The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling

Z Huang, B-K Choi, K Mujoo, X Fan, M Fa, S Mukherjee, N Owiti, N Zhang and Z AnHER3/ErbB3, a member of the epidermal growth factor receptor (EGFR) family, has a pivotal role in cancer and is emerging as atherapeutic antibody target. In this study, we identified NEDD4 (neural precursor cell expressed, developmentally downregulated 4)as a novel interaction partner and ubiquitin E3 ligase of human HER3. Using molecular and biochemical approaches, wedemonstrated that the C-terminal tail of HER3 interacted with the WW domains of NEDD4 and the interaction was independent ofneuregulin-1. Short hairpin RNA knockdown of NEDD4 elevated HER3 levels and resulted in increased HER3 signaling and cancercell proliferation in vitro and in vivo. A similar inverse relationship between HER3 and NEDD4 levels was observed in prostate cancertumor tissues. More importantly, the upregulated HER3 expression by NEDD4 knockdown sensitized cancer cells for growthinhibition by an anti-HER3 antibody. Taken together, our results suggest that low NEDD4 levels may predict activation of HER3signaling and efficacies of anti-HER3 antibody therapies.Oncogene advance online publication, 24 March 2014; doi:10.1038/onc.2014.56INTRODUCTIONHER3 is a member of the human epidermal growth factor receptor(EGFR) family of tyrosine kinases.