Signal Transduction Protein Synthesis and Degradation
Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation*

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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.

Background: Posttranslational regulation of rictor, a key partner of mTOR complex 2, and its underlying mechanism are largely undefined and thus are the focus of this study.

Results: FBXW7 interacts with rictor and mediates its degradation; this process requires phosphorylation of rictor at threonine 1695 by GSK3.

Conclusion: Rictor undergoes GSK3-dependent, FBXW7-mediated ubiquitination and proteasomal degradation.

Significance: A previously unknown mechanism underlying posttranslational regulation of rictor expression is suggested.

Akt PKB
mTOR complex (mTORC)
protein degradation
signal transduction
ubiquitylation (ubiquitination)
FBXW7
GSK3
rictor

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*

This work was supported by National Institutes of Health Grant R01 CA118450 (to S.-Y. S.) and R01 CA160522 (to S.-Y. S.).

1

Both authors share first authorship.

2

Georgia Research Alliance Distinguished Cancer Scientists.