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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

Adaptor Proteins

Signal Transducing/genetics/metabolism

Animals

Apoptosis/physiology

Caco-2 Cells

Cell Movement/*physiology

*Cell Polarity

Cell Proliferation

*Epithelial Cells/cytology/physiology

Golgi Apparatus/metabolism

Humans

Intercellular Signaling Peptides and Proteins/genetics/*metabolism

Intestinal Mucosa/cytology

Microtubule-Organizing Center/metabolism

Wnt Proteins/genetics/metabolism

cdc42 GTP-Binding Protein/genetics/metabolism

Publication and Content Type

ref (subject category)

art (subject category)