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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·2017·Nature Communications
DOI 10.1038/s41467-017-00785-0PMC PMC5622079
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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.

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Metadata

Authors
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., Kang, J. S., Martinis, S. A., Hwang, K. Y., Guo, M., Han, G., Han, J. M., & Kim, S.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-09-29
Volume
8
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-017-00785-0
PMC
PMC5622079
Cited by
88
References
8
Language
en
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