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J. Biol. Chem., Vol. 283, Issue 44, 29920-29928, October 31, 2008

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Compartmentalization of Phosphatidylinositol 4,5-Bisphosphate Signaling Evidenced Using Targeted Phosphatases^*

Corey M. Johnson, Gurunadh R. Chichili, and William Rodgers^¶1

From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, and the Departments of Pathology and ^¶Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Phosphatidylinositol 4,5-bisphosphate (PIP₂) is a prevalent phosphoinositide in cell membranes, with important functions in cell signaling and activation. A large fraction of PIP₂ associates with the detergent-resistant membrane "raft" fraction, but the functional significance of this association remains controversial. To measure the properties of raft and nonraft PIP₂ in cell signaling, we targeted the PIP₂-specific phosphatase Inp54p to either the raft or nonraft membrane fraction using minimal membrane anchors. Interestingly, we observed that targeting Inp54p to the nonraft fraction resulted in an enrichment of raft-associated PIP₂ and striking changes in cell morphology, including a wortmannin-sensitive increase in cell filopodia and cell spreading. In contrast, raft-targeted Inp54p depleted the raft pool of PIP₂ and produced smooth T cells void of membrane ruffling and filopodia. Furthermore, raft-targeted Inp54p inhibited capping in T cells stimulated by cross-linking the T cell receptor, but without affecting the T cell receptor-dependent Ca²⁺ flux. Altogether, these results provide evidence of compartmentalization of PIP₂-dependent signaling in cell membranes such as predicted by the membrane raft model.

Received for publication, July 31, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 GM070001. This work was also supported by American Heart Association Grant 0625648Z. 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: Oklahoma Medical Research Foundation, 825 NE 13th St., MS 45, Oklahoma City, OK 73104. Tel.: 405-271-3550; Fax: 405-271-7417; E-mail: william-rodgers{at}omrf.org.

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