Abstract
The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a homologous to the E6-associated protein C terminus-type E3 ligase frequently overexpressed in human prostate and breast cancers due to gene amplification. Previous studies suggest that WWP1 promotes cell proliferation and survival; however, the mechanism of WWP1 action is still poorly understood. Here, we showed that WWP1 upregulates and maintains erythroblastic leukemia viral oncogene homolog 2 (ErbB2) and epithelial growth factor receptor (EGFR) in multiple cell lines. WWP1 depletion dramatically attenuates the EGF-induced ERK phosphorylation. WWP1 forms a protein complex with RING finger protein 11 (RNF11), a negative regulator of ErbB2 and EGFR. The protein–protein interaction is through the first and third WW domains of WWP1 and the PY motif of RNF11. Although WWP1 is able to ubiquitinate RNF11 in vitro and in vivo, WWP1 neither targets RNF11 for degradation nor changes RNF11's cellular localization. Importantly, inhibition of RNF11 can rescue WWP1 siRNA-induced ErbB2 and EGFR downregulation and growth arrest. Finally, we demonstrated that RNF11 is overexpressed in a panel of prostate and breast cancer cell lines with WWP1 expression. These findings suggest that WWP1 may promote cell proliferation and survival partially through suppressing RNF11-mediated ErbB2 and EGFR downregulation.
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Abbreviations
- EGFR:
-
epithelial growth factor receptor
- ErbB2:
-
erythroblastic leukemia viral oncogene homolog 2
- GST:
-
glutathione S-transferase
- HECT:
-
homologous to the E6-associated protein C terminus
- IHC:
-
immunohistochemistry
- IP:
-
immunoprecipitation
- mUb:
-
monoubiquitination
- RING:
-
really interesting new gene
- RNF11:
-
RING finger protein 11
- TGF-β:
-
transforming growth factor-β
- WT:
-
wild type
- WWP1:
-
WW domain containing E3 ubiquitin protein ligase 1
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Acknowledgements
We thank Dr Roger Y Tsien for the mCherry vector. This work was supported in part by a grant from American Cancer Society (Chen C), a grant from the Department of Defense Prostate Cancer Research Program (W81XWH-07-1-0191, Chen C), a grant (BCTR0503705) from the Susan G Komen Breast Cancer Foundation (Chen C), and from the Canadian Breast Cancer Research Alliance special program grant on metastasis to Arun Seth.
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Chen, C., Zhou, Z., Liu, R. et al. The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11. Oncogene 27, 6845–6855 (2008). https://doi.org/10.1038/onc.2008.288
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DOI: https://doi.org/10.1038/onc.2008.288
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