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J. Biol. Chem., Vol. 283, Issue 23, 16104-16114, June 6, 2008

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Protein Phosphatase 2A Is Targeted to Cell Division Control Protein 6 by a Calcium-binding Regulatory Subunit^*

Anthony J. Davis¹, Zhen Yan, Bobbie Martinez, and Marc C. Mumby²

From the Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041 and the Division of Cardiology, Department of Medicine, Duke University, Medical Center, Durham, North Carolina 27710

The cell division control protein 6 (Cdc6) is essential for formation of pre-replication complexes at origins of DNA replication. Phosphorylation of Cdc6 by cyclin-dependent kinases inhibits ubiquitination of Cdc6 by APC/C^cdh1 and degradation by the proteasome. Experiments described here show that the PR70 member of the PPP2R3 family of regulatory subunits targets protein phosphatase 2A (PP2A) to Cdc6. Interaction with Cdc6 is mediated by residues within the C terminus of PR70, whereas interaction with PP2A requires N-terminal sequences conserved within the PPP2R3 family. Two functional EF-hand calcium-binding motifs mediate a calcium-enhanced interaction of PR70 with PP2A. Calcium has no effect on the interaction of PR70 with Cdc6 but enhances the association of PP2A with Cdc6 through its effects on PR70. Knockdown of PR70 by RNA interference results in an accumulation of endogenous and expressed Cdc6 protein that is dependent on the cyclin-dependent protein kinase phosphorylation sites on Cdc6. Knockdown of PR70 also causes G₁ arrest, suggesting that PR70 function is critical for progression into S phase. These observations indicate that PP2A can be targeted in a calcium-regulated manner to Cdc6 via the PR70 subunit, where it plays a role in regulating protein phosphorylation and stability.

Received for publication, December 19, 2007 , and in revised form, February 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM49505. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1 and S2.

¹ Supported by National Institutes of Health Pharmacological Sciences Training Grant T32 GM07062.

² To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-645-6152; Fax: 214-645-6151; E-mail: marc.mumby{at}utsouthwestern.edu.

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