Related Experiment Video

Updated: Jul 1, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex

Andreas Damianou1,2, Zhu Liang3,2, Frederik Lassen3,4

  • 1Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK andreas.damianou@ndm.ox.ac.uk.

Life Science Alliance
|March 7, 2024
PubMed

Insights

KRAS mutations in cancer disrupt its function as a molecular switch. This study reveals that specific KRAS mutations impair interaction with LZTR1, affecting protein levels and offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Proteomics

Background:

  • KRAS is a proto-oncogene frequently mutated in human cancers.
  • Activating KRAS mutations impair GTP hydrolysis, altering signaling pathways.
  • The precise downstream effects of KRAS mutations remain incompletely understood.

Purpose of the Study:

  • To profile the molecular environment of wild-type (WT) and oncogenic KRAS mutants.
  • To identify proteins differentially interacting with KRAS mutants.
  • To investigate the impact of KRAS mutations on protein turnover.

Main Methods:

  • APEX2 proximity labeling was employed to capture KRAS interactors.
  • Quantitative proteomics was used to analyze the labeled proteins.
  • The study compared WT KRAS with G12D, G13D, and Q61H mutants under different conditions.

Main Results:

  • Known KRAS interactors, including ARAF and LZTR1, were identified.
  • KRAS mutations (G12D, G13D, Q61H) abrogated the association with LZTR1.
  • This disruption affects KRAS protein turnover.

Conclusions:

  • KRAS mutations alter its molecular interactions, impacting protein stability.
  • The abrogation of LZTR1 association by KRAS mutations affects KRAS turnover.
  • Understanding LZTR1-mediated KRAS regulation may inform cancer therapies.

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