of raptor increases apoptosis without altering proliferation rate and is sufficient to impair insulin secretion when fed a HFD. This is accompanied by reduced levels of critical β-cell genes like Ins1, MafA , Ucn3 , Glut2 , Glp1r, and specially PDX1 suggesting an improper β-cell adaptation to HFD. This study identifies that raptor levels play a key role in maintaining PDX1 levels and β-cell function during the adaptation of β-cell to HFD. Finally, we identified that Raptor levels regulate PDX1 levels and β-cell function during β-cell adaptation to HFD by reduction of the mTORC1-mediated negative feedback and activation of the AKT/FOXA2/PDX1 axis. We suggest that Raptor levels are critical to maintaining PDX1 levels and β-cell function in conditions of insulin resistance in male mice. • The mTOR signaling pathway is deregulated in human diseases such as cancer and diabetes. • The role of partial mTORC1 reduction in β-cells during β-cell adaptation to insulin resistance remains unanswered. • Heterozygous raptor deletion in β-cells impaired HFD adaptation by reducing critical β-cell gene expression. • Raptor levels are critical for maintenance of PDX1 levels and β-cell function. • AKT/FOXA2/PDX1 axis plays a role in β-cell adaptation to HFD. [ABSTRACT FROM AUTHOR]

Published
2023
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244. Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

Author

Zhang, Lianjun, primary, Tschumi, Benjamin O., additional, Lopez-Mejia, Isabel C., additional, Oberle, Susanne G., additional, Meyer, Marten, additional, Samson, Guerric, additional, Rüegg, Markus A., additional, Hall, Michael N., additional, Fajas, Lluis, additional, Zehn, Dietmar, additional, Mach, Jean-Pierre, additional, Donda, Alena, additional, and Romero, Pedro, additional

Published
2016
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247. Maximizing the Efficacy of MAPK-Targeted Treatment in PTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

Author

Herkert, Barbara, primary, Kauffmann, Audrey, additional, Mollé, Sandra, additional, Schnell, Christian, additional, Ferrat, Thomas, additional, Voshol, Hans, additional, Juengert, Janina, additional, Erasimus, Hélène, additional, Marszalek, Grégory, additional, Kazic-Legueux, Malika, additional, Billy, Eric, additional, Ruddy, David, additional, Stump, Mark, additional, Guthy, Daniel, additional, Ristov, Mitko, additional, Calkins, Keith, additional, Maira, Sauveur-Michel, additional, Sellers, William R., additional, Hofmann, Francesco, additional, Hall, Michael N., additional, and Brachmann, Saskia M., additional

Published
2016
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248. Architecture of human mTOR complex 1

Author

Aylett, Christopher H. S., primary, Sauer, Evelyn, additional, Imseng, Stefan, additional, Boehringer, Daniel, additional, Hall, Michael N., additional, Ban, Nenad, additional, and Maier, Timm, additional

Published
2016
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249. Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae

Author

Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Sabatini, David M., Liu, Qingsong, Ren, Tao, Fresques, Tara, Oppliger, Wolfgang, Niles, Brad J., Hur, Wooyoung, Hall, Michael N., Powers, Ted, Gray, Nathanael S., Sabatini, David, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Sabatini, David M., Liu, Qingsong, Ren, Tao, Fresques, Tara, Oppliger, Wolfgang, Niles, Brad J., Hur, Wooyoung, Hall, Michael N., Powers, Ted, Gray, Nathanael S., and Sabatini, David

Abstract

The target of rapamycin (TOR) is a critical regulator of growth, survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin has been used extensively to elucidate the TOR related signal pathway but is limited by its inability to inhibit TORC2. We used an unbiased cell proliferation assay of a kinase inhibitor library to discover QL-IX-55 as a potent inhibitor of S. cerevisiae growth. The functional target of QL-IX-55 is the ATP-binding site of TOR2 as evidenced by the discovery of resistant alleles of TOR2 through rational design and unbiased selection strategies. QL-IX-55 is capable of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2) as demonstrated by biochemical IP kinase assays (IC[subscript 50] <50 nM) and cellular assays for inhibition of substrate YPK1 phosphorylation. In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent transcription, which suggests that this compound will be a powerful probe to dissect the Tor2/TORC2-related signaling pathway in yeast.

Published
2015

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