Phosphorylation of Rictor at Thr1135 impairs the Rictor/Cullin-1 complex to ubiquitinate SGK1

doi:10.1007/s13238-010-0123-x

Prot Cell

2010, Vol. 1

Issue (10) : 881-885 https://doi.org/10.1007/s13238-010-0123-x PMID: 21204013

PERSPECTIVE

Phosphorylation of Rictor at Thr1135 impairs the Rictor/Cullin-1 complex to ubiquitinate SGK1

Daming Gao, Lixin Wan, Wenyi Wei(

)

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

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Abstract

The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism, cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase. However, its upstream regulatory pathways as well as whether it has additional function(s) remain largely unknown. We recently reported that Rictor contains a novel ubiquitin E3 ligase activity by forming a novel complex with Cullin-1, but not with other Cullin family members. Furthermore, we identified SGK1 as its downstream target. Interestingly, Rictor, but not Raptor or mTOR, promotes SGK1 ubiquitination. As a result, SGK1 expression is elevated in Rictor^--/-- MEFs. We further defined that as a feedback mechanism, Rictor can be phosphorylated by multiple AGC family kinases including Akt, S6K and SGK1. Phosphorylation of Rictor at the Thr1135 site did not affect its kinase activity towards phosphorylating its conventional substrates including Akt and SGK1. On the other hand, it disrupted the interaction between Rictor and Cullin-1. Consequently, T1135E Rictor was defective in promoting SGK1 ubiquitination and destruction. This finding further expands our knowledge of Rictor’s function. Furthermore, our work also illustrates that Rictor E3 ligase activity could be governed by specific signaling kinase cascades, and that misregulation of this process might contribute to SGK overexpression which is frequently observed in various types of cancers.

Keywords mTORC2 Rictor kinase E3 ubiqutin ligase Cullin-1 SGK1

Corresponding Author(s): Wei Wenyi,Email:wwei2@bidmc.harvard.edu

Issue Date: 01 October 2010

Cite this article:

Daming Gao,Lixin Wan,Wenyi Wei. Phosphorylation of Rictor at Thr1135 impairs the Rictor/Cullin-1 complex to ubiquitinate SGK1[J]. Prot Cell, 2010, 1(10): 881-885.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-010-0123-x
https://academic.hep.com.cn/pac/EN/Y2010/V1/I10/881

Fig.1 By association with a distinct subset of co-factors, Rictor can acquire either kinase or E3 ubiquitin ligase activity.
(A) In association with mTOR, Sin1 and GβL, Rictor could form the mTORC2 complex, which is a Ser/Thr protein kinase complex that could phosphorylate Akt at Ser473 and SGK at Ser422, leading to their full activation. (B) Rictor could form a novel complex with Cullin-1 and Rbx1 to promote SGK1 ubiquitination. It remains unclear whether Skp1, F-box or other unidentified components are also involved in SGK1 ubiquitination.

Fig.2 Phosphorylation of Rictor at Thr1135 minimally affects the mTORC2 kinase activity, but severely impairs the E3 ligase activity of the Rictor/Cullin-1 complex.
In low AGC kinase activity conditions (such as serum starvation condition), mTORC2 activity is low. As a result, neither Akt nor SGK is in its activated state, and the majority of Rictor is not phosphorylated at Thr1135. Non-phosphorylated Rictor forms a complex with Cullin-1 and Rbx-1 to promote SGK1 ubiquitination and degradation. In high AGC kinase activity conditions, mTORC2 complex activity is high, leading to phosphorylation of Akt at Ser473 and SGK1 at Ser422. This modification fully activates both Akt and SGK1, both of which are capable of phosphorylating Rictor at Thr1135. Phosphorylation of Rictor at Thr1135 dissociates Rictor from Cullin-1, thus leading to inactivation of the Rictor/Cullin-1 E3 ligase complex and stabilization of the SGK1 protein.

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