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

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

Rank Difference Analysis of Microarrays (RDAM), a novel approach to statistical analysis of microarray expression profiling data

BACKGROUND: A key step in the analysis of microarray expression profiling data is the identification of genes that display statistically significant changes in expression signals between two biological conditions. RESULTS: We describe a new method, Rank Difference Analysis of Microarrays (RDAM), which estimates the total number of truly varying genes and assigns a p-value to each signal variation. Information on a group of differentially expressed genes includes the sensitivity and the false discovery rate. We demonstrate the feasibility and efficiency of our approach by applying it to a large synthetic expression data set and to a biological data set obtained by comparing vegetatively-growing wild type and tor2-mutant yeast strains. In both cases we observed a significant improvement of the power of analysis when our method is compared to another popular nonparametric method. CONCLUSIONS: This study provided a valuable new statistical method to analyze microarray data. We conclude that the good quality of the results obtained by RDAM is mainly due to the quasi-perfect equalization of variation distribution, which is related to the standardization procedure used and to the measurement of variation by rank difference