Related Experiment Video

Updated: Oct 17, 2025

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
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Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay

Published on: November 11, 2018

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The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS

Chuanchuan Li1, Alberto Vides1, Dongsung Kim1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA.

Science (New York, N.Y.)
|October 7, 2021
PubMed

Insights

KRASG12C inhibitors target the inactive form of the oncoprotein. This study reveals RGS3 enhances KRAS GTPase activity, explaining how these inhibitors work and targeting KRAS lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • KRASG12C inhibitors target the inactive guanosine diphosphate (GDP)–bound state.
  • GTPase-activating proteins (GAPs) normally enhance GTP hydrolysis, but KRAS mutations hinder this.
  • The mechanism for KRASG12C GTP hydrolysis enabling inhibition remained unclear.

Purpose of the Study:

  • To investigate the mechanism of KRASG12C inactivation.
  • To identify factors that enhance GTP hydrolysis in mutant KRAS.
  • To explain the efficacy of KRASG12C inhibitors.

Main Methods:

  • Investigated the interaction between RGS3 and KRAS proteins.
  • Assessed the GTPase activity of wild-type and mutant KRAS in the presence of RGS3.
  • Analyzed the role of RGS3 in KRAS inactivation.

Main Results:

  • RGS3, a known regulator of G protein–coupled receptors, also enhances the GTPase activity of KRAS.
  • RGS3 facilitates GTP hydrolysis for both wild-type and mutant KRAS proteins.
  • This finding provides a mechanism for KRASG12C inactivation.

Conclusions:

  • RGS3 unexpectedly acts as a GAP for KRAS, including the G12C mutant.
  • This mechanism explains the susceptibility of KRASG12C to emerging therapeutics.
  • Identifies RGS3 as a key player in KRAS regulation and a potential therapeutic target.

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