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J. Biol. Chem., Vol. 279, Issue 51, 53717-53724, December 17, 2004

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The Phosphoinositol 3,4-Bisphosphate-binding Protein TAPP1 Interacts with Syntrophins and Regulates Actin Cytoskeletal Organization^*

Angela Hogan, Yury Yakubchyk, Josée Chabot, Christopher Obagi, Elias Daher, Kazuhiko Maekawa, and Stephen H. Gee, Supported by a CIHR New Investigator Award¶

From the Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and the Shionogi Institute for Medical Science, 2-5-1 Mishima, Settsu-shi, Osaka 566-0022, Japan

Syntrophins are scaffold proteins of the dystrophin glycoprotein complex (DGC), which target ion channels, receptors, and signaling proteins to specialized subcellular domains. A yeast two-hybrid screen of a human brain cDNA library with the PSD-95, Discs-large, ZO-1 (PDZ) domain of 1-syntrophin yielded overlapping clones encoding the C terminus of TAPP1, a pleckstrin homology (PH) domain-containing adapter protein that interacts specifically with phosphatidylinositol 3,4-bisphosphate (PI(3,4)P₂). In biochemical assays, the C terminus of TAPP1 bound specifically to the PDZ domains of 1-, 1-, and 2-syntrophin and was required for syntrophin binding and for the correct subcellular localization of TAPP1. TAPP1 is recruited to the plasma membrane of cells stimulated with platelet-derived growth factor (PDGF), a motogen that produces PI(3,4)P₂. Cell migration in response to PDGF stimulation is characterized by a rapid reorganization of the actin cytoskeleton, which gives rise to plasma membrane specializations including peripheral and dorsal circular ruffles. Both TAPP1 and syntrophins were localized to PDGF-induced circular membrane ruffles in NIH-3T3 cells. Ectopic expression of TAPP1 potently blocked PDGF-induced formation of dorsal circular ruffles, but did not affect peripheral ruffling. Interestingly, coexpression of 1- or 1-syntrophin with TAPP1 prevented the blockade of circular ruffling. In addition to syntrophins, several other proteins of the DGC were enriched in circular ruffles. Collectively, our results suggest syntrophins regulate the localization of TAPP1, which may be important for remodeling the actin cytoskeleton in response to growth factor stimulation.

Received for publication, September 15, 2004 , and in revised form, October 8, 2004.

^* This work was supported by the Neuromuscular Research Partnership Program, an alliance of the Amyotrophic Lateral Sclerosis Society of Canada, the Muscular Dystrophy Association of Canada, and the Canadian Institutes of Health Research (CIHR). 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.

^¶ To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, University of Ottawa, 451 Smyth Rd., Ottawa ON K1H 8M5, Canada. Tel.: 613-562-5800 (ext. 8079); Fax: 613-562-5645; E-mail: stevegee{at}uottawa.ca.

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