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Tyrosine phosphorylation controls PCNA function through protein stability

Nature Cell Biology volume 8, pages 1359–1368 (2006)Cite this article

Abstract

The proliferating cell nuclear antigen (PCNA) is an essential protein for DNA replication and damage repair. How its function is controlled remains an important question. Here, we show that the chromatin-bound PCNA protein is phosphorylated on Tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of EGF receptor (EGFR) in the nucleus. Phosphorylation on Tyr 211 by EGFR stabilizes chromatin-bound PCNA protein and associated functions. Consistently, increased PCNA Tyr 211 phosphorylation coincides with pronounced cell proliferation, and is better correlated with poor survival of breast cancer patients, as well as nuclear EGFR in tumours, than is the total PCNA level. These results identify a novel nuclear mechanism linking tyrosine kinase receptor function with the regulation of the PCNA sliding clamp.

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Figure 1: Tyrosine phosphorylation of PCNA.
Figure 2: Y 211 phosphorylation is required for maintaining PCNA protein stability.
Figure 3: Nuclear EGFR associates and phosphorylates PCNA at tyrosine 211.
Figure 4: Protein stability of the chromatin-associated PCNA is controlled by Y 211 phosphorylation.
Figure 5: Tyr 211 phosphorylation of PCNA is associated with cellular and physiological proliferation.
Figure 6: Tyr 211 phosphorylation indirectly regulates the DNA repair and DNA replication functions of PCNA without changing its intrinsic activity.

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Acknowledgements

The anti-phospho-Tyr 211 antibody was generated by Bethyl Laboratories, Inc. as a collaboration. We also thank S. Dent, M. Van Dyke and D. Yu for helpful discussions and comments. This study was supported, in part, by the NIH RO1 109311 and NIH PO1 099031 grants, the National Breast Cancer Foundation, Inc. (to M.-C. H.), and the Cancer Center support grant CA16672.

Author information

Author notes

  1. Yusuke Nakajima, David H. Hawke & Ryuji Kobayashi

    Present address: Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, TX, USA

  2. Long-Yuan Li & Mien-Chie Hung

    Present address: Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan

  3. Shao-Chun Wang, Yusuke Nakajima and Yung-Luen Yu: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, TX, USA

    Shao-Chun Wang, Yusuke Nakajima, Yung-Luen Yu, Weiya Xia, Chun-Te Chen, Cheng-Chieh Yang, Long-Yuan Li & Mien-Chie Hung

  2. Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, TX, USA

    Chun-Te Chen, Cheng-Chieh Yang & Mien-Chie Hung

  3. Bethyl Laboratories, Inc., 25043 W. FM1097, Montgomery, 77356, TX, USA

    Eric W. McIntush

  4. Oral and Maxillofacial Surgery, Department of Oral Restitution, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8549, Japan

    Yusuke Nakajima

  5. Center for Molecular Medicine, China Medical University Hospital, No. 2 Yuh-Der Road, Taichung, 404, Taiwan

    Long-Yuan Li

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Correspondence to Mien-Chie Hung.

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Competing interests

E.W.M is currently an employee of Bethyl Laboratories, Inc. (Montgomery, TX), which has a commerical interest in the antibodies against PCNA and phospho-PCNA. E.W.M. collaborated with the Hung group to develop these antibodies.

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Supplementary Figures S1, S2, S3, S4 and S5 (PDF 655 kb)

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Wang, SC., Nakajima, Y., Yu, YL. et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 8, 1359–1368 (2006). https://doi.org/10.1038/ncb1501

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