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Engineering a single ubiquitin ligase for the selective degradation of all activated ErbB receptor tyrosine kinases

Oncogene volume 33, pages 986–995 (2014)Cite this article

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Abstract

Interrogating specific cellular activities often entails the dissection of posttranslational modifications or functional redundancy conferred by protein families, which demands more sophisticated research tools than simply eliminating a specific gene product by gene targeting or RNA interference. We have developed a novel methodology that involves engineering a single SCFβTrCP-based ubiquitin ligase that is capable of not only simultaneously targeting the entire family of ErbB receptor tyrosine kinases for ubiquitination and degradation, but also selectively recruiting only activated ErbBs. The engineered SCFβTrCP ubiquitin ligase effectively blocked ErbB signaling and attenuated oncogenicity in breast cancer cells, yet had little effect on the survival and growth of non-cancerous breast epithelial cells. Therefore, engineering ubiquitin ligases offers a simple research tool to dissect the specific traits of tumorigenic protein families, and provides a rapid and feasible means to expand the dimensionality of drug discovery by assessing protein families or posttranslational modifications as potential drug targets.

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Acknowledgements

We thank Bruce Mayer (University of Connecticut) for Shc plasmids, Alexandra Grassian for helpful discussions, and Jeffrey Hannah and Jennifer Lee for critical reading of the manuscript. This work is supported by National Institutes of Health Grant CA92792, the Irma T. Hirschl Career Scientist Award and the Speakers Fund from the New York Academy of Medicine to P.Z., and the Natural Science Foundation of China (No. 30901754) and Innovation Funding for Graduates of Tianjin Medical University, third Phase of the 211 Project for Higher Education (No. 2010GSI01).

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  1. F Kong and J Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    F Kong, J Zhang, Y Li & P Zhou

  2. Department of Biotherapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    F Kong, X Hao, X Ren & H Li

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  1. F Kong
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Correspondence to H Li or P Zhou.

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Kong, F., Zhang, J., Li, Y. et al. Engineering a single ubiquitin ligase for the selective degradation of all activated ErbB receptor tyrosine kinases. Oncogene 33, 986–995 (2014). https://doi.org/10.1038/onc.2013.33

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