Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination

Curr Biol. 2010 Aug 10;20(15):1372-7. doi: 10.1016/j.cub.2010.06.051. Epub 2010 Jul 22.


Ras proteins play a central role in transducing signals that control cell proliferation, differentiation, motility, and survival. The location-specific signaling activity of Ras has been previously shown to be regulated by ubiquitination [1]. However, the molecular machinery that controls Ras ubiquitination has not been defined. Here we demonstrate through biochemical and functional analyses that Rabex-5 (also known as RabGEF1) [2, 3] functions as an E3 ligase for Ras. Rabex-5-mediated Ras ubiquitination promotes Ras endosomal localization and leads to the suppression of ERK activation. Moreover, the Ras effector RIN1 [4, 5] is required for Rabex-5-dependent Ras ubiquitination, suggesting a feedback mechanism by which Ras activation can be coupled to ubiquitination. These findings define new elements in the regulatory circuitry that link Ras compartmentalization to signaling output.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Endosomes / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Feedback, Physiological*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • ras Proteins / metabolism*


  • Guanine Nucleotide Exchange Factors
  • Intracellular Signaling Peptides and Proteins
  • RABGEF1 protein, human
  • RIN1 protein, human
  • Ubiquitin-Protein Ligases
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins