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J. Biol. Chem., Vol. 283, Issue 1, 398-404, January 4, 2008

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NOM1 Targets Protein Phosphatase I to the Nucleolus^*

Shanaka R. Gunawardena, Brian L. Ruis, Julia A. Meyer, Meenal Kapoor, and Kathleen F. Conklin^¶1

From the Department of Genetics, Cell Biology and Development, Institute of Human Genetics, and ^¶Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455

Protein phosphatase I (PP1) is an essential eukaryotic serine/threonine phosphatase required for many cellular processes, including cell division, signaling, and metabolism. In mammalian cells there are three major isoforms of the PP1 catalytic subunit (PP1, PP1β, and PP1) that are over 90% identical. Despite this high degree of identity, the PP1 catalytic subunits show distinct localization patterns in interphase cells; PP1 is primarily nuclear and largely excluded from nucleoli, whereas PP1 and to a lesser extent PP1β concentrate in the nucleoli. The subcellular localization and the substrate specificity of PP1 catalytic subunits are determined by their interaction with targeting subunits, most of which bind PP1 through a so-called "RVXF" sequence. Although PP1 targeting subunits have been identified that direct PP1 to a number of subcellular locations and/or substrates, no targeting subunit has been identified that localizes PP1 to the nucleolus. Identification of nucleolar PP1 targeting subunit(s) is important because all three PP1 isoforms are included in the nucleolar proteome, enzymatically active PP1 is present in nucleoli, and PP1 is highly concentrated in nucleoli of interphase cells. In this study, we identify NOM1 (nucleolar protein with MIF4G domain 1) as a PP1-interacting protein and further identify the NOM1 RVXF motif required for its binding to PP1. We also define the NOM1 nucleolar localization sequence. Finally, we demonstrate that NOM1 can target PP1 to the nucleolus and show that a specific NOM1 RVXF motif and the NOM1 nucleolar localization sequence are required for this targeting activity. We therefore conclude that NOM1 is a PP1 nucleolar targeting subunit, the first identified in eukaryotic cells.

Received for publication, August 13, 2007 , and in revised form, October 3, 2007.

^* This work was supported by the University of Minnesota Cancer Center, the Institute of Human Genetics, the Department of Genetics, Cell Biology and Development, and grants from the University of Minnesota sponsored by the Grant-in-aid and the Minnesota Medical Foundation. 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.

¹ To whom correspondence should be addressed: 321 Church St. SE, 6-160 Jackson, Minneapolis, MN 55455. Fax: 612-626-7031; E-mail: conkl001{at}umn.edu.

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