Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction
| العنوان: | Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction |
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| المؤلفون: | Hee Chan Yoo, Seung Joon Park, Min Guo, Hoi Kyoung Kim, Hanchao Zhao, Myeong Youl Lee, Ina Yoon, Gyoonhee Han, Jong Soon Kang, Minji Lee, Chul-Ho Lee, Chang Woo Lee, Seung Jae Jeong, Jieun Yun, Kwang Yeon Hwang, Jong H. Kim, Haipeng Wang, Nam Hoon Kwon, Jee Sun Yang, Soo Jin Oh, Susan A. Martinis, Kibum Kim, Jae Hyun Kim, Jayun Jang, Jung Min Han, Sunghoon Kim |
| المصدر: | Nature Communications Nature communications, vol 8, iss 1 Nature Communications, Vol 8, Iss 1, Pp 1-15 (2017) NATURE COMMUNICATIONS(8) |
| بيانات النشر: | Nature Publishing Group UK, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Science, Nude, General Physics and Astronomy, Mice, Nude, Antineoplastic Agents, mTORC1, GTPase, Plasma protein binding, Biology, Mechanistic Target of Rapamycin Complex 1, Drug Screening Assays, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Mice, Leucine, Cell Line, Tumor, Neoplasms, Animals, Humans, lcsh:Science, PI3K/AKT/mTOR pathway, Inbred BALB C, Cancer, Monomeric GTP-Binding Proteins, Sirolimus, Mice, Inbred BALB C, Multidisciplinary, Tumor, Leucyl-tRNA synthetase, Leucine—tRNA ligase, General Chemistry, Antitumor, 030104 developmental biology, Biochemistry, lcsh:Q, Female, Leucine-tRNA Ligase, Signal transduction, biological phenomena, cell phenomena, and immunity, Drug Screening Assays, Antitumor, Protein Binding, Signal Transduction |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::333a7213363eeb8be9cf13c31daecbfe http://europepmc.org/articles/PMC5622079 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....333a7213363eeb8be9cf13c31daecbfe |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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