Molecular mechanisms of mTOR regulation by stress

Heberle, Alexander Martin; Prentzell, Mirja Tamara; Eunen, Karen van; Bakker, Barbara M.; Grellscheid, Sushma Nagaraja; Thedieck, Kathrin

doi:10.4161/23723548.2014.970489

Cited by 71 publications

(97 citation statements)

References 247 publications

(197 reference statements)

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“…It was reported that there is a crosstalk between ER stress and mTOR signaling in diverse cell types [19, 20]. Firstly, we detected increase of phosphorylated mTOR at Ser2448, not Ser2481 in HG-treated cells compared to NG and MN control (Fig.…”

Section: Resultsmentioning

confidence: 55%

“…It was reported that oxidative stress and ER stress pathways participate in Aldo-induced podocyte injury [18]. Notably, research shows that a cross talk exists between ER stress and the mammalian target of rapamycin (mTOR) signaling, another important signaling pathway that regulates cell survival [19, 20]. In podocytes, mTOR complex 2/Akt/NFκB-mediated activation of selective calcium ion channel protein TRPC6 involves in adriamycin-induced apoptosis [21].…”

Section: Introductionmentioning

confidence: 99%

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High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Lei

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanisms by which high glucose (HG) results in podocyte damage remains unclear. We investigated the potential role of endoplasmic reticulum (ER) stress and mTOR signaling in HG injured podocyte. Methods: In cultured mouse podocytes, cellular apoptosis was assessed using FITC-Annexin V and propidium iodide staining followed by flow cytometry analysis. Apoptosis-related proteins as well as the ER stress and the mTOR signals were evaluated using immunoblot assay. Results: Compared to normal glucose (NG) and osmotic mannitol (MN) control, the percentage of apoptotic cells was increased significantly in HG-treated podocytes. The levels of CHOP, Grp78, phospho-PERKThr982, and caspase-12 were increased significantly following HG treatment. The downstream effects of ER stress were obtained in HG-treated podocytes, showing upregulation of Bax, Bak and cytochrome c, and downregulation of Bcl-2. HG-induced increase of cytochrome c, Bax and active caspase-3 was prevented by both ER inhibitor sodium 4-phenylbultyrate (PBA) and CHOP siRNA (siCHOP). PBA and CHOP knockdown remarkably decreased HG-induced apoptosis. In addition, the levels of phospho-mTORSer2448 and phospho- p70S6kThr389 as well as phospho-AMPKα (a sensor of energy consumption) were increased significantly in HG-treated cells. Moreover, the Erk inhibitor U0126 prevented HG-induced mTOR activation. Increased phospho-AMPKα, CHOP and Grp78 as well as cellular apoptosis were prevented by mTOR inhibitor rapamycin in HG-treated podocytes. Conclusion: Our data demonstrate that the activated mTOR by Erk1/2 results in energy consumption, which in turn leads to ER stress signaling and thus induces apoptosis in HG-treated podocytes.

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Section: Resultsmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Lei

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

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“…Among them is RPS6KB (p70)/p70-S6K (ribosomal protein S6 kinase B 70 kDa) which is phosphorylated at threonine 389 (T389) by MTORC1 10,18,20 . In turn, RPS6KB (p70) activates protein synthesis by promoting expression of ribosomal components, 21 and by phosphorylating translation initiation factors and components of the ribosomal machinery, including RPS6 (ribosomal protein S6) 19 . Little is known about PLK1′s role in the MTORC1 pathway.…”

Section: Introductionmentioning

confidence: 99%

PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy

et al. 2017

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Mechanistic target of rapamycin complex 1 (MTORC1) and polo like kinase 1 (PLK1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1′s and PLK1′s functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro. PLK1 and MTORC1 reside together at lysosomes, the subcellular site where MTORC1 is active. Consistent with an inhibitory role of PLK1 toward MTORC1, PLK1 overexpression inhibits lysosomal association of the PLK1-MTORC1 complex, whereas PLK1 inhibition promotes lysosomal localization of MTOR. PLK1-MTORC1 binding is enhanced by amino acid starvation, a condition known to increase autophagy. MTORC1 inhibition is an important step in autophagy activation. Consistently, PLK1 inhibition mitigates autophagy in cancer cells both under nutrient starvation and sufficiency, and a role of PLK1 in autophagy is also observed in the invertebrate model organism Caenorhabditis elegans. In summary, PLK1 inhibits MTORC1 and thereby positively contributes to autophagy. Since autophagy is increasingly recognized to contribute to tumor cell survival and growth, we propose that cautious monitoring of MTORC1 and autophagy readouts in clinical trials with PLK1 inhibitors is needed to develop strategies for optimized (combinatorial) cancer therapies targeting MTORC1, PLK1, and autophagy.

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“…mTORC1 activates anabolic processes, including protein synthesis and inhibits catabolic processes such as autophagy, which safeguards the cell to maintain protein homoeostasis1357. mTORC1 exerts these effects by phosphorylating several substrates, including the kinases p70-S6K (ribosomal protein S6 kinase) and ULK1 (Unc-51-like kinase-1).…”

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confidence: 99%

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

et al. 2016

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Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.

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Molecular mechanisms of mTOR regulation by stress

Cited by 71 publications

References 247 publications

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

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