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Title 

Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction

Authors 

J H KimC LeeM LeeH WangK KimS J ParkI YoonJ JangH ZhaoH K KimN H KwonS J JeongH C YooJ S YangMyeong Youl LeeChang Woo LeeSoo Jin OhJong Soon KangS A MartinisK Y HwangM GuoG HanJ M HanS Kim

Publisher 

Nature Publishing Group

Issue Date 

2017

Citation 

Nature Communications

Abstract 

Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations

ISSN 

2041-1723

Link 

http://dx.doi.org/10.1038/s41467-017-00785-0

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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