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J. Biol. Chem., Vol. 283, Issue 43, 29273-29284, October 24, 2008

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PP4R4/KIAA1622 Forms a Novel Stable Cytosolic Complex with Phosphoprotein Phosphatase 4^*

Ginny I. Chen¹, Sally Tisayakorn¹, Claus Jorgensen², Lisa M. D'Ambrosio, Marilyn Goudreault, and Anne-Claude Gingras, Holds the Canada Research Chair in Functional Proteomics³

From the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario M4M 2Y8, Canada and the Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Protein serine/threonine phosphatase 4 (PP4c) is an essential polypeptide involved in critical cellular processes such as microtubule growth and organization, DNA damage checkpoint recovery, apoptosis, and tumor necrosis factor signaling. Like other phosphatases of the PP2A family, PP4c interacts with regulatory proteins, which specify substrate targeting and intracellular localization. The identification of these regulatory proteins is, therefore, key to fully understanding the function of this enzyme class. Here, using a sensitive affinity purification/mass spectrometry approach, we identify a novel, stable cytosolic PP4c interacting partner, KIAA1622, which we have renamed PP4R4. PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). The PP4c·PP4R4 interaction is disrupted by mutations analogous to those abrogating the association of PP2Ac with PP2A A subunit. However, unlike the PP2A A subunit, which plays a scaffolding role, PP4R4 does not bridge PP4c with previously characterized PP4 regulatory subunits. PP4c·PP4R4 complexes exhibit phosphatase activity toward a fluorogenic substrate and H2AX, but this activity is lower than that associated with the PP4c·PP4R2·PP4R3 complex, which itself is less active than the free PP4c catalytic subunit. Our data demonstrate that PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2·PP4R3, and 4, and that the regulatory subunits of PP4c have evolved different modes of interaction with the catalytic subunit.

Received for publication, May 6, 2008 , and in revised form, August 13, 2008.

^* This work was supported in part by a grant from the Terry Fox Foundation and the National Cancer Institute of Canada (to A. C. G.). 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–S4.

¹ Supported by studentships from the Ontario Students Opportunity Trust Fund.

² Recipient of a fellowship from the Ludbeck Foundation.

³ To whom correspondence should be addressed: Samuel Lunenfeld Research Institute at Mount Sinai Hospital, 600 University Ave., Rm. 992, Toronto, ON M4M 2Y8, Canada. Tel.: 416-586-5027; Fax: 416-586-8869; E-mail: gingras{at}mshri.on.ca.

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