Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling

Jung, Jae Woo; Macalino, Stephani Joy Y.; Cui, Minghua; Kim, Ji Eon; Kim, Hye Jin; Song, Dae Geun; Nam, Seo Hee; Kim, Semi; Choi, Sun; Lee, Sang Eun

doi:10.1016/j.cmet.2019.03.005

Cited by 57 publications

(79 citation statements)

References 48 publications

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“…mLST8 is associated with the catalytic domain of mTOR and may stabilize the kinase activation loop, DEPTOR on the contrary inhibits mTOR activity, TTI1/TEL2 is a mTOR interacting protein important for mTOR stability and assembly of the mTOR complex and maintain their activities (28) (Figure 1). mTORC1 is activated via growth factors stimulation [epidermal growth factor (EGF), insulin-like growth factor (IGF)], increase in amino acid levels such as leucin and arginine and cellular energy status (29)(30)(31), promoting protein and lipid synthesis, as well as ribosome biogenesis impacting on cell proliferation and growth, autophagy and metabolic processes are also stimulated by mTORC1 action (32). Moreover, it was demonstrated that mTORC1 signaling is strongly implicated in the aging process of diverse organisms, including yeast, worms flies, and mammals (33).…”

Section: Structure and Functions Of Mtorc1mentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Structure and Functions Of Mtorc1mentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…TM4SF5, LARS, and SAMTOR are cytosolic arginine, leucine, and S-adenosylmethionine sensors, respectively membrane, where it interacts with TOR and the SLC38A9 in an arginine-regulated manner. This interaction further causes arginine efflux and actives TORC1 (Jung et al 2019).…”

Section: Figmentioning

confidence: 99%

“…Recently, the discoveries of SLC38A9, Sestrins, CASTOR1, SAMTOR, Transmembrane 4 L Six Family Member 5 (TM4SF5), and leucyl-tRNA synthetase (LARS) represent the dawn of the age of amino acid sensors ( Fig. 3) Han et al 2012;Jung et al 2019;Zheng et al 2016).…”

Section: Figmentioning

confidence: 99%

Recent advances in amino acid sensing and new challenges for protein nutrition in aquaculture

Liu

Wang

Zhou

et al. 2019

Mar Life Sci Technol

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From the conventional knowledge of protein nutrition to the molecular nutrition of amino acids, our understanding of protein/ amino acid nutrition is rapidly increasing. Amino acids control cell growth and metabolism through two amino acid-sensing pathways, i.e. target of rapamycin complex 1 (TORC1) and the general control nonderepressible 2 (GCN2) signaling pathway. In the amino acid-abundant status, TORC1 dominates intracellular signaling and increases protein synthesis and cell growth. In contrast, amino acid deprivation actives GCN2 resulting in repression of general protein synthesis but facilitates the amino acid transport and synthesis process. By integrating and coordinating nutrition and hormone signaling, TORC1 and GCN2 control the switch of the catabolism and anabolism phase in most eukaryotes. Now, we appreciate that the availability of individual amino acids is sensed by intracellular sensors. These cutting-edge findings expand our knowledge of amino acid nutrition. Although the TORC1 and GCN2 were discovered decades ago, the study of molecular amino acid nutrition in aquaculture animals is still at its infancy. The aquaculture industry is highly dependent on the supply of fishmeal, which is the major protein source in aquacultural animal diets. Some concerted efforts were conducted to substitute for fishmeal due to limited supply of it. However, the concomitant issues including the unbalanced amino acid profile of alternative protein sources limited the utilization of those proteins. Continued study of the molecular nutrition of amino acid in aquaculture animals may be expected in the immediate future to expand our knowledge on the utilization of alternative protein sources.Keywords Molecular nutrition · Amino acid sensor · GCN2 · TORC1 · Aquaculture · Fishmeal replacement TORC1, the center of amino acid-dependent signaling for growth and metabolismAs fundamental elements for the growth of all organisms, the input of protein/amino acid initiated a series of subcellular responses. However, the mechanisms by which amino

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“…ATRAID is, like LAMP1, GLMP and OSTM1, a type I transmembrane protein (Figure 2). SLC38A9, a central core of the amino acidsensing machinery [73] interacts with the highly N-glycosylated tetraspanin TM4SF5 [74], but if it acts as an essential accessory subunit needs further investigation. It should be noted that an interaction of SLC38A9 has also been shown with the V-ATPase and NPC1 [73,75].…”

Section: Accepted Articlementioning

confidence: 99%

The lysosomal membrane—export of metabolites and beyond

Rudnik

Damme

2020

The FEBS Journal

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Lysosomes are degradative organelles in eukaryotic cells mediating the hydrolytic catabolism of various macromolecules to small basic building blocks. These low molecular weight metabolites are transported across the lysosomal membrane and re-used in the cytoplasm and other organelles for biosynthetic pathways. Even though in the past 20 years our understanding of the Accepted Article This article is protected by copyright. All rights reserved lysosomal membrane regarding various transporters, other integral-and peripheral-membrane proteins, the lipid composition but also its turnover has greatly improved, there are still many unresolved questions concerning key aspects of the function of the lysosomal membrane. These include a possible function of lysosomes as a cellular storage compartment, yet unidentified transporters mediating the export e.g. of various amino acids, mechanisms mediating the transport of lysosomal membrane proteins from the Golgi apparatus to lysosomes, and the turnover of lysosomal membrane proteins. We here review the current knowledge about the lysosomal membrane and identify some of the open questions that need to be solved in the future for a comprehensive and complete understanding of how lysosomes communicate with other organelles, cellular processes, and pathways.

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Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling

Cited by 57 publications

References 48 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Recent advances in amino acid sensing and new challenges for protein nutrition in aquaculture

The lysosomal membrane—export of metabolites and beyond

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