Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction.

Abstract

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 T1135 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.

• Authors: Daming Gao, Lixin Wan, Hiroyuki Inuzuka, Anders H Berg, Alan Tseng, Bo Zhai, Shavali Shaik, Eric Bennett, Adriana E Tron, Jessica A Gasser, Alan Lau, Steven P Gygi, J Wade Harper, James A DeCaprio, Alex Toker, Wenyi Wei
• Journal: Molecular cell (Mol Cell) Vol. 39 Issue 5 Pg. 797-808 (Sep 10 2010) ISSN: 1097-4164 [Electronic] United States
• PMID: 20832730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• CRTC2 protein, human
• Carrier Proteins
• Cullin 1
• Cullin Proteins
• Immediate-Early Proteins
• Intracellular Signaling Peptides and Proteins
• RICTOR protein, human
• Rapamycin-Insensitive Companion of mTOR Protein
• Transcription Factors
• rictor protein, mouse
• MTOR protein, human
• mTOR protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Amino Acid Motifs
• Animals
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cullin Proteins (genetics, metabolism)
• Humans
• Immediate-Early Proteins (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Neoplasms (genetics, metabolism)
• Phosphorylation (physiology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Rapamycin-Insensitive Companion of mTOR Protein
• TOR Serine-Threonine Kinases
• Transcription Factors (genetics, metabolism)
• Ubiquitination