scholarly journals A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling

2007 ◽  
Vol 403 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Greg M. Findlay ◽  
Lijun Yan ◽  
Julia Procter ◽  
Virginie Mieulet ◽  
Richard F. Lamb
Keyword(s):  
Amino Acids ◽  
Growth Factor ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Signalling Pathway ◽  
Initiation Factor ◽  
S6 Kinase ◽  
Eukaryotic Initiation Factor 4E ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

The mTOR (mammalian target of rapamycin) signalling pathway is a key regulator of cell growth and is controlled by growth factors and nutrients such as amino acids. Although signalling pathways from growth factor receptors to mTOR have been elucidated, the pathways mediating signalling by nutrients are poorly characterized. Through a screen for protein kinases active in the mTOR signalling pathway in Drosophila we have identified a Ste20 family member (MAP4K3) that is required for maximal S6K (S6 kinase)/4E-BP1 [eIF4E (eukaryotic initiation factor 4E)-binding protein 1] phosphorylation and regulates cell growth. Importantly, MAP4K3 activity is regulated by amino acids, but not the growth factor insulin and is not regulated by the mTORC1 inhibitor rapamycin. Our results therefore suggest a model whereby nutrients signal to mTORC1 via activation of MAP4K3.

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

2009 ◽  
Vol 421 (1) ◽  
pp. 29-42 ◽  
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.

scholarly journals Nutrient-responsive mTOR signalling grows on Sterile ground

2007 ◽  
Vol 403 (1) ◽  
Author(s):  
Simon J. Cook ◽  
Simon J. Morley
Keyword(s):  
Amino Acids ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Growth ◽  
Cell Size ◽  
Protein Translation ◽  
Small Gtpase ◽  
Mtor Activity ◽  
Mtor Signalling

The control of cell growth, that is cell size, is largely controlled by mTOR (the mammalian target of rapamycin), a large serine/threonine protein kinase that regulates ribosome biogenesis and protein translation. mTOR activity is regulated both by the availability of growth factors, such as insulin/IGF-1 (insulin-like growth factor 1), and by nutrients, notably the supply of certain key amino acids. The last few years have seen a remarkable increase in our understanding of the canonical, growth factor-regulated pathway for mTOR activation, which is mediated by the class I PI3Ks (phosphoinositide 3-kinases), PKB (protein kinase B), TSC1/2 (the tuberous sclerosis complex) and the small GTPase, Rheb. However, the nutrient-responsive input into mTOR is important in its own right and is also required for maximal activation of mTOR signalling by growth factors. Despite this, the details of the nutrient-responsive signalling pathway(s) controlling mTOR have remained elusive, although recent studies have suggested a role for the class III PI3K hVps34. In this issue of the Biochemical Journal, Findlay et al. demonstrate that the protein kinase MAP4K3 [mitogen-activated protein kinase kinase kinase kinase-3, a Ste20 family protein kinase also known as GLK (germinal centre-like kinase)] is a new component of the nutrient-responsive pathway. MAP4K3 activity is stimulated by administration of amino acids, but not growth factors, and this is insensitive to rapamycin, most likely placing MAP4K3 upstream of mTOR. Indeed, MAP4K3 is required for phosphorylation of known mTOR targets such as S6K1 (S6 kinase 1), and overexpression of MAP4K3 promotes the rapamycin-sensitive phosphorylation of these same targets. Finally, knockdown of MAP4K3 levels causes a decrease in cell size. The results suggest that MAP4K3 is a new component in the nutrient-responsive pathway for mTOR activation and reveal a completely new function for MAP4K3 in promoting cell growth. Given that mTOR activity is frequently deregulated in cancer, there is much interest in new strategies for inhibition of this pathway. In this context, MAP4K3 looks like an attractive drug target since inhibitors of this enzyme should switch off mTOR, thereby inhibiting cell growth and proliferation, and promoting apoptosis.

A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway

2003 ◽  
Vol 8 (1) ◽  
pp. 65-79 ◽  
Author(s):  
Naoki Kimura ◽  
Chiharu Tokunaga ◽  
Sushila Dalal ◽  
Christine Richardson ◽  
Ken-ichi Yoshino ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mammalian Target Of Rapamycin ◽  
Signalling Pathway ◽  
Target Of Rapamycin ◽  
Amp Activated Protein Kinase ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

scholarly journals Cucurbitacin E inhibits osteosarcoma cells proliferation and invasion through attenuation of PI3K/AKT/mTOR signalling pathway

2016 ◽  
Vol 36 (6) ◽  
Author(s):  
Ying Wang ◽  
Shumei Xu ◽  
Yaochi Wu ◽  
Junfeng Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Signalling Pathway ◽  
Cell Counting ◽  
Cell Cycle Distribution ◽  
Mesenchymal Transition ◽  
Cucurbitacin E ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Cucurbitacin E (CuE), a potent member of triterpenoid family isolated from plants, has been confirmed as an antitumour agent by inhibiting proliferation, migration and metastasis in diverse cancer. However, the effects and mechanisms of CuE on osteosarcoma (OS) have not been well understood. The present study aimed to test whether CuE could inhibit growth and invasion of OS cells and reveal its underlying molecular mechanism. After various concentrations of CuE treatment, the anti-proliferative effect of CuE was assessed using the cell counting Kit-8 assay. Flow cytometry analysis was employed to measure apoptosis of OS cells. Cell cycle distribution was analysed by propidium iodide staining. Transwell assay was performed to evaluate the effect of CuE on invasion potential of OS cells. The protein levels were measured by western blot. In addition, the potency of CuE on OS cells growth inhibition was assessed in vivo. Our results showed that CuE inhibited cell growth and invasion, induced a cell cycle arrest and triggered apoptosis and modulated the expression of cell growth, cell cycle and cell apoptosis regulators. Moreover, CuE inhibited the PI3K/Akt/mTOR pathway and epithelial–mesenchymal transition (EMT), which suppressed the invasion and metastasis of OS. In addition, we also found that CuE inhibited OS cell growth in vivo. Taken together, our study demonstrated that CuE could inhibit OS tumour growth and invasion through inhibiting the PI3K/Akt/mTOR signalling pathway. Our findings suggest that CuE can be considered to be a promising anti-cancer agent for OS.

scholarly journals Amino acid sensing and mTOR regulation: inside or out?

2009 ◽  
Vol 37 (1) ◽  
pp. 248-252 ◽  
Author(s):  
Deborah C.I. Goberdhan ◽  
Margret H. Ögmundsdóttir ◽  
Shubana Kazi ◽  
Bruno Reynolds ◽  
Shivanthy M. Visvalingam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Environmental Conditions ◽  
Detection System ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Sensing ◽  
The Impact ◽  
Mtor Signalling

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

scholarly journals MicroRNA‑138 modulates glioma cell growth, apoptosis and invasion through the suppression of the AKT/mTOR signalling pathway by targeting CREB1

2020 ◽  
Vol 44 (6) ◽  
pp. 2559-2568
Author(s):  
Chi Zhang ◽  
Qi Wang ◽  
Xiaowen Zhou ◽  
Lei Zhang ◽  
Ying Yao ◽  
...  
Keyword(s):  
Cell Growth ◽  
Glioma Cell ◽  
Signalling Pathway ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

scholarly journals Distinct Signaling Events Downstream of mTOR Cooperate To Mediate the Effects of Amino Acids and Insulin on Initiation Factor 4E-Binding Proteins

2005 ◽  
Vol 25 (7) ◽  
pp. 2558-2572 ◽  
Author(s):  
Xuemin Wang ◽  
Anne Beugnet ◽  
Mirei Murakami ◽  
Shinya Yamanaka ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Tissue Growth ◽  
Mtor Signaling ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Terminal Site ◽  
New Strategies

ABSTRACT Signaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes phosphorylation at multiple sites. Here we show that amino acids regulate the N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a rapamycin-insensitive manner. Several criteria indicate this reflects a rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated phosphorylation of the C-terminal site Ser64/65 is generally sensitive to rapamycin, as is phosphorylation of another well-characterized target for mTOR signaling, S6K1. Our data imply that it is unlikely that mTOR directly phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows no such preference. These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling.

Mammalian target of rapamycin/eukaryotic initiation factor 4F pathway regulates follicle growth and development of theca cells in mice

2017 ◽  
Vol 29 (4) ◽  
pp. 768 ◽  
Author(s):  
Chao Zhang ◽  
Xiao-Ran Liu ◽  
Yong-Chun Cao ◽  
Jin-Ling Tian ◽  
Di Zhen ◽  
...  
Keyword(s):  
Growth And Development ◽  
Mammalian Target Of Rapamycin ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Follicle Growth ◽  
Thecal Cell ◽  
Thecal Cells ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

The aim of the present study was to clarify the roles of the mammalian target of rapamycin (mTOR) signalling pathway in follicular growth and development of thecal cells. Using in vivo-grown and in vitro-cultured ovaries, histological changes were evaluated using haematoxylin and eosin (HE) staining. Differentially expressed genes (DEGs) from 0 day post partum (d.p.p.) to 8 d.p.p. ovaries were screened by microarray and verified by quantitative real-time polymerase chain reaction. Forty-two DEGs related to cell proliferation and differentiation were screened out, with most DEGs being related to the to mTOR signalling pathway. Then, 3 d.p.p. ovaries were retrieved and used to verify the role of mTOR signalling in follicle and thecal cell development using its activators (Ras homologue enriched in brain (Rheb) and GTP) and inhibitor (rapamycin). The development of follicles and thecal cells was significantly impaired in ovaries cultured in vitro Day 3 to Day 8. In in vitro-cultured ovaries, Rheb and GTP (is 100 ng mL–1 Rheb and 500 ng mL–1 GTP for 48 h) significantly increased follicle diameter, the percentage of primary and secondary follicles and the umber of thecal cells, and upregulated expression of mTOR, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), eukaryotic initiation factor (eIF) 4F and cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1). Rapamycin (10 nM rapamycin for 24 h) had opposite effects to those of Rheb and GTP, and partly abrogated (significant) the effects of Rheb and GTP when added to the culture in combination with these drugs. Thus, mTOR signalling plays an important role in follicle growth and thecal cell development.

scholarly journals Leucine supplementation during late gestation globally altered placental metabolism and nutrient transport via modulation of the PI3K/AKT/mTOR signalling pathway

2021 ◽  
Author(s):  
Chang Cui ◽  
Caichi Wu ◽  
Pengwei Zhu ◽  
Jun Wang ◽  
Ziwei Ma ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Nutrient Transport ◽  
Signalling Pathway ◽  
Late Gestation ◽  
Control Group ◽  
Nutrient Transporters ◽  
Leucine Supplementation ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Abstract Background Our previous study found that sow dietary leucine supplementation signicicantly improved fetal intrauterine growth and newborn piglet birth weight. But we still have limited knowledge how leucine regulated placental functions to promote the nutrient supply to fetus to support its intrauterine development. Methods 150 sows at day 90 of gestiation were divided into three groups and fed with either control diet (CON), CON + 0.4% Leu or CON + 0.8% Leu separately until parturition. Placental metabolomics, full spectrum amino acids and nutrient transporters were systematically analyzed. Results Leu supplementation lead to an altered placental metabolism with higher amount of metabolites related to glycolysis and fatty acids oxidatation, and more amino acids accumulation in placenta. Besides, nutrient transporters including amino acids transporters, glucose transporters and fatty acids transporters in placenta were globally enhanced and several enzymes related to energy metabolism including hexokinase, succinatede hydrogenase, lactated hydrogenase, glycogen phosphorylase and hydroxyaryl-CoA-dehydrogenase were significantly increased with no change in antioxidative status in the groups with Leu supplementation. Futhermore, Leu supplementation significantly increased phosphalation of PI3K, Akt, and mTOR in placenta compared with control group. Conclusions Leu supplementation during late gestation globally altered placental metabolism, nutrient transport (amino acids, glucose, and fatty acids) via modulation of the PI3K/Akt/mTOR signalling pathway.

A dose escalation, single arm, phase Ib/II combination study of BEZ235 with everolimus to determine the safety, pharmacodynamics, and pharmacokinetics in subjects with advanced solid malignancies including glioblastoma multiforme.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3116-TPS3116
Author(s):  
Mohamad Adham Salkeni ◽  
Muhammad Shaalan Beg ◽  
Olugbenga Olanrele Olowokure ◽  
Hassana Fathallah ◽  
Hala Thomas ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Competitive Inhibitor ◽  
Initiation Factor ◽  
Phase 2 ◽  
S6 Kinase ◽  
Eukaryotic Initiation Factor 4E ◽  
Solid Malignancies ◽  
Phase 1B

TPS3116 Background: Downregulation of a number of signaling pathways, including the mammalian target of rapamycin (mTOR) pathway, has been demonstrated to be efficacious in a large range of solid tumors such as breast, colon, endometrial, glial and hepatocellular carcinoma (HCC). However, we find that rapamycins lead to suppression of a negative feedback loop from S6 Kinase 1 (S6K1) to Protein Kinase B (PKB), leading to hyperactivation of PKB. In pre-clinical studies using a mouse model of carcinogen-induced HCC, we have demonstrated that combining BEZ235 (a potent and highly selective reversible ATP site competitive inhibitor of PI3K and mTOR) with everolimus (an allosteric inhibitor of mTOR) synergizes to inhibit tumor growth. BEZ235, an orally administered agent, has demonstrated preliminary antitumor activity in a first-in-human phase I study. The current study will evaluate this combination in patients with a variety of solid malignancies that includes glioblastoma multiforme (GBM). Methods: This study is divided into a phase 1b portion designed to determine safety of increasing doses of the combination, with extensive pharmacokinetics, pharmacodynamics and pharmacogenomics analysis; and a phase 2 portion that includes both solid tumors and GBM based on predominance of the mTOR and PI3K deregulation in these tumors, to determine preliminary anti-tumor activity and the recommended dose for phase 2 studies. We will also integrate biomarker assessment for gene expression products of the mTOR downstream pathway such as eukaryotic initiation factor 4E binding protein (4EBP1) and S6 kinase (S6K). The phase 1b portion has started accruing.

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