Regulation of RAS oncogenicity by acetylation

Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):10843-8. doi: 10.1073/pnas.1201487109. Epub 2012 Jun 18.

Abstract

Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Genes, ras / physiology*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanosine Triphosphate / chemistry
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysine / metabolism
  • Mutagenesis, Site-Directed
  • Prenylation / physiology
  • Protein Processing, Post-Translational / physiology*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary / physiology
  • Structure-Activity Relationship
  • ras Proteins / chemistry*
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Guanine Nucleotide Exchange Factors
  • Guanosine Triphosphate
  • ras Proteins
  • Lysine