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Originally published In Press as doi:10.1074/jbc.M207519200 on August 28, 2002

J. Biol. Chem., Vol. 277, Issue 44, 41756-41761, November 1, 2002
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Ionizing Radiation Activates Nuclear Protein Phosphatase-1 by ATM-dependent Dephosphorylation*

Chang Y. GuoDagger , David L. Brautigan§, and James M. LarnerDagger

From the Dagger  Department of Radiation Oncology, University of Virginia Health System, Charlottesville, Virginia 22908 and § Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Ionizing radiation (IR) is known to activate multiple signaling pathways, resulting in diverse stress responses including apoptosis, cell cycle arrest, and gene induction. IR-activated cell cycle checkpoints are regulated by Ser/Thr phosphorylation, so we tested to see if protein phosphatases were targets of an IR-activated damage-sensing pathway. Jurkat cells were subjected to IR or sham radiation followed by brief 32P metabolic labeling. Nuclear extracts were subjected to microcystin affinity chromatography to recover phosphatases, and the proteins were analyzed by two-dimensional gel electrophoresis. Protein sequencing revealed that the microcystin-bound proteins with the greatest reduction in 32P intensity following IR were the alpha  and delta  isoforms of protein phosphatase 1 (PP1). Both of these PP1 isoforms contain an Arg-Pro-Ile/Val-Thr-Pro-Pro-Arg sequence near the C terminus, a known site of phosphorylation by Cdc/Cdk kinases, and phosphorylation attenuates phosphatase activity. In wild-type Jurkat cells or ataxia telangiectasia (AT) cells that are stably transfected with full-length ATM kinase, IR resulted in net dephosphorylation of this site in PP1 and produced activation of PP1. However, in AT cells that are deficient in ATM, IR failed to induce dephosphorylation or activation of PP1. IR-induced PP1 activation in the nucleus may be a critical component in an ATM-mediated pathway controlling checkpoint activation.

* This study was supported by National Institutes of Health Grants CA 72622 (to J. M. L.) and GM 56362 and CA 40042 (to D. L. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: University of Virginia Health System, Box 800383, Charlottesville, VA 22908-0383. Tel.: 434-924-5191; Fax: 434-982-3262; E-mail: jml2p@virginia.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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