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
共 48 条
[1]   A probability-based approach for high-throughput protein phosphorylation analysis and site localization [J].
Beausoleil, Sean A. ;
Villen, Judit ;
Gerber, Scott A. ;
Rush, John ;
Gygi, Steven P. .
NATURE BIOTECHNOLOGY, 2006, 24 (10) :1285-1292
[2]   Ubiquitin-proteasome degradation of serum- and glucocorticoid-regulated kinase-1 (SGK-1) is mediated by the chaperone-dependent E3 ligase CHIP [J].
Belova, Larissa ;
Sharma, Sanjay ;
Brickley, Deanna R. ;
Nicolarsen, Jeremy R. ;
Patterson, Cam ;
Conzen, Suzanne D. .
BIOCHEMICAL JOURNAL, 2006, 400 (02) :235-244
[3]   Transformation of human and murine fibroblasts without viral oncoproteins [J].
Boehm, JS ;
Hession, MT ;
Bulmer, SE ;
Hahn, WC .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (15) :6464-6474
[4]   A novel N-terminal hydrophobic motif mediates constitutive degradation of serum- and glucocorticoid-induced kinase-1 by the ubiquitin-proteasome pathway [J].
Bogusz, Agata M. ;
Brickley, Deanna R. ;
Pew, Travis ;
Conzen, Suzanne D. .
FEBS JOURNAL, 2006, 273 (13) :2913-2928
[5]   Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1) [J].
Brickley, DR ;
Mikosz, CA ;
Hagan, CR ;
Conzen, SD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (45) :43064-43070
[6]   Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a) [J].
Brunet, A ;
Park, J ;
Tran, H ;
Hu, LS ;
Hemmings, BA ;
Greenberg, ME .
MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (03) :952-965
[7]   SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 [J].
Carrano, AC ;
Eytan, E ;
Hershko, A ;
Pagano, M .
NATURE CELL BIOLOGY, 1999, 1 (04) :193-199
[8]   Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis [J].
Chiang, CW ;
Kanies, C ;
Kim, KW ;
Fang, WB ;
Parkhurst, C ;
Xie, MH ;
Henry, T ;
Yang, E .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (18) :6350-6362
[9]   Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery [J].
Datta, SR ;
Dudek, H ;
Tao, X ;
Masters, S ;
Fu, HA ;
Gotoh, Y ;
Greenberg, ME .
CELL, 1997, 91 (02) :231-241
[10]   Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression [J].
Debonneville, C ;
Flores, SY ;
Kamynina, E ;
Plant, PJ ;
Tauxe, C ;
Thomas, MA ;
Münster, C ;
Chraïbi, A ;
Pratt, JH ;
Horisberger, JD ;
Pearce, D ;
Loffing, J ;
Staub, O .
EMBO JOURNAL, 2001, 20 (24) :7052-7059