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

Jong Hyun Kim, Chulho Lee, Minji Lee, Haipeng Wang, Kibum Kim, Seung Joon Park, Ina Yoon, Jayun Jang, Hanchao Zhao, Hoi Kyoung Kim, Nam Hoon Kwon, Seung Jae Jeong, Hee Chan Yoo, Jae Hyun Kim, Jee Sun Yang, Myeong Youl Lee, Chang Woo Lee, Jieun Yun, Soo Jin Oh, Jong Soon Kang, Susan A. Martinis, Kwang Yeon Hwang, Min Guo, Gyoonhee Han, Jung Min Han () and Sunghoon Kim ()
Additional contact information
Jong Hyun Kim: College of Pharmacy, Seoul National University
Chulho Lee: Yonsei University
Minji Lee: Yonsei University
Haipeng Wang: The Scripps Research Institute, Scripps Florida
Kibum Kim: Yonsei University
Seung Joon Park: Yonsei University
Ina Yoon: College of Pharmacy, Seoul National University
Jayun Jang: College of Pharmacy, Seoul National University
Hanchao Zhao: University of Illinois at Urbana
Hoi Kyoung Kim: College of Pharmacy, Seoul National University
Nam Hoon Kwon: College of Pharmacy, Seoul National University
Seung Jae Jeong: College of Pharmacy, Seoul National University
Hee Chan Yoo: College of Pharmacy, Yonsei University
Jae Hyun Kim: Yonsei University
Jee Sun Yang: Yonsei University
Myeong Youl Lee: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology
Chang Woo Lee: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology
Jieun Yun: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology
Soo Jin Oh: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology
Jong Soon Kang: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology
Susan A. Martinis: University of Illinois at Urbana
Kwang Yeon Hwang: College of Life Sciences and Biotechnology, Korea University
Min Guo: The Scripps Research Institute, Scripps Florida
Gyoonhee Han: Yonsei University
Jung Min Han: Yonsei University
Sunghoon Kim: College of Pharmacy, Seoul National University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00785-0

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