The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor

J Cell Sci. 2013 Mar 15;126(Pt 6):1366-80. doi: 10.1242/jcs.116129. Epub 2013 Feb 15.


Activation of the epidermal growth factor receptor (EGFR) results in internalization and ubiquitin-dependent endosomal sorting, leading to lysosomal degradation. Here we describe the role of the RING-finger-domain-containing protein RNF126 and the related protein, Rabring7 in EGFR endosomal sorting. We demonstrate that RNF126 specifies K48-linked chains with UbcH5b and also functions with Ubc13/Uev1a to form K63-linked chains in vitro. RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In the absence of c-Cbl or in cells expressing Cbl-70Z, the binding of RNF126 and Rabring7 to the EGFR is reduced, suggesting that RNF126 and Rabring7 function downstream of c-Cbl. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. In addition, depletion of RNF126 or Rabring7 destabilizes ESCRT-II and reduces the number of multivesicular bodies formed after EGF stimulation. We also show that the depletion of Rabring7 attenuates the degradation of MET and that both RNF126 and Rabring7 regulate the sorting of CXCR4 from an early endocytic compartment. Together these data suggest that RNF126 and Rabring7 play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors.

Keywords: E3 ubiquitin ligase; Epidermal growth factor receptor; K63 ubiquitin; Multi-vesicular endosome; RNF126; Rabring7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endosomes / metabolism*
  • ErbB Receptors / metabolism*
  • Fibroblasts / metabolism*
  • Gene Knockdown Techniques
  • Genetic Engineering
  • HeLa Cells
  • Humans
  • Mice
  • Mutation / genetics
  • Protein Transport
  • Proteolysis
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, CXCR4 / metabolism
  • Transgenes / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism


  • CXCR4 protein, mouse
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Proto-Oncogene Proteins c-cbl
  • RNF115 protein, human
  • RNF126 protein, human
  • Ubiquitin-Protein Ligases
  • ErbB Receptors
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3