共 48 条
Rictor Forms a Complex with Cullin-1 to Promote SGK1 Ubiquitination and Destruction
被引:88
作者:
Gao, Daming
[1
]
Wan, Lixin
[1
]
Inuzuka, Hiroyuki
[1
]
Berg, Anders H.
[1
]
Tseng, Alan
[1
]
Zhai, Bo
[2
]
Shaik, Shavali
[1
]
Bennett, Eric
[3
]
Tron, Adriana E.
[4
]
Gasser, Jessica A.
[1
]
Lau, Alan
[1
]
Gygi, Steven P.
[2
]
Harper, J. Wade
[3
]
DeCaprio, James A.
[4
]
Toker, Alex
[1
]
Wei, Wenyi
[1
]
机构:
[1] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA
基金:
美国国家卫生研究院;
关键词:
KINASE SGK;
PHOSPHORYLATION ANALYSIS;
AKT PHOSPHORYLATION;
SURVIVAL SIGNALS;
SERUM;
MTOR;
RAPTOR;
DEGRADATION;
TARGET;
IDENTIFICATION;
D O I:
10.1016/j.molcel.2010.08.016
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
The Rictor/mTOR complex (also known as mTORC2) plays a critical role in cellular homeostasis by phosphorylating AGC kinases such as Akt and SGK at their hydrophobic motifs to activate downstream signaling. However, the regulation of mTORC2 and whether it has additional function(s) remain largely unknown. Here, we report that Rictor associates with Cullin-1 to form a functional E3 ubiquitin ligase. Rictor, but not Raptor or mTOR alone, promotes SGK1 ubiquitination. Loss of Rictor/Cullin-1-mediated ubiquitination leads to increased SGK1 protein levels as detected in Rictor null cells. Moreover, as part of a feedback mechanism, phosphorylation of Rictor at 11135 by multiple AGC kinases disrupts the interaction between Rictor and Cullin-1 to impair SGK1 ubiquitination. These findings indicate that the Rictor/Cullin-1 E3 ligase activity is regulated by a specific signal relay cascade and that misregulation of this mechanism may contribute to the frequent overexpression of SGK1 in various human cancers.
引用
收藏
页码:797 / 808
页数:12
相关论文