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J. Biol. Chem., Vol. 281, Issue 25, 17140-17149, June 23, 2006

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Membrane Localization of Adenomatous Polyposis Coli Protein at Cellular Protrusions

TARGETING SEQUENCES AND REGULATION BY -CATENIN^*

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

Adenomatous polyposis coli protein (APC) translocates to, and stabilizes, the plus-ends of microtubules. In microtubule-dependent cellular protrusions, APC frequently accumulates in peripheral clusters at the basal membrane. APC targeting to membrane clusters is important for cell migration, but the localization mechanism is poorly understood. In this study, we performed deletion mapping and defined a minimal sequence (amino acids 1–2226) that efficiently targets APC to membrane clusters. This sequence lacks DLG-1 and EB1 binding sites, suggesting that these partners are not absolutely required for APC membrane targeting. A series of APC sequences were transiently expressed in cells and compared for their ability to compete endogenous APC at the membrane; potent inhibition of endogenous APC targeting was elicited by the Armadillo- (binds KAP3A, B56, and ASEF) and -catenin-binding domains. The Armadillo domain was predicted to inhibit APC membrane localization through sequestration of the kinesin-KAP3A complex. The role of -catenin in APC membrane localization was unexpected but affirmed by overexpressing the APC binding sequence of -catenin, which similarly reduced APC membrane staining. Furthermore, we used RNA interference to show that loss of -catenin reduced APC at membrane clusters in migrating cells. In addition, we report that transiently expressed APC-yellow fluorescent protein co-localized with -catenin, KAP3A, EB1, and DLG-1 at membrane clusters, but only -catenin stimulated APC anchorage at the membrane. Our findings identify -catenin as a regulator of APC targeting to membrane clusters and link these two proteins to cell migration.

Received for publication, December 6, 2005 , and in revised form, March 24, 2006.

^* This work was supported in part by grants from the National Health and Medical Research Council (NHMRC), the NSW Cancer Council, and the Cure Cancer Foundation, 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–S10.

¹ Both authors contributed equally to this work.

² Present address: Cell and Developmental Biology, University of Dundee, WTB/MSI, Dow St., Dundee DD15EH, United Kingdom.

³ Present address: Dept. of Pharmacology, University of Sydney, NSW 2006, Australia.

⁴ An NHMRC Senior Research Fellow. To whom correspondence should be addressed: Westmead Millennium Inst., 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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