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J. Biol. Chem., Vol. 283, Issue 40, 27179-27188, October 3, 2008

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ADP-ribosylation Factor-like GTPase ARFRP1 Is Required for Trans-Golgi to Plasma Membrane Trafficking of E-cadherin^*

Claudia Zahn¹, Alexander Jaschke¹, Jörg Weiske, Angela Hommel, Deike Hesse, Robert Augustin, Lei Lu^¶, Wanjin Hong^¶, Simone Florian^||, Andrea Scheepers, Hans-Georg Joost, Otmar Huber, and Annette Schürmann²

From the Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany, Central Department of Laboratory Medicine and Pathobiochemistry, Charité-Campus Benjamin Franklin, 12200 Berlin, Germany, ^¶Membrane Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore, and the ^||Department of Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany

ADP-ribosylation factor-related protein 1 (ARFRP1) plays a specific role in Golgi function controlling recruitment of GRIP domain proteins and ARL1 to the trans-Golgi. Deletion of the mouse Arfrp1 gene causes embryonic lethality during early gastrulation, because epiblast cells detach from the ectodermal cell layer and do not differentiate to mesodermal tissue. Here we show that in Arfrp1^-/- embryos E-cadherin is mistargeted to intracellular compartments, whereas in control embryos it is present at the cell surface of trophectodermal and ectodermal cells. In enterocytes of intestine-specific Arfrp1 null mutants (Arfrp1^vil-/-), E-cadherin is associated with intracellular membranes, partially colocalizing with the cis-Golgi marker GM130 or with punctae close to the cell surface. In contrast, in control enterocytes E-cadherin is exclusively located in the lateral membranes. In addition, ARL1 is dislocated from Golgi membranes to the cytosol of Arfrp1^vil-/- enterocytes. Depletion of endogenous ARFRP1 by RNA interference leads to a dislocation of E-cadherin from the cell surface in HeLa cells and to a reduced cell aggregation in Ltk^-Ecad cells. ARFRP1 was coimmunoprecipitated in a complex with E-cadherin, -catenin, β-catenin, -catenin, and p120^ctn from lysates of Madin-Darby canine kidney cells stably expressing myc-ARFRP1. These data indicate that knock-out of Arfrp1 disrupts the trafficking of E-cadherin through the Golgi and suggest an essential role of the GTPase in trans-Golgi network function.

Received for publication, March 17, 2008 , and in revised form, June 19, 2008.

^* This work was supported by the Deutsche Forschungsgemeinschaft Grants Schu 750/5-2 and Schu 750/5-3 (to A. S.) and the Sonnenfeld-Stiftung (to O. H.). 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. 1–5.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany. Tel.: 49-33200-88368; Fax: 49-33200-88334; E-mail: schuermann{at}dife.de.

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