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; Sunghoon Kim

doi:10.1038/s41467-017-00785-0

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

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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 language	English
Article number	732
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00785-0
Publication status	Published - 2017 Dec 1

Bibliographical note

Publisher Copyright:
© 2017 The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-017-00785-0

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Kim, J. H., Lee, C., Lee, M., Wang, H., Kim, K., Park, S. J., Yoon, I., Jang, J., Zhao, H., Kim, H. K., Kwon, N. H., Jeong, S. J., Yoo, H. C., Kim, J. H., Yang, J. S., Lee, M. Y., Lee, C. W., Yun, J., Oh, S. J., ... Kim, S. (2017). Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction. Nature communications, 8(1), Article 732. https://doi.org/10.1038/s41467-017-00785-0

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

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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.",

author = "Kim, {Jong Hyun} and Chulho Lee and Minji Lee and Haipeng Wang and Kibum Kim and Park, {Seung Joon} and Ina Yoon and Jayun Jang and Hanchao Zhao and Kim, {Hoi Kyoung} and Kwon, {Nam Hoon} and Jeong, {Seung Jae} and Yoo, {Hee Chan} and Kim, {Jae Hyun} and Yang, {Jee Sun} and Lee, {Myeong Youl} and Lee, {Chang Woo} and Jieun Yun and Oh, {Soo Jin} and Kang, {Jong Soon} and Martinis, {Susan A.} and Hwang, {Kwang Yeon} and Min Guo and Gyoonhee Han and Han, {Jung Min} and Sunghoon Kim",

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AU - Kim, Jong Hyun

AU - Lee, Chulho

AU - Lee, Minji

AU - Wang, Haipeng

AU - Kim, Kibum

AU - Park, Seung Joon

AU - Yoon, Ina

AU - Jang, Jayun

AU - Zhao, Hanchao

AU - Kim, Hoi Kyoung

AU - Kwon, Nam Hoon

AU - Jeong, Seung Jae

AU - Yoo, Hee Chan

AU - Kim, Jae Hyun

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

PY - 2017/12/1

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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