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Volume 29, No 2, Feb 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 2, February 2019: 136-150   |  Open Access

ORIGINAL ARTICLES

Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

Lu Deng 1, Lei Chen 1,2,3, Linlin Zhao 1, Yan Xu 4, Xiaoping Peng 1, Xinbo Wang 1, Lin Ding 1, Jiali Jin 1, Hongqi Teng 1, Yanming Wang 1, Weijuan Pan 4, Fei Yu 1, Lujian Liao 4, Li Li 5, Xin Ge 6 and Ping Wang 1

1Tongji Unviersity Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, School of Life Sciences and Technolog, Tongji University, 200092 Shanghai, China; 2Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; 3College of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China; 4Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 200241 Shanghai, China; 5Institute of Aging Research, Hangzhou Normal University, 311121 Hangzhou, China and 6Department of Clinical Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 200072 Shanghai, China
 Correspondence: Correspondence: Ping Wang (wangp@tongji.edu.cn)These authors contributed equally: Lu Deng, Lei Chen

Mechanistic target of rapamycin mTOR complex 1 (mTORC1) plays a key role in the integration of various environmental signals to regulate cell growth and metabolism. mTORC1 is recruited to the lysosome where it is activated by its interaction with GTP-bound Rheb GTPase. However, the regulatory mechanism of Rheb activity remains largely unknown. Here, we show that ubiquitination governs the nucleotide-bound status of Rheb. Lysosome-anchored E3 ligase RNF152 catalyzes Rheb ubiquitination and promotes its binding to the TSC complex. EGF enhances the deubiquitination of Rheb through AKT-dependent USP4 phosphorylation, leading to the release of Rheb from the TSC complex. Functionally, ubiquitination of Rheb is linked to mTORC1-mediated signaling and consequently regulates tumor growth. Thus, we propose a mechanistic model whereby Rheb–mediated mTORC1 activation is dictated by a dynamic opposing act between Rheb ubiquitination and deubiquitination that are catalyzed by RNF152 and USP4 respectively.


https://doi.org/10.1038/s41422-018-0120-9

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