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Brendan D.Manning

Gerta Hoxhaj, Issam Ben-Sahra, Sophie E Lockwood, Rebecca C Timson, Vanessa Byles, Graham T Henning, Peng Gao, Laura M Selfors, John M Asara, Brendan D Manning
Nicotinamide adenine dinucleotide phosphate (NADP+ ) is essential for producing NADPH, the primary cofactor for reductive metabolism. We find that growth factor signaling through the phosphoinositide 3-kinase (PI3K)-Akt pathway induces acute synthesis of NADP+ and NADPH. Akt phosphorylates NAD kinase (NADK), the sole cytosolic enzyme that catalyzes the synthesis of NADP+ from NAD+ (the oxidized form of NADH), on three serine residues (Ser44 , Ser46 , and Ser48 ) within an amino-terminal domain. This phosphorylation stimulates NADK activity both in cells and directly in vitro, thereby increasing NADP+ production...
March 8, 2019: Science
Pengda Liu, Wenjian Gan, Hiroyuki Inuzuka, Adam S Lazorchak, Daming Gao, Omotooke Arojo, Dou Liu, Lixin Wan, Bo Zhai, Yonghao Yu, Min Yuan, Byeong Mo Kim, Shavali Shaik, Suchithra Menon, Steven P Gygi, Tae Ho Lee, John M Asara, Brendan D Manning, John Blenis, Bing Su, Wenyi Wei
In the version of this Article originally published, the labels for Rictor and mTOR in the whole cell lysate (WCL) blots were swapped in Fig. 3b and the mTOR blot was placed upside down. Unprocessed blots of mTOR were also missing from Supplementary Fig. 9. The corrected Figs are shown below. In addition, control blots for the mTOR antibody (Cell Signalling Technology #2972) were also missing. These are now provided below, as Fig. 9, and show that the lower band is likely non-specific.
February 19, 2019: Nature Cell Biology
Brendan D Manning
No abstract text is available yet for this article.
February 2019: Nature
Min Yuan, Daniel M Kremer, He Huang, Susanne B Breitkopf, Issam Ben-Sahra, Brendan D Manning, Costas A Lyssiotis, John M Asara
Targeted tandem mass spectrometry (LC-MS/MS) has been extremely useful for profiling small molecules extracted from biological sources, such as cells, bodily fluids and tissues. Here, we present a protocol for analysing incorporation of the non-radioactive stable isotopes carbon-13 (13 C) and nitrogen-15 (15 N) into polar metabolites in central carbon metabolism and related pathways. Our platform utilizes selected reaction monitoring (SRM) with polarity switching and amide hydrophilic interaction liquid chromatography (HILIC) to capture transitions for carbon and nitrogen incorporation into selected metabolites using a hybrid triple quadrupole (QQQ) mass spectrometer...
February 2019: Nature Protocols
Alban Longchamp, Teodelinda Mirabella, Alessandro Arduini, Michael R MacArthur, Abhirup Das, J Humberto Treviño-Villarreal, Christopher Hine, Issam Ben-Sahra, Nelson H Knudsen, Lear E Brace, Justin Reynolds, Pedro Mejia, Ming Tao, Gaurav Sharma, Rui Wang, Jean-Marc Corpataux, Jacques-Antoine Haefliger, Kyo Han Ahn, Chih-Hao Lee, Brendan D Manning, David A Sinclair, Christopher S Chen, C Keith Ozaki, James R Mitchell
Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1α. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α...
March 22, 2018: Cell
Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Natalia Martín-Martín, Sonia Fernandez-Ruiz, James D Sutherland, Michelle Clasquin, Julen Tomas-Cortazar, Jose Jimenez, Ines Torres, Phong Quang, Pilar Ximenez-Embun, Ruzica Bago, Aitziber Ugalde-Olano, Ana Loizaga-Iriarte, Isabel Lacasa-Viscasillas, Miguel Unda, Verónica Torrano, Diana Cabrera, Sebastiaan M van Liempd, Ylenia Cendon, Elena Castro, Stuart Murray, Ajinkya Revandkar, Andrea Alimonti, Yinan Zhang, Amelia Barnett, Gina Lein, David Pirman, Ana R Cortazar, Leire Arreal, Ludmila Prudkin, Ianire Astobiza, Lorea Valcarcel-Jimenez, Patricia Zuñiga-García, Itziar Fernandez-Dominguez, Marco Piva, Alfredo Caro-Maldonado, Pilar Sánchez-Mosquera, Mireia Castillo-Martín, Violeta Serra, Naiara Beraza, Antonio Gentilella, George Thomas, Mikel Azkargorta, Felix Elortza, Rosa Farràs, David Olmos, Alejo Efeyan, Juan Anguita, Javier Muñoz, Juan M Falcón-Pérez, Rosa Barrio, Teresa Macarulla, Jose M Mato, Maria L Martinez-Chantar, Carlos Cordon-Cardo, Ana M Aransay, Kevin Marks, José Baselga, Josep Tabernero, Paolo Nuciforo, Brendan D Manning, Katya Marjon, Arkaitz Carracedo
This corrects the article DOI: 10.1038/nature22964.
February 22, 2018: Nature
Benjamin E Housden, Zhongchi Li, Colleen Kelley, Yuanli Wang, Yanhui Hu, Alexander J Valvezan, Brendan D Manning, Norbert Perrimon
Synthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells, but this approach generally suffers from low consistency between screens. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population...
December 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
Ilana Kelsey, Marie Zbinden, Vanessa Byles, Margaret Torrence, Brendan D Manning
The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that is often aberrantly activated in cancer. However, mTORC1 inhibitors, such as rapamycin, have limited effectiveness as single agent cancer therapies, with feedback mechanisms inherent to the signaling network thought to diminish the anti-tumor effects of mTORC1 inhibition. Here, we identify the protein kinase and proto-oncogene PIM3 as being repressed downstream of mTORC1 signaling. PIM3 expression is suppressed in cells with loss of the tuberous sclerosis complex (TSC) tumor suppressors, which exhibit growth factor-independent activation of mTORC1, and in the mouse liver upon feeding-induced activation of mTORC1...
November 23, 2017: Scientific Reports
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
Alexander J Valvezan, Marc Turner, Amine Belaid, Hilaire C Lam, Spencer K Miller, Molly C McNamara, Christian Baglini, Benjamin E Housden, Norbert Perrimon, David J Kwiatkowski, John M Asara, Elizabeth P Henske, Brendan D Manning
The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. We find that pharmacological inhibitors of guanylate nucleotide synthesis have selective deleterious effects on TSC-deficient cells, including in mouse tumor models...
November 13, 2017: Cancer Cell
Brendan D Manning
New England Journal of Medicine, Volume 377, Issue 13, Page 1299-1301, September 2017.
September 28, 2017: New England Journal of Medicine
Caroline Heintz, Thomas K Doktor, Anne Lanjuin, Caroline C Escoubas, Yue Zhang, Heather J Weir, Sneha Dutta, Carlos Giovanni Silva-García, Gitte H Bruun, Ianessa Morantte, Gerta Hoxhaj, Brendan D Manning, Brage S Andresen, William B Mair
This corrects the article DOI: 10.1038/nature20789.
July 27, 2017: Nature
Susanne B Breitkopf, Stéphane J H Ricoult, Min Yuan, Ying Xu, David A Peake, Brendan D Manning, John M Asara
INTRODUCTION: Advances in high-resolution mass spectrometry have created renewed interest for studying global lipid biochemistry in disease and biological systems. OBJECTIVES: Here, we present an untargeted 30 min. LC-MS/MS platform that utilizes positive/negative polarity switching to perform unbiased data dependent acquisitions (DDA) via higher energy collisional dissociation (HCD) fragmentation to profile more than 1000-1500 lipid ions mainly from methyl-tert-butyl ether (MTBE) or chloroform:methanol extractions...
March 2017: Metabolomics: Official Journal of the Metabolomic Society
Brendan D Manning, Alex Toker
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body...
April 20, 2017: Cell
Issam Ben-Sahra, Brendan D Manning
mTOR [mechanistic target of rapamycin] is a serine/threonine protein kinase that, as part of mTORC1 (mTOR complex 1), acts as an important molecular connection between nutrient signals and the metabolic processes indispensable for cell growth. While there has been pronounced interest in the upstream mechanisms regulating mTORC1, the full range of downstream molecular targets through which mTORC1 signaling stimulates cell growth is only recently emerging. It is now evident that mTORC1 promotes cell growth primarily through the activation of key anabolic processes...
April 2017: Current Opinion in Cell Biology
Karl L Skorecki, Jessica H Lee, Carl D Langefeld, Saharon Rosset, Shay Tzur, Walter G Wasser, Revital Shemer, Gregory A Hawkins, Jasmin Divers, Rulan S Parekh, Man Li, Matthew G Sampson, Matthias Kretzler, Martin R Pollak, Shrijal Shah, Daniel Blackler, Brendan Nichols, Michael Wilmot, Seth L Alper, Barry I Freedman, David J Friedman
Background: Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans. Methods: We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD...
February 1, 2018: Nephrology, Dialysis, Transplantation
Jessica J Howell, Kristina Hellberg, Marc Turner, George Talbott, Matthew J Kolar, Debbie S Ross, Gerta Hoxhaj, Alan Saghatelian, Reuben J Shaw, Brendan D Manning
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion...
February 7, 2017: Cell Metabolism
Caroline Heintz, Thomas Koed Doktor, Anne Lanjuin, Caroline Escoubas, Yue Zhang, Heather J Weir, Sneha Dutta, Carlos Giovanni Silva-García, Gitte Hoffmann Bruun, Ianessa Morantte, Gerta Hoxhaj, Brendan D Manning, Brage S Andresen, William B Mair
Ageing is driven by a loss of transcriptional and protein homeostasis and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses. However, the role of splicing homeostasis in healthy ageing remains unclear...
January 5, 2017: Nature
Erika Ilagan, Brendan D Manning
The movement toward precision medicine with targeted therapeutics for cancer treatment has been hindered by both innate and acquired resistance. Understanding the molecular wiring and plasticity of oncogenic signaling networks is essential to the development of therapeutic strategies to avoid or overcome resistance. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) represents a highly integrated signaling node that is dysregulated in the majority of human cancers. Several studies have revealed that sustained mTORC1 inhibition is essential to avoid resistance to targeted therapeutics against the driving oncogenic pathway in a given cancer...
May 2016: Trends in Cancer
Stéphane J H Ricoult, Christian C Dibble, John M Asara, Brendan D Manning
Sterol regulatory element binding protein (SREBP) is a major transcriptional regulator of the enzymes underlying de novo lipid synthesis. However, little is known about the SREBP-mediated control of processes that indirectly support lipogenesis, for instance, by supplying reducing power in the form of NAPDH or directing carbon flux into lipid precursors. Here, we characterize isocitrate dehydrogenase 1 (IDH1) as a transcriptional target of SREBP across a spectrum of cancer cell lines and human cancers. IDH1 promotes the synthesis of lipids specifically from glutamine-derived carbons...
September 15, 2016: Molecular and Cellular Biology
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