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Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

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 mechan...

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Detalles Bibliográficos
Autores principales: Deng, Lu, Chen, Lei, Zhao, Linlin, Xu, Yan, Peng, Xiaoping, Wang, Xinbo, Ding, Lin, Jin, Jiali, Teng, Hongqi, Wang, Yanming, Pan, Weijuan, Yu, Fei, Liao, Lujian, Li, Li, Ge, Xin, Wang, Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355928/
https://www.ncbi.nlm.nih.gov/pubmed/30514904
http://dx.doi.org/10.1038/s41422-018-0120-9
Descripción
Sumario: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.