The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis

In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as lipids and amino acids. Consequently, the energy and nutrient status of the cell is acutely monitored and carefully maintained. mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] is often considered to be the master regulator of cell growth that enhances cellular biomass through up-regulation of protein translation. In order for cells to control cellular homoeostasis during growth, there is close signalling interplay between mTORC1 and two other protein kinases, AMPK (AMP-activated protein kinase) and ULK1 (Unc-51-like kinase 1). This kinase triad collectively senses the energy and nutrient status of the cell and appropriately dictates whether the cell will actively favour energy- and amino-acid-consuming anabolic processes such as cellular growth, or energy- and amino-acid-generating catabolic processes such as autophagy. The present review discusses important feedback mechanisms between these three homoeostatic protein kinases that orchestrate cell growth and autophagy, with a particular focus on the mTORC1 component raptor (regulatory associated protein of mammalian target of rapamycin), as well as the autophagy-initiating kinase ULK1.

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Rag proteins regulate amino-acid-induced mTORC1 signalling

Biochemical Society Transactions ◽

10.1042/bst0370289 ◽

2009 ◽

Vol 37 (1) ◽

pp. 289-290 ◽

Cited By ~ 58

Author(s):

Yasemin Sancak ◽

David M. Sabatini

Keyword(s):

Amino Acid ◽

Protein Kinase ◽

Cell Growth ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Master Regulator ◽

Growth And Survival ◽

Field Identification ◽

Rag Proteins ◽

Cell Growth And Survival

The serum- and nutrient-sensitive protein kinase mTOR (mammalian target of rapamycin) is a master regulator of cell growth and survival. The mechanisms through which nutrients regulate mTOR have been one of the major unanswered questions in the mTOR field. Identification of the Rag (Ras-related GTPase) family of GTPases as mediators of amino acid signalling to mTOR is an important step towards our understanding of this mechanism.

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Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation

Biochemical Journal ◽

10.1042/bj3440427 ◽

1999 ◽

Vol 344 (2) ◽

pp. 427-431 ◽

Cited By ~ 419

Author(s):

Barbara T. NAVÉ ◽

D. Margriet OUWENS ◽

Dominic J. WITHERS ◽

Dario R. ALESSI ◽

Peter R. SHEPHERD

Keyword(s):

Amino Acid ◽

Protein Kinase ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Protein Translation ◽

Target Of Rapamycin ◽

Direct Target ◽

Regulatory Effects ◽

Stimulation Of

Growth factor induced activation of phosphoinositide 3-kinase and protein kinase B (PKB) leads to increased activity of the mammalian target of rapamycin (mTOR). This subsequently leads to increased phosphorylation of eIF4E binding protein-1 (4EBP1) and activation of p70 ribosomal S6 protein kinase (p70S6K), both of which are important steps in the stimulation of protein translation. The stimulation of translation is attenuated in cells deprived of amino acids and this is associated with the attenuation of 4EBP1 phosphorylation and p70S6K activation. It has been suggested that PKB regulates mTOR function by phosphorylation although direct phosphorylation of mTOR by PKB has not been demonstrated previously. In the present work, we have found that PKB directly phosphorylates mTOR and, using phosphospecific antibodies, we have shown this phosphorylation occurs at Ser2448. Insulin also induces phosphorylation on Ser2448 and this effect is blocked by wortmannin but not rapamycin, consistent with the effect being mediated by PKB. Amino-acid starvation rapidly attenuated the reactivity of the Ser2448 phosphospecific antibody with mTOR and this could not be restored by either insulin stimulation of cells or incubation with PKB in vitro. Our findings demonstrate that mTOR is a direct target for PKB and support the conclusion that regulation of phosphorylation of Ser2448 is a point of convergence for the counteracting regulatory effects of growth factors and amino acid levels.

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Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22020817 ◽

2021 ◽

Vol 22 (2) ◽

pp. 817

Author(s):

Junfang Yan ◽

Yi Xie ◽

Jing Si ◽

Lu Gan ◽

Hongyan Li ◽

...

Keyword(s):

Cell Growth ◽

Cell Survival ◽

Cell Fate ◽

Cellular Stress ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Dependent Manner ◽

Caspase Family ◽

Mediate Cell

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

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New Mammalian Target of Rapamycin (mTOR) Modulators Derived from Natural Product Databases and Marine Extracts by Using Molecular Docking Techniques

Marine Drugs ◽

10.3390/md16100385 ◽

2018 ◽

Vol 16 (10) ◽

pp. 385 ◽

Cited By ~ 9

Author(s):

Verónica Ruiz-Torres ◽

Maria Losada-Echeberría ◽

Maria Herranz-López ◽

Enrique Barrajón-Catalán ◽

Vicente Galiano ◽

...

Keyword(s):

Natural Products ◽

Molecular Docking ◽

Side Effects ◽

Inhibitory Activity ◽

Mammalian Target Of Rapamycin ◽

Therapeutic Use ◽

Cellular Growth ◽

Target Of Rapamycin ◽

Computational Techniques ◽

Chemical Derivatives

Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.

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Sialyltransferase ST3GAL6 mediates the effect of microRNA-26a on cell growth, migration, and invasion in hepatocellular carcinoma through the protein kinase B/mammalian target of rapamycin pathway

Cancer Science ◽

10.1111/cas.13128 ◽

2017 ◽

Vol 108 (2) ◽

pp. 267-276 ◽

Cited By ~ 14

Author(s):

Mingming Sun ◽

Xuzi Zhao ◽

Leilei Liang ◽

Xufeng Pan ◽

Hao Lv ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Kinase ◽

Cell Growth ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Migration And Invasion

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Mitochondrial General Control of Amino Acid Synthesis 5 Like 1 Regulates Glutaminolysis, Mammalian Target of Rapamycin Complex 1 Activity, and Murine Liver Regeneration

Hepatology ◽

10.1002/hep.30876 ◽

2019 ◽

Vol 71 (2) ◽

pp. 643-657 ◽

Cited By ~ 1

Author(s):

Lingdi Wang ◽

Lu Zhu ◽

Kaiyuan Wu ◽

Yong Chen ◽

Duck‐Yeon Lee ◽

...

Keyword(s):

Amino Acid ◽

Liver Regeneration ◽

Mammalian Target Of Rapamycin ◽

Acid Synthesis ◽

Target Of Rapamycin ◽

General Control ◽

Amino Acid Synthesis ◽

Murine Liver

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Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)

Biochemical Journal ◽

10.1042/bj20090489 ◽

2009 ◽

Vol 421 (1) ◽

pp. 29-42 ◽

Cited By ~ 318

Author(s):

Juan M. García-Martínez ◽

Jennifer Moran ◽

Rosemary G. Clarke ◽

Alex Gray ◽

Sabina C. Cosulich ◽

...

Keyword(s):

Protein Kinase ◽

Cell Growth ◽

Mammalian Target Of Rapamycin ◽

Specific Inhibitor ◽

Initiation Factor ◽

Target Of Rapamycin ◽

S6 Kinase ◽

Class 1 ◽

Hydrophobic Motif ◽

Ribosomal S6 Kinase

mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 (mTOR complex-1) phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of ∼10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 3-kinases) at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK (ribosomal S6 kinase), an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1 (3-phosphoinositide-dependent protein kinase-1). We interpret this as implying phosphorylation of Ser473 promotes phosphorylation of Thr308 and/or induces a conformational change that protects Thr308 from dephosphorylation. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) than rapamycin, even in mTORC2-deficient cells, suggesting a form of mTOR distinct from mTORC1, or mTORC2 phosphorylates 4E-BP1. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.

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