Smith CJ, Berry DM, McGlade CJ

Activation of the 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 ...

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with Ubc13/Uev1a to form K63-linked chains in vitro. RNF126 and Rabring7 associate with the epidermal growth factor receptor (EGFR) through a ubiquitin binding zinc finger domain and both E3s promote ubiquitination 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. In addition, we show that the depletion of Rabring7 also 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 down regulation of membrane receptors.

Date: Feb. 15, 2013

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