Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors Academic Article uri icon


MeSH Major

  • Models, Molecular
  • Protein Binding
  • Proto-Oncogene Proteins
  • Ubiquitination
  • ras Proteins


  • The guanosine triphosphate (GTP)--loaded form of the guanosine triphosphatase (GTPase) Ras initiates multiple signaling pathways by binding to various effectors, such as the kinase Raf and phosphatidylinositol 3-kinase (PI3K). Ras activity is increased by guanine nucleotide exchange factors that stimulate guanosine diphosphate release and GTP loading and is inhibited by GTPase-activating proteins that stimulate GTP hydrolysis. KRAS is the most frequently mutated RAS gene in cancer. Here, we report that monoubiquitination of lysine-147 in the guanine nucleotide-binding motif of wild-type K-Ras could lead to enhanced GTP loading. Furthermore, ubiquitination increased the binding of the oncogenic Gly12Val mutant of K-Ras to the downstream effectors PI3K and Raf. Thus, monoubiquitination could enhance GTP loading on K-Ras and increase its affinity for specific downstream effectors, providing a previously unidentified mechanism for Ras activation.

publication date

  • March 8, 2011



  • Academic Article



  • eng

PubMed Central ID

  • PMC3437993

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2001518

PubMed ID

  • 21386094

Additional Document Info

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  • ra13


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