Back to Search
Start Over
Ubiquitination of Rheb governs growth factor-induced mTORC1 activation
- Source :
- Cell Research
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- 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.
- Subjects :
- Male
Ubiquitin-Protein Ligases
Mice, Nude
mTORC1
Mechanistic Target of Rapamycin Complex 1
Biology
Transfection
Article
Gene Knockout Techniques
Mice
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Animals
Humans
Molecular Biology
Mechanistic target of rapamycin
030304 developmental biology
Mice, Knockout
Sirolimus
0303 health sciences
HEK 293 cells
Ubiquitination
Cell Biology
HCT116 Cells
Xenograft Model Antitumor Assays
Tumor Burden
Cell biology
Ubiquitin ligase
HEK293 Cells
biology.protein
Intercellular Signaling Peptides and Proteins
Phosphorylation
Ras Homolog Enriched in Brain Protein
Ubiquitin-Specific Proteases
biological phenomena, cell phenomena, and immunity
Colorectal Neoplasms
Lysosomes
030217 neurology & neurosurgery
Deubiquitination
RHEB
Subjects
Details
- ISSN :
- 17487838 and 10010602
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Cell Research
- Accession number :
- edsair.doi.dedup.....5041b550b19bf90de15157285ecb0ab2