Related Experiment Video

Updated: Jun 2, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

17.8K

Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development

Han Koo1,2, Kyung Chan Park1,2, Hyun Ahm Sohn1

  • 1Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.

Nature Communications
|January 17, 2025
PubMed

Insights

KRAS-mutant cancers rely on NDRG3 protein for growth. Inhibiting the KRAS-NDRG3 interaction through deubiquitination by USP9X offers a new therapeutic strategy for KRAS-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Activating KRAS mutations are common in cancers but difficult to treat.
  • Targeting KRAS remains a significant challenge in oncology.

Purpose of the Study:

  • To investigate the post-translational regulation of KRAS protein.
  • To identify novel therapeutic strategies for KRAS-driven cancers.

Main Methods:

  • Investigated the interaction between KRAS, NDRG3, and USP9X.
  • Utilized conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma.
  • Employed dominant-negative NDRG3 fragments to disrupt KRAS-NDRG3 interaction.

Main Results:

  • NDRG3 scaffolds KRAS and USP9X, promoting KRAS deubiquitination and up-regulation.
  • KRAS protein expression, signaling, and growth are dependent on NDRG3 in KRAS-mutant cells.
  • NDRG3 depletion suppressed Kras protein expression and pancreatic intraepithelial neoplasia in vivo.
  • Disrupting the KRAS-NDRG3 interaction suppressed KRAS protein expression and cancer cell growth.

Conclusions:

  • KRAS protein deubiquitination by USP9X/NDRG3 is critical for KRAS-driven cancer development.
  • Targeting the KRAS-NDRG3 interaction presents a promising therapeutic approach for KRAS-addicted cancers.

More Related Videos

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein07:08

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

5.6K
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

3.0K

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.1K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K
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...
3.4K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
3.9K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
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...
2.4K