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Vol. 20, Issue 22, 4816-4825, November 15, 2009

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Dkk-1 Inhibits Intestinal Epithelial Cell Migration by Attenuating Directional Polarization of Leading Edge Cells

Stefan Koch^*, Christopher T. Capaldo^*, Stanislav Samarin^*, Porfirio Nava^*, Irmgard Neumaier, Arne Skerra, David B. Sacks, Charles A. Parkos^*, and Asma Nusrat^*

*Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; Biologische Chemie, Technische Universitaet Muenchen, D-85350 Freising-Weihenstephan, Germany; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

Submitted May 20, 2009; Revised September 4, 2009; Accepted September 14, 2009
Monitoring Editor: Keith E. Mostov

Wnt signaling pathways regulate proliferation, motility, and survival in a variety of human cell types. Dickkopf-1 (Dkk-1) is a secreted Wnt antagonist that has been proposed to regulate tissue homeostasis in the intestine. In this report, we show that Dkk-1 is secreted by intestinal epithelial cells after wounding and that it inhibits cell migration by attenuating the directional orientation of migrating epithelial cells. Dkk-1 exposure induced mislocalized activation of Cdc42 in migrating cells, which coincided with a displacement of the polarity protein Par6 from the leading edge. Consequently, the relocation of the microtubule organizing center and the Golgi apparatus in the direction of migration was significantly and persistently inhibited in the presence of Dkk-1. Small interfering RNA-induced down-regulation of Dkk-1 confirmed that extracellular exposure to Dkk-1 was required for this effect. Together, these data demonstrate a novel role of Dkk-1 in the regulation of directional polarization of migrating intestinal epithelial cells, which contributes to the effect of Dkk-1 on wound closure in vivo.

Address correspondence to: Asma Nusrat (anusrat{at}emory.edu)

Abbreviations used: Dkk-1, Dickkopf-1; IEC, intestinal epithelial cell; MTOC, microtubule organizing center; rDkk-1, recombinant Dkk-1.