Correction: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.

Thoreen, Carson C.; Kang, Seong A.; Chang, Jae Won; Liu, Qingsong; Zhang, Jianming; Gao, Yi; Reichling, Laurie J.; Sim, Taebo; Sabatini, David M.; Gray, Nathanael S.

doi:10.1074/jbc.aac120.012837

Cited by 5 publications

(3 citation statements)

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“…Only TORC1 is highly sensitive to rapamycin, while TORC2 is either insensitive, or sensitive, to rapamycin only after long exposure to the drug [12,[20][21][22][23]. The use of rapamycin to probe mTORC1-dependent activities has played an important role in accelerating our understanding of mTORC1 signaling, although it should be borne in mind that TORC1 executes both rapamycin-sensitive and -insensitive functions [24,25]. TOR-specific ATP-competitive inhibitors that inhibit both TORC1 and TORC2 are also available and are being tested in clinical trials [26].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee

Weisman

2020

Genes

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The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic stability. TOR affects nuclear functions indirectly through its activity in the cytoplasm, but also directly through active nuclear TOR pools. The mechanisms by which TOR regulates its nuclear functions are less well-understood compared with its cytoplasmic activities. TOR is an important pharmacological target for several diseases, including cancer, metabolic and neurological disorders. Thus, studies of the nuclear functions of TOR are important for our understanding of basic biological processes, as well as for clinical implications.

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Section: Introductionmentioning

confidence: 99%

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee

Weisman

2020

Genes

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“…The role of Rapamycin in inhibiting the mTOR phosphorylation had been described previously by Ballou and Lin ( 56 ), and Thoreen et al. ( 57 ) ( 56 , 58 ). We have also reported that Rapamycin inhibits phosphorylation of p-S6, which is the activation state of m-TOR and upregulated in presence of infection ( Figure 3D ).…”

Section: Discussionmentioning

confidence: 76%

Gefitinib Results in Robust Host-Directed Immunity Against Salmonella Infection Through Proteo-Metabolomic Reprogramming

et al. 2021

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The global rise of antibiotic-resistant strains of Salmonella has necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against Salmonella. Further, using the proteome analysis of Salmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of Salmonella via mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of Salmonella within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by Salmonella infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against Salmonella infection and might be useful for the treatment of other intracellular infections.

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“…In mammalian cells, the upstream amino acids signal through specific sensors such as GATOR2 (GAP activity towards Rags 2) which activate TOR when amino acids are abundant. In both yeast and mammals, the inactivation of TORC1 induces autophagy, even in nutrient-replete conditions, indicating that TOR negatively regulates autophagy [95][96][97].…”

Section: Upstream Regulators Of Torc1mentioning

confidence: 99%

Analysis of the effect of autophagy on lipid content and the impact of vps45-3 point mutation on plant growth in Arabidopsis thaliana

Mugume

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Target of rapamycin (TOR) is an evolutionarily conserved serine/threonine kinase that senses and integrates signals from the environment to coordinate developmental and metabolic processes. TOR senses nutrients, hormones, metabolites, and stress signals to promote cell and organ growth when conditions are favorable. However, TOR is inhibited when conditions are unfavorable, promoting catabolic processes such as autophagy. Autophagy is a macromolecular degradation pathway by which cells degrade and recycle cytoplasmic materials. TOR negatively regulates autophagy through phosphorylation of ATG13, preventing activation of the autophagyinitiating ATG1-ATG13 kinase complex. Here we review TOR complex composition and function in photosynthetic and non-photosynthetic organisms. We also review recent developments in the identification of upstream TOR activators and downstream effectors of TOR. Finally, we discuss recent developments in our understanding of the regulation of autophagy by TOR in photosynthetic organisms.

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Correction: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.

Abstract: There was an error in Fig. 4A. The immunoblot for total levels of S6K was mistakenly duplicated for both WT and rictor Ϫ/Ϫ MEFs. This error has now been corrected and does not affect the results or conclusions of this work. Figure 4A. ADDITIONS AND CORRECTIONS 2886

Cited by 5 publications

References 0 publications

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Gefitinib Results in Robust Host-Directed Immunity Against Salmonella Infection Through Proteo-Metabolomic Reprogramming

Analysis of the effect of autophagy on lipid content and the impact of vps45-3 point mutation on plant growth in Arabidopsis thaliana

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