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J. Biol. Chem., Vol. 282, Issue 11, 8545-8556, March 16, 2007

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IQ-domain GTPase-activating Protein 1 Regulates -Catenin at Membrane Ruffles and Its Role in Macropinocytosis of N-cadherin and Adenomatous Polyposis Coli^*

From the Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, New South Wales 2145, Australia

-Catenin is an integral component of E-cadherin dependent cell-cell junctions. Here we show that -catenin co-localizes with IQ-domain GTPase-activating protein 1 (IQGAP1), adenomatous polyposis coli (APC), and N-cadherin at actin-positive membrane ruffles in NIH 3T3 fibroblasts. We used deletion mapping to identify the membrane ruffle-targeting region of -catenin, localizing it to amino acids 47-217, which overlap the IQGAP1 binding site. Knockdown by small interference RNA (siRNA) revealed IQGAP1-dependent membrane targeting of -catenin, APC, and N-cadherin. Transient overexpression of IQGAP1 or N-cadherin increased -catenin at membrane ruffles. IQGAP1/APC regulates cell migration, and using a wound healing assay we demonstrate that siRNA-mediated loss of -catenin also caused a modest reduction in the rate of cell migration. More significantly, we discovered that -catenin is internalized by Arf6-dependent macropinocytosis near sites of membrane ruffling. The -catenin macropinosomes co-stained for APC, N-cadherin, and to a lesser extent IQGAP1, and internalization of each binding partner was abrogated by siRNA-dependent knockdown of -catenin. In addition, -catenin macropinosomes co-localized with the lysosomal marker, lysosome associated membrane protein 1, consistent with their recycling by the late endosomal machinery. Our findings expand on current knowledge of -catenin function. We propose that in motile cells -catenin is recruited by IQGAP1 and N-cadherin to active membrane ruffles, wherein -catenin mediates the internalization and possible recycling of the membrane-associated proteins N-cadherin and APC.

Received for publication, November 3, 2006 , and in revised form, January 8, 2007.

^* This work was generously supported by grants from the New South Wales Cancer Council, the Australian Research Council, and the National Health and Medical Research Council of Australia. 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 Figs. S1—S6.

¹ A Senior Research Fellow of the National Health and Medical Research Council of Australia. To whom correspondence should be addressed: Westmead Millennium Institute, Darcy Rd., P. O. Box 412, Westmead, NSW 2145, Australia. Tel.: 61-2-9845-9057; Fax: 61-2-9845-9102; E-mail: beric_henderson{at}wmi.usyd.edu.au.

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