Differences in the regulation of K-Ras and H-Ras isoforms by monoubiquitination

J Biol Chem. 2013 Dec 27;288(52):36856-62. doi: 10.1074/jbc.C113.525691. Epub 2013 Nov 18.


Ras GTPases are signaling switches that control critical cellular processes including gene expression, differentiation, and apoptosis. The major Ras isoforms (K, H, and N) contain a conserved core GTPase domain, but have distinct biological functions. Among the three Ras isoforms there are clear differences in post-translational regulation, which contribute to differences in localization and signaling output. Modification by ubiquitination was recently reported to activate Ras signaling in cells, but the mechanisms of activation are not well understood. Here, we show that H-Ras is activated by monoubiquitination and that ubiquitination at Lys-117 accelerates intrinsic nucleotide exchange, thereby promoting GTP loading. This mechanism of Ras activation is distinct from K-Ras monoubiquitination at Lys-147, which leads to impaired regulator-mediated GTP hydrolysis. These findings reveal that different Ras isoforms are monoubiquitinated at distinct sites, with distinct mechanisms of action, but with a common ability to chronically activate the protein in the absence of a receptor signal or oncogenic mutation.

Keywords: GTPase; Monoubiquitination; Oncogene; Post-translational Modification; Protein Chemical Modification; Ras; Signal Transduction; Ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Activation / physiology
  • Guanosine Triphosphate / genetics
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mutation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction / physiology*
  • Ubiquitination / physiology*
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Isoenzymes
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Guanosine Triphosphate
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins