| First Author | Deng L | Year | 2019 |
| Journal | Cell Res | Volume | 29 |
| Issue | 2 | Pages | 136-150 |
| PubMed ID | 30514904 | Mgi Jnum | J:298778 |
| Mgi Id | MGI:6488685 | Doi | 10.1038/s41422-018-0120-9 |
| Citation | Deng L, et al. (2019) Ubiquitination of Rheb governs growth factor-induced mTORC1 activation. Cell Res 29(2):136-150 |
| abstractText | 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. |
