Related Experiment Video

Updated: Nov 23, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.5K

mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of RICTOR

Lidia Wrobel1, Farah H Siddiqi1, Sandra M Hill1

  • 1Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, Cambridge, UK.

Cell Reports
|December 30, 2020
PubMed

Insights

Growth factors stimulate mechanistic target of rapamycin complex 2 (mTORC2) assembly and activity. This occurs via ubiquitin-specific protease 9X (USP9X) deubiquitinase, which promotes RICTOR and mTOR interaction, crucial for cell metabolism and survival.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin complex 2 (mTORC2) is crucial for cell metabolism and survival.
  • Dysregulation of mTORC2 signaling is implicated in cancer and metabolic disorders.
  • Factors regulating mTORC2 assembly and activity remain incompletely understood, particularly the role of growth factors.

Purpose of the Study:

  • To elucidate the mechanism by which growth factors regulate mTORC2 assembly and activity.
  • To identify key molecular players involved in growth factor-mediated mTORC2 regulation.

Main Methods:

  • Experiments were conducted using human cell lines and mice.
  • Investigated the role of ubiquitin-specific protease 9X (USP9X) in mTORC2 regulation.
  • Analyzed the effect of USP9X on RICTOR ubiquitination and its interaction with mTOR.

Main Results:

  • Growth factors were found to regulate USP9X deubiquitinase activity.
  • USP9X was shown to remove Lys63-linked ubiquitin from RICTOR.
  • This deubiquitination event promotes the interaction between RICTOR and mTOR, facilitating mTORC2 assembly and signaling.

Conclusions:

  • A novel mechanism for growth factor-mediated mTORC2 activation has been identified.
  • USP9X plays a critical role in promoting mTORC2 assembly by regulating RICTOR ubiquitination.
  • Understanding this pathway is vital for comprehending cellular homeostasis and developing therapeutic strategies for diseases linked to mTORC2 dysregulation.
Keywords:
RICTORUSP9Xgrowth factor signalingmTORC2mechanistic target of rapamycin complex 2posttranslational modificationubiquitin-specific protease 9X

More Related Videos

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates09:47

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates

Published on: May 10, 2022

2.9K
In Vitro Analysis of E3 Ubiquitin Ligase Function06:06

In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

5.7K

Related Concept Videos

Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.8K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
4.7K
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
8.1K
Regulated Protein Degradation02:58

Regulated Protein Degradation

2.8K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
5.9K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.8K