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J. Biol. Chem., Vol. 280, Issue 25, 23884-23891, June 24, 2005

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Phosphatidylinositol Phosphate Kinase Type I Directly Associates with and Regulates Shp-1 Tyrosine Phosphatase^*

Shawn F. Bairstow, Kun Ling, and Richard A. Anderson

From the Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706

Tyrosine phosphorylation plays a critical role in many regulatory aspects of cellular signaling, and dephosphorylation of phosphotyrosine residues is crucial for termination of signals initiated by tyrosine kinases. Previous work has shown that the tyrosine kinase Src phosphorylates Tyr⁶⁴⁴ on phosphatidylinositol phosphate kinase type I (PIPKI) 661 in a focal adhesion kinase-dependent manner. Phosphorylation of this residue is essential for high affinity binding of PIPKI661 to the focal adhesion protein talin and for targeting of PIPKI661 to focal adhesions. A yeast two-hybrid screen performed with the C-terminal 178-amino acid tail of PIPKI661 identified an interaction with the phosphatase domain of the tyrosine phosphatase Shp-1. The interaction between PIPKI661 and Shp-1 was confirmed via co-immunoprecipitation from HEK293 cell lysates. In addition, Src-phosphorylated PIPKI661 is a substrate for Shp-1, and Shp-1 modulates both the association between PIPKI661 and talin and the targeting of PIPKI661 to focal adhesions in mammalian cells. Finally, we showed that Shp-1 phosphatase activity is inhibited by the product of PIPKI661, phosphatidylinositol 4,5-bisphosphate, in vitro. These combined results suggest a model in which the reciprocal actions of Src tyrosine kinase and Shp-1 tyrosine phosphatase dynamically regulate the association between PIPKI661 and talin.

Received for publication, January 18, 2005 , and in revised form, April 18, 2005.

^* This work was supported in part by National Institutes of Health Biotechnology Training Program Grant GM08349 (to S. F. B.), American Heart Association Grant 133-EY51 (to K. L.), and National Institutes of Health Grants GM57549 and CA104708 (to R. A. A.). 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.

A graduate student in the Bimolecular Chemistry Predoctoral Training Program.

To whom correspondence should be addressed: Dept. of Pharmacology, 3750 Medical Science Center, 1300 University Ave., University of Wisconsin Medical School, Madison, WI 53706. Tel.: 608-262-3753; Fax: 608-262-1257; E-mail: raanders{at}wisc.edu.

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