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 KangSusan A. Martinis, Kwang Yeon Hwang, Min Guo, Gyoonhee Han, Jung Min Han, Sunghoon Kim

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article number732
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

Fingerprint

Amino Acyl-tRNA Synthetases
leucine
Leucine
cancer
catalytic activity
interactions
Catalyst activity
Neoplasms
sensors
mutations
inhibitors
GTP Phosphohydrolases
Sensors
Sirolimus
Growth
tumors
activation
Tumors
Chemical activation
Cells

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction. / Kim, Jong Hyun; Lee, Chulho; Lee, Minji; Wang, Haipeng; Kim, Kibum; Park, Seung Joon; Yoon, Ina; Jang, Jayun; Zhao, Hanchao; Kim, Hoi Kyoung; Kwon, Nam Hoon; Jeong, Seung Jae; Yoo, Hee Chan; Kim, Jae Hyun; Yang, Jee Sun; Lee, Myeong Youl; Lee, Chang Woo; Yun, Jieun; Oh, Soo Jin; Kang, Jong Soon; Martinis, Susan A.; Hwang, Kwang Yeon; Guo, Min; Han, Gyoonhee; Han, Jung Min; Kim, Sunghoon.

In: Nature Communications, Vol. 8, No. 1, 732, 01.12.2017.

Research output: Contribution to journalArticle

Kim, JH, Lee, C, Lee, M, Wang, H, Kim, K, Park, SJ, Yoon, I, Jang, J, Zhao, H, Kim, HK, Kwon, NH, Jeong, SJ, Yoo, HC, Kim, JH, Yang, JS, Lee, MY, Lee, CW, Yun, J, Oh, SJ, Kang, JS, Martinis, SA, Hwang, KY, Guo, M, Han, G, Han, JM & Kim, S 2017, 'Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction', Nature Communications, vol. 8, no. 1, 732. https://doi.org/10.1038/s41467-017-00785-0
Kim, Jong Hyun ; Lee, Chulho ; Lee, Minji ; Wang, Haipeng ; Kim, Kibum ; Park, Seung Joon ; Yoon, Ina ; Jang, Jayun ; Zhao, Hanchao ; Kim, Hoi Kyoung ; Kwon, Nam Hoon ; Jeong, Seung Jae ; Yoo, Hee Chan ; Kim, Jae Hyun ; Yang, Jee Sun ; Lee, Myeong Youl ; Lee, Chang Woo ; Yun, Jieun ; Oh, Soo Jin ; Kang, Jong Soon ; Martinis, Susan A. ; Hwang, Kwang Yeon ; Guo, Min ; Han, Gyoonhee ; Han, Jung Min ; Kim, Sunghoon. / Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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AU - Kim, Kibum

AU - Park, Seung Joon

AU - Yoon, Ina

AU - Jang, Jayun

AU - Zhao, Hanchao

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AU - Yoo, Hee Chan

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AU - Yang, Jee Sun

AU - Lee, Myeong Youl

AU - Lee, Chang Woo

AU - Yun, Jieun

AU - Oh, Soo Jin

AU - Kang, Jong Soon

AU - Martinis, Susan A.

AU - Hwang, Kwang Yeon

AU - Guo, Min

AU - Han, Gyoonhee

AU - Han, Jung Min

AU - Kim, Sunghoon

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