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mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of RICTOR.

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Wrobel, Lidia 
Siddiqi, Farah H 
Hill, Sandra M 
Son, Sung Min 


The mechanistic target of rapamycin complex 2 (mTORC2) controls cell metabolism and survival in response to environmental inputs. Dysregulation of mTORC2 signaling has been linked to diverse human diseases, including cancer and metabolic disorders, highlighting the importance of a tightly controlled mTORC2. While mTORC2 assembly is a critical determinant of its activity, the factors regulating this event are not well understood, and it is unclear whether this process is regulated by growth factors. Here, we present data, from human cell lines and mice, describing a mechanism by which growth factors regulate ubiquitin-specific protease 9X (USP9X) deubiquitinase to stimulate mTORC2 assembly and activity. USP9X removes Lys63-linked ubiquitin from RICTOR to promote its interaction with mTOR, thereby facilitating mTORC2 signaling. As mTORC2 is central for cellular homeostasis, understanding the mechanisms regulating mTORC2 activation toward its downstream targets is vital for our understanding of physiological processes and for developing new therapeutic strategies in pathology.



RICTOR, USP9X, growth factor signaling, mTORC2, mechanistic target of rapamycin complex 2, posttranslational modification, ubiquitin-specific protease 9X, Animals, Cell Line, Tumor, Female, Gene Expression Regulation, Gene Knockdown Techniques, HEK293 Cells, HeLa Cells, Humans, Intercellular Signaling Peptides and Proteins, Male, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Protein Binding, Protein Processing, Post-Translational, Rapamycin-Insensitive Companion of mTOR Protein, Signal Transduction, Ubiquitin Thiolesterase, Ubiquitination

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Cell Rep

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Elsevier BV