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Nat Commun. 2017 Sep 29;8(1):732. doi: 10.1038/s41467-017-00785-0.

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

Author information

1
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, 08826, South Korea.
2
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seodaemun-gu, Seoul, 03722, South Korea.
3
Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul, 03722, South Korea.
4
Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL, 33458, USA.
5
Department of Biochemistry, University of Illinois at Urbana, Urbana, IL, 61820, USA.
6
College of Pharmacy, Yonsei University, Seodaemun-gu, Seoul, 03722, South Korea.
7
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, 363-883, South Korea.
8
Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul, 136-701, South Korea.
9
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seodaemun-gu, Seoul, 03722, South Korea. jhan74@yonsei.ac.kr.
10
College of Pharmacy, Yonsei University, Seodaemun-gu, Seoul, 03722, South Korea. jhan74@yonsei.ac.kr.
11
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, 08826, South Korea. sungkim@snu.ac.kr.
12
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Gwanak-gu, Seoul, 08826, South Korea. sungkim@snu.ac.kr.

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.Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.

PMID:
28963468
PMCID:
PMC5622079
DOI:
10.1038/s41467-017-00785-0
[Indexed for MEDLINE]
Free PMC Article

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