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Regulation of RAS oncogenicity by acetylation

Moon Hee Yang1, Seth Nickerson, Eric T Kim

  • 1Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 20, 2012
PubMed

Insights

RAS acetylation on lysine 104 negatively regulates its activity by impacting the Switch II domain. This finding suggests targeting RAS acetylation as a potential cancer therapy.

Area of Science:

  • Cellular signaling and signal transduction pathways.
  • Molecular mechanisms of protein regulation.
  • Cancer biology and therapeutic targets.

Background:

  • RAS small GTPases are key regulators of cellular responses to external signals.
  • RAS activity is influenced by subcellular localization and nucleotide binding, which are modulated by posttranslational modifications.
  • Understanding these regulatory mechanisms is crucial for deciphering cancer development.

Purpose of the Study:

  • To identify and characterize novel posttranslational modifications of RAS proteins.
  • To investigate the functional and structural consequences of RAS acetylation.
  • To explore the therapeutic potential of targeting RAS acetylation in cancer.

Main Methods:

  • Utilized molecular dynamics simulations to model the effects of acetylation on RAS.
  • Employed acetylation-mimetic mutations in K-RAS4B for functional studies.
  • Assessed guanine nucleotide exchange factor (GEF)-induced nucleotide exchange in vitro.
  • Evaluated the impact of acetylation on RAS transforming activity.

Main Results:

  • Identified lysine 104 as a novel site of RAS posttranslational acetylation.
  • Demonstrated that acetylation of lysine 104 affects the conformational stability of the RAS Switch II domain.
  • Showed that acetylation-mimetic mutations suppress GEF-induced nucleotide exchange and inhibit in vitro transforming activity.
  • Established lysine acetylation as a negative regulatory modification of RAS.

Conclusions:

  • RAS acetylation on lysine 104 is a critical regulatory mechanism impacting RAS signaling.
  • The conformational changes induced by acetylation impair RAS interaction with guanine nucleotide exchange factors.
  • Targeting RAS acetylation presents a promising novel therapeutic strategy for cancers with RAS mutations.

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