mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome

Rabanal-Ruíz, Yoana; Korolchuk, Viktor I.

doi:10.3390/ijms19030818

Cited by 125 publications

(92 citation statements)

References 196 publications

(300 reference statements)

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“…The exchange of glutamine with essential amino acids stimulates some signaling pathways, which support cell growth and proliferation. For instance, mammalian target of rapamycin 1 (mTORC1) is activated by glutamine, stimulating protein synthesis [59]. mTORC is a master regulator of cell growth, as well as an inhibitor of apoptosis and autophagy.…”

Section: Glutamine Metabolism In Cancermentioning

confidence: 99%

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

Ortiz-Pedraza

Muñoz-Bello

Olmedo-Nieva

et al. 2020

IJMS

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Cancer cells exhibit exacerbated metabolic activity to maintain their accelerated proliferation and microenvironmental adaptation in order to survive under nutrient-deficient conditions. Tumors display an increase in glycolysis, glutaminolysis and fatty acid biosynthesis, which provide their energy source. Glutamine is critical for fundamental cellular processes, where intermediate metabolites produced through glutaminolysis are necessary for the maintenance of mitochondrial metabolism. These include antioxidants to remove reactive oxygen species, and the generation of the nonessential amino acids, purines, pyrimidines and fatty acids required for cellular replication and the activation of cell signaling. Some cancer cells are highly dependent on glutamine consumption since its catabolism provides an anaplerotic pathway to feed the Krebs cycle. Intermediate members of the glutaminolysis pathway have been found to be deregulated in several types of cancers and have been proposed as therapeutic targets and prognostic biomarkers. This review summarizes the main players in the glutaminolysis pathway, how they have been found to be deregulated in cancer and their implications for cancer maintenance. Furthermore, non-coding RNAs are now recognized as new participants in the regulation of glutaminolysis; therefore, their involvement in glutamine metabolism in cancer is discussed in detail.Int. J. Mol. Sci. 2020, 21, 2872 2 of 26 an increased glucose consumption in relation to normal differentiated tissues. Now we know that glutamine metabolism is as important as glucose metabolism for the production of macromolecules in cancer [1].Glutamine is an abundant amino acid involved in energy production, homeostasis in pro/antioxidant species and the activation of signaling pathways in cancer. In addition to the antioxidant glutathione (GSH), nucleotides, lipids and amino acids are formed from glutamine metabolism. All of these are needed for many metabolic functions such as growth, proliferation, cell survival and defense against oxidative stress [2]. Glutamine contributes, with reduced nitrogen, to the de novo biosynthesis of diverse nitrogen-containing compounds, such as purine and pyrimidine nucleotides, glucosamine-6-phosphate and nonessential amino acids.As glutamine is the most abundant amino acid in the blood and muscle tissue, normal proliferating cells use glutamine metabolism as an energy source, mediated by its catabolic products, glutamate and α-ketoglutarate (α-kG), the latter being an intermediate of the tricarboxylic acid cycle (TCA) or Krebs cycle [3]. In 1950, Harry Eagle observed that HeLa tumor cells require an excess of glutamine, in relation to other amino acids in the culture medium, for optimal growth. Furthermore, it has been reported that tumors consume glutamine faster than the surrounding normal tissue [4]. Moreover, most cancer cells are dependent on glutamine being unable to survive under glutamine starvation, an effect that has been termed glutamine addiction [5]. Various types of cancers are high...

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Section: Glutamine Metabolism In Cancermentioning

confidence: 99%

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

Ortiz-Pedraza

Muñoz-Bello

Olmedo-Nieva

et al. 2020

IJMS

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“…Since the discovery of the mTOR complexes, extensive efforts have been made to characterize them and to distinguish their functions. Whereas mTORC2 regulates cell survival, metabolism and cytoskeletal structure (Oh and Jacinto, 2011), mTORC1 functions as a central regulator of metabolism, ensuring that the cell grows only under favorable conditions (Rabanal-Ruiz and Korolchuk, 2018). The dysregulation of the mTORC1 signaling pathway is thereby associated with many forms of cancer and metabolic disorders (Guertin and Sabatini, 2007;Saxton and Sabatini, 2017;Mossmann et al, 2018).…”

Section: The Flcn Complex Regulates the Mtorc1 Signaling Pathway Thromentioning

confidence: 99%

“…mTOR signaling is dependent on its serine/threonine kinase activity toward target substrates. The mTORC1 complex triggers cell proliferation and cell growth by promoting anabolic processes and suppressing catabolic metabolism through the phosphorylation of key effector proteins such as ribosomal protein S6 kinase (S6K) and the translation repressor eukaryotic translation initiation factor 4E-binding protein (4E-BP) (Rabanal-Ruiz and Korolchuk, 2018;Kim and Guan, 2019).…”

Section: The Flcn Complex Regulates the Mtorc1 Signaling Pathway Thromentioning

confidence: 99%

Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin

Garrido

Chs

2020

Front. Cell Dev. Biol.

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FLCN was identified as the gene responsible for Birt-Hogg-Dubé (BHD) syndrome, a hereditary syndrome associated with the appearance of familiar renal oncocytomas. Most mutations affecting FLCN result in the truncation of the protein, and therefore loss of its associated functions, as typical for a tumor suppressor. FLCN encodes the protein folliculin (FLCN), which is involved in numerous biological processes; mutations affecting this protein thus lead to different phenotypes depending on the cellular context. FLCN forms complexes with two large interacting proteins, FNIP1 and FNIP2. Structural studies have shown that both FLCN and FNIPs contain longin and differentially expressed in normal versus neoplastic cells (DENN) domains, typically involved in the regulation of small GTPases. Accordingly, functional studies show that FLCN regulates both the Rag and the Rab GTPases depending on nutrient availability, which are respectively involved in the mTORC1 pathway and lysosomal positioning. Although recent structural studies shed light on the precise mechanism by which FLCN regulates the Rag GTPases, which in turn regulate mTORC1, how FLCN regulates membrane trafficking through the Rab GTPases or the significance of the intriguing FLCN-FNIP-AMPK complex formation are questions that still remain unanswered. We discuss the recent progress in our understanding of FLCN regulation of both growth signaling and lysosomal positioning, as well as future approaches to establish detailed mechanisms to explain the disparate phenotypes caused by the loss of FLCN function and the development of BHD-associated and other tumors.

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“…Being committed to ageing research, Korolchuk introduced the central role of mammalian target of rapamycin complex 1 (mTORC1) and the lysosomal compartment in cellular senescence. A key regulator of mTORC1 is the lysosome that serves as a physical platform allowing mTORC1 activation but also represents the ultimate compartment where autophagy takes place [23]. In senescent cells, mTORC1 may become constitutively active and "blind" to exogenous nutrient starvation.…”

Section: Other Workhopsmentioning

confidence: 99%

Report of the 23rd Meeting on Signal Transduction 2019—Trends in Cancer and Infection

Schirmer

Giehl

Kubatzky

2020

IJMS

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The annual meeting "Signal Transduction-Receptors, Mediators and Genes" of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating the signalling pathways underlying the physiological or pathological processes in health and disease of humans, animals, plants, fungi, prokaryotes and protists. The 23rd meeting on signal transduction was held from 4-6 November 2019 in Weimar, Germany, and focused on "Trends in Cancer and Infection". As usual, keynote presentations by invited scientists introduced the respective workshops and were followed by speakers chosen from the submitted abstracts. Ample time had been reserved for discussion of the presented data during the workshops. In this report, we provide a concise summary of the various workshops and further aspects of the scientific program.

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mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome

Cited by 125 publications

References 196 publications

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin

Report of the 23rd Meeting on Signal Transduction 2019—Trends in Cancer and Infection

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