Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation
Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation
Rictor, an essential component of mTOR complex 2 (mTORC2), plays a pivotal role in regulating mTOR signaling and other biological functions. Posttranslational regulation of rictor (e.g. via degradation) and its underlying mechanism are largely undefined and thus are the focus of this study. Chemical inhibition of the proteasome increased rictor ubiquitination and levels. Consistently, inhibition of FBXW7 with various genetic means including knockdown, knock-out, and enforced expression of a dominant-negative mutant inhibited rictor ubiquitination and increased rictor levels, whereas enforced expression of FBXW7 decreased rictor stability and levels. Moreover, we detected an interaction between FBXW7 and rictor. Hence, rictor is degraded through an FBXW7-mediated ubiquitination/proteasome mechanism. We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability. Finally, enforced activation of Akt enhanced rictor levels and increased mTORC2 activity as evidenced by increased formation of mTORC2 and elevated phosphorylation of Akt, SGK1, and PKCα. Hence we suggest that PI3K/Akt signaling may positively regulate mTORC2 signaling, likely through suppressing GSK3-dependent rictor degradation.
- Emory Healthcare United States
- Winship Cancer Institute United States
- Emory University United States
Binding Sites, F-Box-WD Repeat-Containing Protein 7, F-Box Proteins, Amino Acid Motifs, Cell Cycle Proteins, Mechanistic Target of Rapamycin Complex 2, Gene Expression Regulation, Neoplastic, Glycogen Synthase Kinase 3, HEK293 Cells, Rapamycin-Insensitive Companion of mTOR Protein, Gene Expression Regulation, Cell Line, Tumor, Multiprotein Complexes, Mutation, Humans, Phosphorylation, RNA, Small Interfering, Carrier Proteins, Plasmids, Protein Binding
Binding Sites, F-Box-WD Repeat-Containing Protein 7, F-Box Proteins, Amino Acid Motifs, Cell Cycle Proteins, Mechanistic Target of Rapamycin Complex 2, Gene Expression Regulation, Neoplastic, Glycogen Synthase Kinase 3, HEK293 Cells, Rapamycin-Insensitive Companion of mTOR Protein, Gene Expression Regulation, Cell Line, Tumor, Multiprotein Complexes, Mutation, Humans, Phosphorylation, RNA, Small Interfering, Carrier Proteins, Plasmids, Protein Binding
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