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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 
 Proceedings of the National Academy of Sciences of the United States of America, Vol.115(23) : E5279-e5288, 2018 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
Issue Date
GTPase-activating protein ; Rag GTPase ; Sestrin2 ; leucyl-tRNA synthetase ; mTORC1
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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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Jeonghyun(강정현) ORCID logo https://orcid.org/0000-0001-7311-6053
Lee, Kang Young(이강영)
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