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雷帕霉素增强 mTOR 的溶酶体积累。

Lysosomal accumulation of mTOR is enhanced by rapamycin.

机构信息

Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

出版信息

Histochem Cell Biol. 2010 Dec;134(6):537-44. doi: 10.1007/s00418-010-0759-x. Epub 2010 Nov 10.


DOI:10.1007/s00418-010-0759-x
PMID:21063721
Abstract

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth that integrates signals from growth factors and nutrients. Recent studies have shown that an mTOR-containing complex, mTORC1, is targeted to lysosomes in the presence of amino acids and activated by Rheb GTPase resident in that compartment. In this study, we found that treatment with the mTOR inhibitors rapamycin and Torin1 significantly enhanced lysosomal accumulation of mTOR and Raptor. This phenomenon was not observed in the absence of amino acids but was restored upon addition of L-leucine or protein synthesis inhibitors. mTOR was not concentrated in autophagosomes that were induced by rapamycin. These results suggest that the lysosome harbors both active and inactive forms of mTOR in the presence of amino acids.

摘要

哺乳动物雷帕霉素靶蛋白(mTOR)是细胞生长的关键调节剂,它整合了来自生长因子和营养物质的信号。最近的研究表明,在氨基酸存在的情况下,一种包含 mTOR 的复合物 mTORC1 被靶向到溶酶体,并被驻留在该隔室中的 Rheb GTPase 激活。在这项研究中,我们发现用 mTOR 抑制剂雷帕霉素和 Torin1 处理可显著增强 mTOR 和 Raptor 在溶酶体中的积累。在没有氨基酸的情况下没有观察到这种现象,但添加 L-亮氨酸或蛋白质合成抑制剂后即可恢复。mTOR 没有集中在由雷帕霉素诱导的自噬体中。这些结果表明,在氨基酸存在的情况下,溶酶体中既存在有活性的 mTOR 形式,也存在无活性的 mTOR 形式。

相似文献

[1]
Lysosomal accumulation of mTOR is enhanced by rapamycin.

Histochem Cell Biol. 2010-11-10

[2]
RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells.

Cell Signal. 2013-12-3

[3]
Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging.

J Biol Chem. 2013-12-11

[4]
Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment.

Mol Biol Cell. 2019-9-18

[5]
Amino acid signalling upstream of mTOR.

Nat Rev Mol Cell Biol. 2013-1-30

[6]
Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.

Cell. 2010-4-8

[7]
Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.

Elife. 2016-1-7

[8]
mTOR direct interactions with Rheb-GTPase and raptor: sub-cellular localization using fluorescence lifetime imaging.

BMC Cell Biol. 2013-1-12

[9]
Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome.

PLoS One. 2014-4-16

[10]
Mammalian target of rapamycin complex I (mTORC1) activity in ras homologue enriched in brain (Rheb)-deficient mouse embryonic fibroblasts.

PLoS One. 2013-11-26

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[3]
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J Cell Biol. 2021-2-1

[4]
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Exp Neurol. 2020-12

[5]
PtdIns3P controls mTORC1 signaling through lysosomal positioning.

J Cell Biol. 2017-12-4

[6]
Altered mTOR signalling in nephropathic cystinosis.

J Inherit Metab Dis. 2016-5

[7]
Lysosome biogenesis/scattering increases host cell susceptibility to invasion by Trypanosoma cruzi metacyclic forms and resistance to tissue culture trypomastigotes.

Cell Microbiol. 2015-12-27

[8]
Dynamic Visualization of mTORC1 Activity in Living Cells.

Cell Rep. 2015-3-17

[9]
Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion.

Cell Res. 2013-1-22

[10]
The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis.

Sci Signal. 2012-6-12

本文引用的文献

[1]
Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.

Cell. 2010-4-8

[2]
mTOR regulation of autophagy.

FEBS Lett. 2010-1-18

[3]
Dissecting the role of mTOR: lessons from mTOR inhibitors.

Biochim Biophys Acta. 2010-3

[4]
mTOR signaling: at the crossroads of plasticity, memory and disease.

Trends Neurosci. 2009-12-4

[5]
An emerging role of mTOR in lipid biosynthesis.

Curr Biol. 2009-12-1

[6]
Regulation mechanisms and signaling pathways of autophagy.

Annu Rev Genet. 2009

[7]
Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein.

J Biol Chem. 2009-5-8

[8]
Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathway.

FEBS Lett. 2009-3-18

[9]
An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.

J Biol Chem. 2009-3-20

[10]
Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor.

Biochem Soc Trans. 2009-2

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