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Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction

Oncogene volume 29, pages 3324–3334 (2010)Cite this article

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Abstract

The Cdc25A protein phosphatase drives cell-cycle transitions by activating cyclin-dependent protein kinases. Failure to regulate Cdc25A leads to deregulated cell-cycle progression, bypass of cell-cycle checkpoints and genome instability. Ubiquitin-mediated proteolysis has an important role in balancing Cdc25A levels. Cdc25A contains a DS82G motif whose phosphorylation is targeted by β-TrCP E3 ligase during interphase. Targeting β-TrCP to Cdc25A requires phosphorylation of serines 79 (S79) and 82 (S82). Here, we report that casein kinase 1 α (CK1α) phosphorylates Cdc25A on both S79 and S82 in a hierarchical manner requiring prior phosphorylation of S76 by Chk1 or GSK-3β. This facilitates β-TrCP binding and ubiquitin-mediated proteolysis of Cdc25A throughout interphase and after exposure to genotoxic stress. The priming of Cdc25A by at least three kinases (Chk1, GSK-3β, CK1α), some of which also require priming, ensures diverse extra- and intracellular signals interface with Cdc25A to precisely control cell division.

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Acknowledgements

We thank Dr Van Leung-Pineda and Dr Tiebang Kang for helpful suggestions. We also thank Chris Ryan for editorial assistance. We thank Chris Ryan, Yonghao Hou, Mei-Shya Chen, Dr Jiandong Chen and Dr Binhua P Zhou for providing expression plasmids. This work was supported by grants from the National Institutes of Health (GM047017 and P50 CA94056). We acknowledge the p50 Molecular Imaging Center and the Alvin J. Siteman Cancer Center at Washington University School of Medicine for the use of the High Throughput Core. The Siteman Cancer Center was supported in part by an NCI Cancer Center Support Grant No. P30 CA91842. H.P.-W. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA

    Y Honaker & H Piwnica-Worms

  2. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA

    H Piwnica-Worms

  3. Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO, USA

    H Piwnica-Worms

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Correspondence to H Piwnica-Worms.

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Honaker, Y., Piwnica-Worms, H. Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction. Oncogene 29, 3324–3334 (2010). https://doi.org/10.1038/onc.2010.96

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