mTORC1 Controls Synthesis of Its Activator GTP

In this issue of Cell Reports, Emmanuel et al. (2017) report that mTORC1 activity is regulated by purine availability. This increases the number of mTORC1 regulators to include metabolites whose synthesis mTORC1 controls

Combining metformin with lactate transport inhibitors as a treatment modality for cancer-recommendation proposal

Highly glycolytic cancer cells excrete lactate to maintain cellular homeostasis. Inhibiting lactate export by pharmacological targeting of plasma membrane lactate transporters is being pursued as an anti-cancer therapy. Work from many laboratories show that the simultaneous inhibition of lactate export and mitochondrial respiration elicits strong synthetic lethality. The mitochondrial inhibitor, metformin, has been the subject of numerous clinical trials as an anti-cancer agent. We propose that, in future clinical trials, metformin be combined with lactate transport inhibitors to exploit this synergistic interaction

Lactate jump-starts mTORC1 in cancer cells

The kinase mammalian target of rapamycin ( mTOR ) is a major regulatory hub that senses and integrates nutrient, energy, and growth factor inputs to promote cell growth. In this issue of EMBO Reports , Byun et al [1] report that high intracellular levels of lactate activate mTORC 1 in KRAS transformed cells independently of a growth factor input. This suggests a mechanism for how mTORC 1 can be co‐opted to support oncogenic growth and proliferation

Regulation of mTORC2 Signaling

Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 appears to exist in functionally distinct pools, but few mTORC2 effectors/substrates have been identified. Here, we review recent advances in our understanding of mTORC2 signaling, with particular emphasis on factors that control mTORC2 activity

Growth and aging: a common molecular mechanism

It is commonly assumed that growth and aging are somehow linked, but the nature of this link has been elusive. Here we review the aging process as a continuation of TOR-driven growth. TOR is absolutely essential for developmental growth, but upon completion of development it causes aging and age-related diseases. Thus, the nutrient-sensing and growth-promoting TOR signaling pathway may provide a molecular link between growth and aging that is universal from yeast to human

Activating Mutations in TOR Are in Similar Structures As Oncogenic Mutations in PI3KCα

TOR (Target of Rapamycin) is a highly conserved Ser/Thr kinase and a central controller of cell growth. Using the crystal structure of the related lipid kinase PI3KCgamma, we built a model of the catalytic region of TOR, from the FAT domain to near the end of the FATC domain. The model reveals that activating mutations in TOR, identified in yeast in a genetic selection for Rheb-independence, correspond to hotspots for oncogenic mutations in PI3KCalpha. The activating mutations are in the catalytic domain (helices kalpha3, kalpha9, kalpha11) and the helical domain of TOR. Docking studies with small molecule inhibitors (PP242, NVP-BEZ235, and Ku-0063794) show that drugs currently in development utilize a novel pharmacophore space to achieve specificity. Thus, our model provides insight on the regulation of TOR and may be useful in the design of new anticancer drugs

mTOR signalling and cellular metabolism are mutual determinants in cancer

Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy

Determining Glucose Isomerization Mechanisms on Lewis Acidic Beta Zeolites Using Isotropic Tracer Studies and 1H NMR

Biofuels synthesized from biomass sources are becoming necessary for sustainable production due to their significantly lower net CO2 production than fuels synthesized from fossil-based carbon sources such as petroleum. Catalytic pathways for the primary biomass-to-biofuels reaction pathway include the isomerization of glucose to fructose, which can be catalyzed by either Lewis acids or bases. Isolated metal atoms and metal oxide particles on Beta zeolites serve as active sites that catalyze this reaction through a Lewis acid 1,2-intramolecular hydride shift or by a Lewis base proton transfer mechanism, respectively. The Lewis acid mechanism has proven to have higher fructose selectivity than the Lewis base mechanism. Determining the glucose-fructose isomerization mechanism provides critical information about the active site placement in catalysts prepared by different methods, making it an ideal test of quality control for new material syntheses. Using glucose reactants deuterated at the second carbon, catalytic reaction mechanisms could be determined by tracing the location of the deuterium atom in the sugar products using 1H NMR spectroscopy. Comparison of fructose product spectra with an unlabeled fructose standard was used to show that glucose isomerization to fructose followed the Lewis acidic pathway on the samples in this study. The outcomes of these isotopic labeling studies provide insight into the placement of Lewis acid metals in zeolite frameworks and help to further understand this important step in biomass conversion to biofuels

mTORC2 regulates auditory hair cell structure and function

mTOR broadly controls cell growth, but little is known about the role of mTOR complex 2 (mTORC2) in the inner ear. To investigate the role of mTORC2 in sensory hair cells (HCs), we generated HC-specific; Rictor; knockout (HC-RicKO) mice. HC-RicKO mice exhibited early-onset, progressive, and profound hearing loss. Increased DPOAE thresholds indicated outer HC dysfunction. HCs are lost, but this occurs after hearing loss. Ultrastructural analysis revealed stunted and absent stereocilia in outer HCs. In inner HCs, the number of synapses was significantly decreased and the remaining synapses displayed a disrupted actin cytoskeleton and disorganized Ca; 2+; channels. Thus, the mTORC2 signaling pathway plays an important role in regulating auditory HC structure and function via regulation of the actin cytoskeleton. These results provide molecular insights on a central regulator of cochlear HCs and thus hearing