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

Abstract	HER3/ErbB3, a member of the epidermal growth factor receptor (EGFR) family, has a pivotal role in cancer and is emerging as a therapeutic 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, we demonstrated that the C-terminal tail of HER3 interacted with the WW domains of NEDD4 and the interaction was independent of neuregulin-1. Short hairpin RNA knockdown of NEDD4 elevated HER3 levels and resulted in increased HER3 signaling and cancer cell proliferation in vitro and in vivo. A similar inverse relationship between HER3 and NEDD4 levels was observed in prostate cancer tumor tissues. More importantly, the upregulated HER3 expression by NEDD4 knockdown sensitized cancer cells for growth inhibition by an anti-HER3 antibody. Taken together, our results suggest that low NEDD4 levels may predict activation of HER3 signaling and efficacies of anti-HER3 antibody therapies.
Authors	Z Huang, B-K Choi, K Mujoo, X Fan, M Fa, S Mukherjee, N Owiti, N Zhang, Z An
Journal	Oncogene (Oncogene) Vol. 34 Issue 9 Pg. 1105-15 (Feb 26 2015) ISSN: 1476-5594 [Electronic] England
PMID	24662824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Endosomal Sorting Complexes Required for Transport NRG1 protein, human Neuregulin-1 RNA, Small Interfering Nedd4 Ubiquitin Protein Ligases Nedd4 protein, human Nedd4l protein, mouse Ubiquitin-Protein Ligases ERBB3 protein, human Receptor, ErbB-3
Topics	Animals Binding Sites (drug effects) CHO Cells Cell Line, Tumor Cell Proliferation (drug effects) Cricetulus Endosomal Sorting Complexes Required for Transport (chemistry, metabolism) Gene Knockdown Techniques HEK293 Cells Humans MCF-7 Cells Mice Mice, Nude Nedd4 Ubiquitin Protein Ligases Neoplasm Transplantation Neoplasms (metabolism, pathology) Neuregulin-1 (metabolism) RNA, Small Interfering (pharmacology) Receptor, ErbB-3 (chemistry, metabolism) Signal Transduction (drug effects) Ubiquitin-Protein Ligases (chemistry, metabolism) Ubiquitination

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!