Rictor undergoes GSK3-dependent, FBXW7-mediated ubiquitination and proteasomal degradation [Protein Synthesis and Degradation]

April 20th, 2015 by Koo, J., Wu, X., Mao, Z., Khuri, F. R., Sun, S.-Y.

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, knockout 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 GSK3: GSK3 was associated with rictor and directly phosphorylated the Thr1695 site in a putative CDC4 phospho-degron (CPD) 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 PKCalpha. Hence we suggest that PI3K/Akt signaling may positively regulate mTORC2 signaling, likely through suppressing GSK3-dependent rictor degradation.