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The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11

Oncogene volume 27, pages 6845–6855 (2008)Cite this article

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

References

  • Anderson LR, Betarbet R, Gearing M, Gulcher J, Hicks AA, Stefansson K et al. (2007). PARK10 candidate RNF11 is expressed by vulnerable neurons and localizes to Lewy bodies in Parkinson disease brain. J Neuropathol Exp Neurol 66: 955–964.

    Article  CAS  Google Scholar 

  • Angers A, Ramjaun AR, McPherson PS . (2004). The HECT domain ligase itch ubiquitinates endophilin and localizes to the trans-Golgi network and endosomal system. J Biol Chem 279: 11471–11479.

    Article  CAS  Google Scholar 

  • Azmi P, Seth A . (2005). RNF11 is a multifunctional modulator of growth factor receptor signalling and transcriptional regulation. Eur J Cancer 41: 2549–2560.

    Article  CAS  Google Scholar 

  • Burger A, Amemiya Y, Kitching R, Seth AK . (2006). Novel RING E3 ubiquitin ligases in breast cancer. Neoplasia 8: 689–695.

    Article  CAS  Google Scholar 

  • Chen C, Matesic LE . (2007). The Nedd4-like family of E3 ubiquitin ligases and cancer. Cancer Metastasis Rev 26: 587–604.

    Article  CAS  Google Scholar 

  • Chen C, Sun X, Guo P, Dong XY, Sethi P, Cheng X et al. (2005). Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells. J Biol Chem 280: 41553–41561.

    Article  CAS  Google Scholar 

  • Chen C, Sun X, Guo P, Dong XY, Sethi P, Zhou W et al. (2007a). Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Oncogene 26: 2386–2394.

    Article  CAS  Google Scholar 

  • Chen C, Zhou Z, Ross JS, Zhou W, Dong JT . (2007b). The amplified WWP1 gene is a potential molecular target in breast cancer. Int J Cancer 121: 2834–2841.

    Google Scholar 

  • Courbard JR, Fiore F, Adelaide J, Borg JP, Birnbaum D, Ollendorff V . (2002). Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. J Biol Chem 277: 45267–45275.

    Article  CAS  Google Scholar 

  • Flasza M, Nguyen Huu NS, Mazaleyrat S, Clemence S, Villemant C, Clarke R et al. (2006). Regulation of the nuclear localization of the human Nedd4-related WWP1 protein by Notch. Mol Membr Biol 23: 269–276.

    Article  Google Scholar 

  • Hoeller D, Crosetto N, Blagoev B, Raiborg C, Tikkanen R, Wagner S et al. (2006). Regulation of ubiquitin-binding proteins by monoubiquitination. Nat Cell Biol 8: 163–169.

    Article  CAS  Google Scholar 

  • Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ, Glimcher LH . (2006). Regulation of adult bone mass by the zinc-finger adapter protein Schnurri-3. Science 312: 1223–1227.

    Article  CAS  Google Scholar 

  • Katz M, Shtiegman K, Tal-Or P, Yakir L, Mosesson Y, Harari D et al. (2002). Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and Hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4. Traffic 3: 740–751.

    Article  CAS  Google Scholar 

  • Kitching R, Wong MJ, Koehler D, Burger AM, Landberg G, Gish G et al. (2003). The RING-H2 protein RNF11 is differentially expressed in breast tumours and interacts with HECT-type E3 ligases. Biochim Biophys Acta 1639: 104–112.

    Article  CAS  Google Scholar 

  • Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K et al. (2004). Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23: 6914–6923.

    Article  CAS  Google Scholar 

  • Laine A, Ronai Z . (2007). Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 26: 1477–1483.

    Article  CAS  Google Scholar 

  • Li H, Seth A . (2004). An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein. Oncogene 23: 1801–1808.

    Article  CAS  Google Scholar 

  • Magnifico A, Ettenberg S, Yang C, Mariano J, Tiwari S, Fang S et al. (2003). WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation. J Biol Chem 278: 43169–43177.

    Article  CAS  Google Scholar 

  • Marchese A, Raiborg C, Santini F, Keen JH, Stenmark H, Benovic JL . (2003). The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell 5: 709–722.

    Article  CAS  Google Scholar 

  • Martin-Serrano J, Eastman SW, Chung W, Bieniasz PD . (2005). HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway. J Cell Biol 168: 89–101.

    Article  CAS  Google Scholar 

  • Moren A, Imamura T, Miyazono K, Heldin CH, Moustakas A . (2005). Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J Biol Chem 280: 22115–22123.

    Article  CAS  Google Scholar 

  • Mosser EA, Kasanov JD, Forsberg EC, Kay BK, Ney PA, Bresnick EH . (1998). Physical and functional interactions between the transactivation domain of the hematopoietic transcription factor NF-E2 and WW domains. Biochemistry 37: 13686–13695.

    Article  CAS  Google Scholar 

  • Murdaca J, Treins C, Monthouel-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E et al. (2004). Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. J Biol Chem 279: 26754–26761.

    Article  CAS  Google Scholar 

  • Plant PJ, Yeger H, Staub O, Howard P, Rotin D . (1997). The C2 domain of the ubiquitin protein ligase Nedd4 mediates Ca2+-dependent plasma membrane localization. J Biol Chem 272: 32329–32336.

    Article  CAS  Google Scholar 

  • Qiu L, Joazeiro C, Fang N, Wang HY, Elly C, Altman Y et al. (2000). Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem 275: 35734–35737.

    Article  CAS  Google Scholar 

  • Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N et al. (2005). Towards a proteome-scale map of the human protein–protein interaction network. Nature 437: 1173–1178.

    Article  CAS  Google Scholar 

  • Seo SR, Lallemand F, Ferrand N, Pessah M, L’Hoste S, Camonis J et al. (2004). The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J 23: 3780–3792.

    Article  CAS  Google Scholar 

  • Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY . (2004). Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol 22: 1567–1572.

    Article  CAS  Google Scholar 

  • Shen R, Chen M, Wang YJ, Kaneki H, Xing L, O’Keefe RJ et al. (2006). Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem 281: 3569–3576.

    Article  CAS  Google Scholar 

  • Subramaniam V, Li H, Wong M, Kitching R, Attisano L, Wrana J et al. (2003). The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase. Br J Cancer 89: 1538–1544.

    Article  CAS  Google Scholar 

  • Vecchione A, Marchese A, Henry P, Rotin D, Morrione A . (2003). The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol 23: 3363–3372.

    Article  CAS  Google Scholar 

  • Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME, Hunter T et al. (2003). Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol Cell 11: 249–259.

    Article  CAS  Google Scholar 

  • Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S et al. (2006). HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10: 25–38.

    Article  Google Scholar 

  • Woelk T, Oldrini B, Maspero E, Confalonieri S, Cavallaro E, Di Fiore PP et al. (2006). Molecular mechanisms of coupled monoubiquitination. Nat Cell Biol 8: 1246–1254.

    Article  CAS  Google Scholar 

  • Yarden Y . (2001). The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37 (Suppl 4): S3–S8.

    Article  CAS  Google Scholar 

  • Zhang X, Srinivasan SV, Lingrel JB . (2004). WWP1-dependent ubiquitination and degradation of the lung Kruppel-like factor, KLF2. Biochem Biophys Res Commun 316: 139–148.

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. The Center for Cell Biology and Cancer Research, MS355, Albany Medical College, Albany, NY, USA

    C Chen, Z Zhou, R Liu & Y Li

  2. Division of Molecular and Cellular Biology, and Department of Laboratory Medicine and Pathobiology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada

    P B Azmi & A K Seth

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  1. C Chen
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  2. Z Zhou
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  3. R Liu
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Correspondence to C Chen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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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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