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

Oncogene volume 34, pages 1105–1115 (2015)Cite this article

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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.

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Acknowledgements

We thank Dr Hui Deng for help on cell cultures; Professor Renping Zhou and Dr Kendra Carmon for critical comments on the manuscript; Dr Stephen Hewitt of NIH/NCI for providing the prostate cancer clinical samples; and Dr Rabih Said for interpretation of immunohistochemistry experiments. The work was partially funded by grants from the Texas Emerging Technology Fund, Johnson and Johnson, and the Welch Foundation grant no. AU00024 to ZA.

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Authors and Affiliations

  1. Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    Z Huang, B-K Choi, K Mujoo, X Fan, M Fa, S Mukherjee, N Owiti, N Zhang & Z An

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  1. Z Huang
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Huang, Z., Choi, BK., Mujoo, K. et al. The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling. Oncogene 34, 1105–1115 (2015). https://doi.org/10.1038/onc.2014.56

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