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© The Rockefeller University Press, 0021-9525/2003/12/1339 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1339-1349

Tyrosine phosphorylation of type I phosphatidylinositol phosphate kinase by Src regulates an integrin–talin switch

¹ Department of Pharmacology, Program in Molecular and Cellular Pharmacology
² Department of Medicine, University of Wisconsin Medical School, Madison, WI 53706
³ Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Address correspondence to Richard A. Anderson, Dept. of Pharmacology, 3710 Medical Science Center, 1300 University Ave., University of Wisconsin Medical School, Madison, WI 53706. Tel.: (608) 262-3753. Fax: (608) 262-1257. email: raanders{at}facstaff.wisc.edu

Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type I phosphatidylinositol phosphate kinase (PIPKI661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKI661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKI661 and Src. The phosphorylation of Y644 results in an 15-fold increase in binding affinity to the talin head domain and blocks ß-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a "molecular switch" for talin binding between PIPKI661 and ß-integrin that may regulate dynamic FA turnover.

Key Words: PIPKI661; focal adhesion; phosphotyrosine-binding domain; FAK; ß-integrin

Abbreviations used in this paper: FA, focal adhesion; FERM, band 4.1, ezrin, radixin, moesin homology; PI4,5P₂, phosphatidylinositol 4,5-bisphosphate; PIPKI661, type I phosphatidylinositol phosphate kinase 661; PTB, phosphotyrosine binding; pY, phosphotyrosine.

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