A growing role for mTOR in promoting anabolic metabolism

2013 ◽  
Vol 41 (4) ◽  
pp. 906-912 ◽  
Author(s):  
Jessica J. Howell ◽  
Stéphane J.H. Ricoult ◽  
Issam Ben-Sahra ◽  
Brendan D. Manning
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Nucleic Acids ◽  
Tumour Growth ◽  
Building Blocks ◽  
Mechanistic Target Of Rapamycin ◽  
Metabolic Functions ◽  
Molecular Events ◽  
Cell Growth And Proliferation ◽  
Mtor Complex 1

mTOR [mammalian (or mechanistic) target of rapamycin] is a protein kinase that, as part of mTORC1 (mTOR complex 1), acts as a critical molecular link between growth signals and the processes underlying cell growth. Although there has been intense interest in the upstream mechanisms regulating mTORC1, the full repertoire of downstream molecular events through which mTORC1 signalling promotes cell growth is only recently coming to light. It is now recognized that mTORC1 promotes cell growth and proliferation in large part through the activation of key anabolic processes. Through a variety of downstream targets, mTORC1 alters cellular metabolism to drive the biosynthesis of building blocks and macromolecules fundamentally essential for cell growth, including proteins, lipids and nucleic acids. In the present review, we focus on the metabolic functions of mTORC1 as they relate to the control of cell growth and proliferation. As mTORC1 is aberrantly activated in a number of tumour syndromes and up to 80% of human cancers, we also discuss the importance of this mTORC1-driven biosynthetic programme in tumour growth and progression.

scholarly journals Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance

2017 ◽  
Vol 61 (6) ◽  
pp. 699-710 ◽  
Author(s):  
Charlotte E. Johnson ◽  
Andrew R. Tee
Keyword(s):  
Cell Growth ◽  
Cancer Cells ◽  
Energy Homeostasis ◽  
Cellular Stress ◽  
Growth Control ◽  
Potential Therapeutic Target ◽  
Wide Range ◽  
Cell Growth And Proliferation ◽  
Mtor Complex 1 ◽  
Cell Growth Control

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) at lysosomes plays a pivotal role in cell growth control where an array of large multiprotein complexes relay nutrient, energy, and growth signal inputs through mTORC1. In cancer cells, such regulation often becomes disconnected, leading to uncontrolled cell growth and an elevation in cellular stress. Consequently, cancer cells often lose homeostatic balance as they grow in unfavorable conditions, i.e. when nutrients and energy are limited yet mTORC1 is still aberrantly activated. Cancer cells lose signaling flexibility because of hyperactive mTORC1 that leads to heightened cellular stress and loss of nutrient and energy homeostasis, all of which are potential avenues for cancer therapy. Cancer cells often enhance mTORC1 to drive cell growth and proliferation, while also maintaining their survival. Autophagy regulation by mTORC1 is critically involved in nutrient and energy homeostasis, cell growth control, and survival. Studying mTORC1 and autophagy as a potential therapeutic target for cancer treatment has been the focus of a wide range of research over the past few decades. This review will explore the signaling pathways central to mTORC1 and autophagy regulation, and cancer vulnerabilities while considering anticancer therapies.

scholarly journals mTOR as a central regulator of lifespan and aging

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 998 ◽  
Author(s):  
David Papadopoli ◽  
Karine Boulay ◽  
Lawrence Kazak ◽  
Michael Pollak ◽  
Frédérick Mallette ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fuel Cell ◽  
Cell Growth ◽  
Life Span ◽  
Cellular Senescence ◽  
Cell Function ◽  
Nutrient Sensing ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Cell Growth And Proliferation

The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.

scholarly journals Stability of tuberous sclerosis complex 2 is controlled by methylation at R1457 and R1459

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Seishu Gen ◽  
Yu Matsumoto ◽  
Ken-Ichi Kobayashi ◽  
Tsukasa Suzuki ◽  
Jun Inoue ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Posttranslational Modifications ◽  
Complex Disease ◽  
Protein Kinase B ◽  
Arginine Methyltransferase ◽  
Mechanistic Target Of Rapamycin ◽  
Protein Arginine Methyltransferase 1 ◽  
Cell Growth And Proliferation

AbstractMutations in genes that encode components of tuberous sclerosis complex 2 (TSC2) are associated with tuberous sclerosis complex disease. TSC2 interacts with tuberous sclerosis complex 1 to form a complex that negatively regulates cell growth and proliferation via the inactivation of mechanistic target of rapamycin complex 1. The activity of TSC2 is mainly regulated via posttranslational modifications such as phosphorylation. However, the control of TSC2 activity is not entirely achieved by phosphorylation. In this study, we show that TSC2 is methylated at R1457 and R1459 by protein arginine methyltransferase 1 (PRMT1). Methylation of these two residues can affect the phosphorylation status through protein kinase B (Akt) of TSC2 at T1462 and is essential for TSC2 stability. Taken together, these findings indicate that novel posttranslational modifications are important for the regulation of TSC2 stability through PRMT1-mediated methylation.

scholarly journals TSC-Insensitive Rheb Mutations Induce Oncogenic Transformation Through a Combination of Hyperactive mTORC1 Signalling and Metabolic Reprogramming

2020 ◽  
Author(s):  
Jianling Xie ◽  
Stuart P. De Poi ◽  
Sean J. Humphrey ◽  
Leanne K. Hein ◽  
John Bruning ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tuberous Sclerosis Complex ◽  
Tumour Growth ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Mechanistic Target Of Rapamycin ◽  
Differential Interaction ◽  
Oncogenic Pathways ◽  
Important Regulator

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1, that might act as driver oncogenes by causing hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, Tuberous Sclerosis Complex.We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth, proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving metabolic reprogramming and an increased rate of glycolysis, while Rheb-E40K regulates the translation factor eEF2 and autophagy, likely through a differential interaction with AMPK.Our findings suggest that unique ‘bespoke’ combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.

Liensinine induces gallbladder cancer apoptosis and G2/M arrest by inhibiting ZFX-induced PI3K/AKT pathway

2019 ◽  
Vol 51 (6) ◽  
pp. 607-614 ◽  
Author(s):  
Yitong Shen ◽  
Rui Bian ◽  
Yaxiong Li ◽  
Yuan Gao ◽  
Yingbin Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Growth ◽  
Gallbladder Cancer ◽  
Protein Kinase B ◽  
Cyclin B1 ◽  
Phosphorylated Protein ◽  
Cell Growth And Proliferation

Abstract Gallbladder carcinoma (GBC) is the most common and aggressive cancer of the biliary tract. Liensinine has been proved to have hypotensive effect. However, the effect of liensinine on GBC is still unknown. The aim of this study is to investigate the effect and mechanism of liensinine in human GBC cells. Cell viability assay and colony formation assay were performed to assess cell growth and proliferation. Flow cytometry analysis was used to investigate cell cycle apoptosis in vitro. Hoechst 33342 staining was also used to evaluate cell apoptosis. Western blot analysis was used to determine the expression of proteins corresponding to the related cell cycle and apoptosis. The effect of liensinine treatment in vivo was experimented with xenografted tumors. We found that liensinine significantly inhibited the growth of GBC cells both in vivo and in vitro. In vitro, cell growth and proliferation were significantly suppressed by liensinine in a dose- and time-dependent manner. In vivo, liensinine inhibited tumor growth. Liensinine could induce GBC cells G2/M phase arrest by up-regulating the levels of Cyclin B1 and CDK1 proteins. Liensinine also affected GBC cell cycle progression and induced apoptosis by down-regulating phosphorylated protein kinase B (AKT), phosphorylated protein kinase B (p-AKT), phosphatidylinositol 3-kinase (PI3K), and Zinc finger X-chromosomal protein (ZFX) proteins. Liensinine induced G2/M arrest and apoptosis in gallbladder cancer, suggesting that liensinine might represent a novel and effective agent against gallbladder cancer.

scholarly journals Regulation of mTORC2 Signaling

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1045 ◽  
Author(s):  
Wenxiang Fu ◽  
Michael N. Hall
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Master Regulator ◽  
Recent Advances ◽  
Mtorc1 Signaling ◽  
Mtor Complex 1

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.

scholarly journals Activation of the essential kinase PDK1 by phosphoinositide-driven autophosphorylation

2021 ◽  
Author(s):  
Aleksandra Levina ◽  
Kaelin D Fleming ◽  
John E Burke ◽  
Thomas A Leonard
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Signaling Pathways ◽  
Protein Kinases ◽  
Crucial Role ◽  
Ph Domain ◽  
Face To Face ◽  
Regulatory Motifs ◽  
Positive Cooperativity ◽  
Cell Growth And Proliferation

3-phosphoinositide-dependent kinase 1 (PDK1) is an essential serine/threonine protein kinase, which plays a crucial role in cell growth and proliferation. It is often referred to as a master kinase due to its ability to activate at least 23 downstream protein kinases implicated in various signaling pathways. In this study, we have elucidated the mechanism of phosphoinositide-driven PDK1 auto-activation. We show that PDK1 trans-autophosphorylation is mediated by a PIP3-mediated face-to-face dimer. We report regulatory motifs in the kinase-PH interdomain linker that allosterically activate PDK1 autophosphorylation via a linker-swapped dimer mechanism. Finally, we show that PDK1 is autoinhibited by its PH domain and that positive cooperativity of PIP3 binding drives switch-like activation of PDK1. Our work implies that the PDK1-mediated activation of effector kinases, including Akt, PKC, Sgk, S6K and RSK, many of whom are not directly regulated by phosphoinositides, is also likely to be dependent on PIP3 or PI(3,4)P2.

scholarly journals GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling

2015 ◽  
Vol 470 (2) ◽  
pp. 207-221 ◽  
Author(s):  
Clare Stretton ◽  
Thorsten M. Hoffmann ◽  
Michael J. Munson ◽  
Alan Prescott ◽  
Peter M. Taylor ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Cell Growth ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Mechanistic Target Of Rapamycin ◽  
Amino Acid Availability ◽  
Cellular Autophagy ◽  
Mtor Complex 1

Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of raptor on Ser859, which crucially supports activation of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signalling in response to amino acid availability. GSK3 inhibition is associated with reduced mTORC1 signalling that impacts negatively on cell growth, protein synthesis and promotes cellular autophagy.

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