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Molecular and Cellular Biology, November 2003, p. 7488-7497, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7488-7497.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Chk1 Kinase Negatively Regulates Mitotic Function of Cdc25A Phosphatase through 14-3-3 Binding

Mei-Shya Chen,1,2,{dagger} Christine E. Ryan,1,2 and Helen Piwnica-Worms1,2,3*

Howard Hughes Medical Institute,1 Department of Cell Biology and Physiology,2 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110-10933

Received 16 April 2003/ Returned for modification 20 June 2003/ Accepted 21 July 2003

The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. Mutation of T507 to alanine (T507A) enhanced the biological activity of Cdc25A. Cdc25A(T507A) was more efficient in binding to cyclin B1, activating cyclin B1-Cdk1, and promoting premature entry into mitosis. We propose that the Chk1/Cdc25A/14-3-3 pathway functions to prevent cells from entering into mitosis prior to replicating their genomes to ensure the fidelity of the cell division process.

* Corresponding author. Mailing address: Department of Cell Biology and Physiology and Howard Hughes Medical Institute, Washington University School of Medicine, Box 8228, 660 South Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-6812. Fax: (314) 362-3709. E-mail: hpiwnica{at}cellbio.wustl.edu.

{dagger} Present address: Division of Cancer Research, National Health Research Institutes, Cancer Research Cooperative Laboratory, NTUH, Taipei 100, Taiwan, Republic of China.

Molecular and Cellular Biology, November 2003, p. 7488-7497, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7488-7497.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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