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Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression

Oncogene volume 31, pages 4599–4608 (2012)Cite this article

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Abstract

Once stimulated, the epidermal growth factor receptor (EGFR) undergoes self-phosphorylation, which, on the one hand, instigates signaling cascades, and on the other hand, recruits CBL ubiquitin ligases, which mark EGFRs for degradation. Using RNA interference screens, we identified a deubiquitinating enzyme, Cezanne-1, that opposes receptor degradation and enhances EGFR signaling. These functions require the catalytic- and ubiquitin-binding domains of Cezanne-1, and they involve physical interactions and transphosphorylation of Cezanne-1 by EGFR. In line with the ability of Cezanne-1 to augment EGF-induced growth and migration signals, the enzyme is overexpressed in breast cancer. Congruently, the corresponding gene is amplified in approximately one third of mammary tumors, and high transcript levels predict an aggressive disease course. In conclusion, deubiquitination by Cezanne-1 curtails degradation of growth factor receptors, thereby promotes oncogenic growth signals.

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Acknowledgements

We thank the Tissue Bank of the National Center for Tumor Diseases, Heidelberg University Hospital (Heidelberg, Germany). Our research is supported by grants from the National Cancer Institute (5R37CA072981, CCSG and P30 CA16672), the European Commission, the German-Israeli Project Cooperation, the Israel Cancer Research Fund, the Dr Miriam and Sheldon G Adelson Medical Research Foundation and the MD Moross Institute for Cancer Research. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

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Authors and Affiliations

  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    F Pareja, D A Ferraro, C Rubin, H Cohen-Dvashi, N Ben-Chetrit, G Pines, W Köstler, S Carvalho, S Lavi & Y Yarden

  2. Department of Systems Biology, The University of Texas MD Anderson Cancer Center Box 950, Houston, TX, USA

    F Zhang & G B Mills

  3. Institute of Pathology, Heidelberg University, Heidelberg, Germany

    S Aulmann & P Sinn

  4. Agilent Laboratories, Tel Aviv, Israel

    R Navon & Z Yakhini

  5. Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University, Frankfurt, Germany

    N Crosetto & I Dikic

  6. IPATIMUP -Institute of Molecular Pathology and Immunology of the University of Porto and Medical Faculty of the University of Porto, Porto, Portugal

    S Carvalho & F Schmitt

  7. Department of Computer Sciences, Technion—Israel Institute of Technology, Technion City, Haifa, Israel

    Z Yakhini

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  1. F Pareja
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Correspondence to Y Yarden.

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Pareja, F., Ferraro, D., Rubin, C. et al. Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression. Oncogene 31, 4599–4608 (2012). https://doi.org/10.1038/onc.2011.587

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  • DOI: https://doi.org/10.1038/onc.2011.587

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