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J. Biol. Chem., Vol. 282, Issue 2, 1249-1256, January 12, 2007

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Phosphoinositide 3-Kinase C2 Links Clathrin to Microtubule-dependent Movement^*

From the Department of Biochemistry and Molecular Biology, and the Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Phosphoinositide 3-kinase C2 (PI3K-C2) is a type II PI-3-kinase that has been implicated in several important membrane transport and signaling processes. We previously found that overexpression of PI3K-C2 inhibits clathrin-mediated membrane trafficking and induces proliferation of novel clathrin-coated structures within the cytoplasm. Using fluorescently tagged fusions of PI3K-C2 and clathrin, we explored the behavior of these structures in intact cells. Both proteins are present in the structures, and using rapid image acquisition and fluorescence photoactivation probes, we find that they exhibit localized, rapid mobility (5–20 µm/s). The movement is micro-tubule-based as revealed by use of inhibitors, and PI3K-C2 accumulates on microtubules rapidly and reversibly following cytoplasmic acidification, which also blocks movement. Dynactin mediates the movement of these clathrin-PI3K-C2 structures, since disruption of dynactin function by overexpression of its p50 subunit also inhibits movement. Finally, immunoprecipitation experiments reveal an interaction between endogenous PI3K-C2 and dynactin subunits. Together, these results reveal a molecular linkage between PI3K-C2 and the microtubule motor machinery, with implications for membrane trafficking in intact cells.

Received for publication, July 24, 2006 , and in revised form, October 3, 2006.

^* This work was supported by National Institutes of Health Grant GM-49217 (to J. H. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Videos 1–10 and Figs. S1 and S2.

¹ Present address: Arena Pharmaceuticals, San Diego, CA 92121.

² To whom correspondence should be addressed: Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., BLSB/915, Philadelphia, PA 19107. Tel.: 215-503-4624; Fax: 215-503-0622; E-mail: jim.keen{at}mail.jci.tju.edu.

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