Ubiquitination of Rheb governs growth factor-induced mTORC1 activation  

作　　者：Lu Deng Lei Chen Linlin Zhao Yan Xu Xiaoping Peng Xinbo Wang Lin Ding Jiali Jin Hongqi Teng Yanming Wang Weijuan Pan Fei Yu Lujian Liao Li Li Xin Ge Ping Wang 

机构地区：[1]Tongji Unviersity Cancer Center,Shanghai Tenth People's Hospital,School of Medicine,School of Life Sciences and Technolog,Tongji University,200092 Shanghai,China [2]Institute of Biophysics,Chinese Academy of Sciences,100101 Beijing,China [3]College of Life Sciences,University of Chinese Academy of Sciences,100049 Beijing,China [4]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,200241 Shanghai,China [5]Institute of Aging Research,Hangzhou Normal University,311121 Hangzhou,China [6]Department of Clinical Medicine,Shanghai Tenth People's Hospital,Tongji University School of Medicine,200072 Shanghai,China

出　　处：《Cell Research》2019年第2期136-150,共15页细胞研究（英文版）

基　　金：grants from the National Key Research and Development Program of China (2016YFC0902102);the National Natural Science Foundation of China (81625019,91440104,91519322,31600725,318300.53,and 31801177);the Science Technology Commission of Shanghai Municipality (16JC1404500);the Shanghai Sailing Program (18YF1419.500,18YF1419300);the Fundamental Research Funds for the Central Universities (22120180043,22120170212,and 22120180045).

摘　　要：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.

关 键 词：UBIQUITINATION RHEB governs growth factor-induced mTORC1 ACTIVATION 

分 类 号：Q[生物学]