This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mi, J. Articles by Larner, J. M. Search for Related Content PubMed PubMed Citation Articles by Mi, J. Articles by Larner, J. M.

Protein Phosphatase-1 Regulates Centrosome Splitting through Nek2

¹ Department of Radiation Oncology, University of Virginia Health System and ² Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia

Requests for reprints: James M. Larner, University of Virginia, P.O. Box 800383, Charlottesville, VA 22908. Phone: 434-924-5564; Fax: 434-982-3262; E-mail: jml2p{at}virginia.edu.

ATM is a central mediator of the cellular response to the DNA damage produced by ionizing radiation. We recently showed that protein phosphatase 1 (PP1) is activated by ATM. Because Nek2 is activated by autophosphorylation, and because its dephosphorylation is catalyzed by PP1, we asked if the radiation damage signal to Nek2 was mediated by PP1. Overexpression of Nek2 induces premature centrosome splitting probably by phosphorylating centrosome cohesion proteins C-Nap1 and Rootletin. In this study, we show isoform specificity of PP1 binding and regulation of Nek2. Although both PP1 and PP1 coimmunoprecipitated with Nek2, only PP1 regulated Nek2 function. Ionizing radiation inhibited Nek2 activity, and this response was dependent on ATM and on PP1 binding to Nek2 and coincident with Thr³²⁰ dephosphorylation of PP1. Radiation-induced inhibition of centrosome splitting was abrogated in cells expressing Nek2 mutated in the PP1-binding motif outside the kinase domain. Conversely, cells depleted of PP1 by small interfering RNA showed enhanced centrosome splitting and loss of radiation-induced inhibition of centrosome splitting. The identification of a PP1-specific isoform mediating a checkpoint response opens up the possibility of selectively targeting phosphatases as novel radiation sensitizers. [Cancer Res 2007;67(3):1082–9]

This article has been cited by other articles:

				H.-S. Huang and E. Y. C. Lee Protein Phosphatase-1 Inhibitor-3 Is an in Vivo Target of Caspase-3 and Participates in the Apoptotic Response J. Biol. Chem., June 27, 2008; 283(26): 18135 - 18146. [Abstract] [Full Text] [PDF]

				J. Russo, G. A. Balogh, I. H. Russo, and and the Fox Chase Cancer Center Hospital Network P Full-term Pregnancy Induces a Specific Genomic Signature in the Human Breast Cancer Epidemiol. Biomarkers Prev., January 1, 2008; 17(1): 51 - 66. [Abstract] [Full Text] [PDF]