Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway

Minji Lee, Jong Hyun Kim, Ina Yoon, Chulho Lee, Mohammad Fallahi Sichani, Jong Soon Kang, Jeonghyun Kang, Min Guo, Kang Young Lee, Gyoonhee Han, Sunghoon Kim, Jung Min Han

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating “ON” switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an “OFF” switch by controlling GTP hydrolysis of RagB in the Rag GTPase–mTORC1 axis. The LRS–RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP–GDP cycle of the RagD–RagB pair, rather than the RagC–RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD–RagB pair can overcome the absence of the RagC–RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD–RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acid-sensing mechanism.

Original languageEnglish
Pages (from-to)E5279-E5288
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number23
DOIs
Publication statusPublished - 2018 Jun 5

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Amino Acyl-tRNA Synthetases
GTP Phosphohydrolases
Leucine
Guanosine Triphosphate
leucylleucine
Hydrolysis
Autophagy
Growth
Neoplasms
Proteins
mechanistic target of rapamycin complex 1
Amino Acids
Enzymes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, Minji ; Kim, Jong Hyun ; Yoon, Ina ; Lee, Chulho ; Sichani, Mohammad Fallahi ; Kang, Jong Soon ; Kang, Jeonghyun ; Guo, Min ; Lee, Kang Young ; Han, Gyoonhee ; Kim, Sunghoon ; Han, Jung Min. / Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 23. pp. E5279-E5288.
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abstract = "A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating “ON” switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an “OFF” switch by controlling GTP hydrolysis of RagB in the Rag GTPase–mTORC1 axis. The LRS–RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP–GDP cycle of the RagD–RagB pair, rather than the RagC–RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD–RagB pair can overcome the absence of the RagC–RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD–RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acid-sensing mechanism.",
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Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway. / Lee, Minji; Kim, Jong Hyun; Yoon, Ina; Lee, Chulho; Sichani, Mohammad Fallahi; Kang, Jong Soon; Kang, Jeonghyun; Guo, Min; Lee, Kang Young; Han, Gyoonhee; Kim, Sunghoon; Han, Jung Min.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 23, 05.06.2018, p. E5279-E5288.

Research output: Contribution to journalArticle

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AU - Lee, Minji

AU - Kim, Jong Hyun

AU - Yoon, Ina

AU - Lee, Chulho

AU - Sichani, Mohammad Fallahi

AU - Kang, Jong Soon

AU - Kang, Jeonghyun

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AU - Lee, Kang Young

AU - Han, Gyoonhee

AU - Kim, Sunghoon

AU - Han, Jung Min

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