Nrdp1 targets nascent ErbB3 receptor for ligand-dependent degradation by ERAD.

摘要

Ligand-induced downregulation of receptor tyrosine kinases has been intensively studied and involves receptor ubiquitination, internalization through clathrin-coated pits, and endocytic trafficking to the lysosome where the receptor is then degraded. Conversely, mechanisms controlling steady-state, or ligand-independent, levels of receptor tyrosine kinases remain poorly understood. Overexpression of ErbB receptors is particularly prevalent in breast cancer and while ErbB2 overexpression is known to be largely the result of genetic amplification, accumulating evidence indicates that the ErbB3 co- receptor becomes overexpressed due to loss of post-transcriptional regulation. We previously identified the RING-finger E3 ubiquitin ligase Neuregulin receptor degradation protein-1 (Nrdp1) as an ErbB3-interacting protein that mediates ubiquitination and degradation of ErbB3 receptor in a ligand-independent manner. Further studies by our group demonstrated that Nrdp1 expression is lost in human mammary tumors, coincident with ErbB3 overexpression, suggesting that loss of Nrdp1 suppresses steady-state ErbB3 receptor degradation. Here we demonstrate that Nrdp1 interacts exclusively with newly synthesized ErbB3 and mediates its ubiquitination and degradation via the endoplasmic-reticulum associated degradation (ERAD) pathway. Our results suggest a model of ligand-independent receptor degradation that is quite different from the canonical ligand-dependent model based on EGFR.