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Molecular and Cellular Biology, October 2006, p. 7529-7538, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00447-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Chk1 by ATR Is Antagonized by a Chk1-Regulated Protein Phosphatase 2A Circuit{dagger}

Van Leung-Pineda,1 Christine E. Ryan,3 and Helen Piwnica-Worms1,2,3*

Department of Cell Biology and Physiology,1 Department of Internal Medicine,2 Howard Hughes Medical Institute, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, Missouri 63110-10933

Received 14 March 2006/ Returned for modification 20 April 2006/ Accepted 25 July 2006

In higher eukaryotic organisms, the checkpoint kinase 1 (Chk1) contributes essential functions to both cell cycle and checkpoint control. Chk1 executes these functions, in part, by targeting the Cdc25A protein phosphatase for ubiquitin-mediated proteolysis. In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. Here, we report that inhibition of Chk1 kinase activity paradoxically leads to the accumulation of S317- and S345-phosphorylated Chk1 in vivo and that ATR catalyzes Chk1 phosphorylation under these conditions. We demonstrate that Chk1 phosphorylation by ATR is antagonized by protein phosphatase 2A (PP2A). Importantly, dephosphorylation of Chk1 by PP2A is regulated, in part, by the kinase activity of Chk1. We propose that the ATR-Chk1-PP2A regulatory circuit functions to keep Chk1 in a low-activity state during an unperturbed cell division cycle but at the same time keeps Chk1 primed to respond rapidly in the event that cells encounter genotoxic stress.

* Corresponding author. Mailing address: Department of Cell Biology and Physiology & 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}cellbiology.wustl.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2006, p. 7529-7538, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00447-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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