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J. Biol. Chem., Vol. 282, Issue 39, 29043-29051, September 28, 2007

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Phosphatase Activity, Trimerization, and the C-terminal Polybasic Region Are All Required for PRL1-mediated Cell Growth and Migration^*

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

The phosphatase of regenerating liver (PRL) phosphatases are implicated in a number of tumorigenesis and metastasis processes. The PRLs are unique among protein-tyrosine phosphatases in that they have extremely low phosphatase activity, a high propensity for trimer formation, and a polybasic region that precedes the C-terminal prenylation motif. To investigate the functional significance of these distinctive biochemical and structural features, we established a cell-based system in which ectopic PRL1 expression increased cell proliferation and migration, whereas knockdown of endogenous PRL1 abrogated these cellular activities. We showed that the intrinsic PRL1 phosphatase activity is obligatory for its biological function. We provided evidence that trimerization may be a general property for all PRL enzymes, and that PRL1 trimer formation is essential for the PRL1-mediated cell growth and migration. This finding indicates a novel mechanism for phosphatase regulation. We further demonstrated that the conserved C-terminal polybasic region is important for specific phosphoinositide recognition by PRL1. Both the polybasic residues and the adjacent prenylation motif are required for proper PRL1 subcellular localization and full biological activity.

Received for publication, April 27, 2007 , and in revised form, June 27, 2007.

^* This work was supported by National Institutes of Health Grant CA69202. 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 Both authors contributed equally to this work.

² Present address: Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

³ To whom correspondence should be addressed. E-mail: zyzhang{at}iupui.edu.

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