Dkk-1 inhibits intestinal epithelial cell migration by attenuating directional polarization of leading edge cells.
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.
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Stefan
S
Koch
Christopher T
CT
Capaldo
Stanislav
S
Samarin
Porfirio
P
Nava
Irmgard
I
Neumaier
Arne
A
Skerra
David B
DB
Sacks
Charles A
CA
Parkos
Asma
A
Nusrat
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018938:Caco-2 Cells; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology; D022101:Microtubule-Organizing Center / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C499657:PARD6A protein, human; D051153:Wnt Proteins; D020764:cdc42 GTP-Binding Protein