Related Experiment Video

Updated: Jan 2, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

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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DIRAS3 (ARHI) Blocks RAS/MAPK Signaling by Binding Directly to RAS and Disrupting RAS Clusters

Margie N Sutton1, Zhen Lu1, Yao-Cheng Li2

  • 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cell Reports
|December 12, 2019
PubMed

Insights

DIRAS3 re-expression inhibits cancer growth by disrupting RAS protein clustering and signaling. This discovery offers a new strategy for targeting oncogenic RAS in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • Oncogenic RAS mutations are key drivers in numerous cancers.
  • RAS protein dimerization, multimerization, and clustering are linked to RAS signaling activation.

Purpose of the Study:

  • To investigate the role of DIRAS3, a tumor suppressor, in regulating RAS signaling.
  • To explore DIRAS3's potential as a therapeutic strategy against RAS-driven cancers.

Main Methods:

  • Assessing the effect of DIRAS3 re-expression on RAS/mitogen-activated protein kinase (MAPK) signaling.
  • Analyzing DIRAS3's interaction with RAS proteins (K-RAS and H-RAS) and its effect on clustering.
  • Evaluating the inhibition of cancer cell transformation, growth, and xenograft progression.

Main Results:

  • DIRAS3 re-expression inhibits RAS/MAPK signaling.
  • DIRAS3 directly interacts with RAS-forming heteromers, disrupting RAS clustering.
  • Disruption of K-RAS cluster formation depends on DIRAS3's N terminus and plasma membrane localization.
  • DIRAS3 inhibits cancer cell transformation, growth, and xenograft tumor progression.

Conclusions:

  • DIRAS3 suppresses oncogenic RAS signaling by disrupting RAS clustering.
  • DIRAS3's interaction with both K-RAS and H-RAS presents a potential therapeutic strategy for inhibiting oncogenic RAS function in various cancers.
Keywords:
ARHIDIRAS3RAS inhibitorclusterdimerheteromerovarian cancerpancreatic cancertransformation

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