TY - JOUR
T1 - Dkk-1 inhibits intestinal epithelial cell migration by attenuating directional polarization of leading edge cells
AU - Koch, Stefan
AU - Capaldo, Christopher T.
AU - Samarin, Stanislav
AU - Nava, Porfirio
AU - Neumaier, Irmgard
AU - Skerra, Arne
AU - Sacks, David B.
AU - Parkos, Charles A.
AU - Nusrat, Asma
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=73949114462&partnerID=8YFLogxK
U2 - 10.1091/mbc.E09-05-0415
DO - 10.1091/mbc.E09-05-0415
M3 - Article
C2 - 19776352
AN - SCOPUS:73949114462
SN - 1059-1524
VL - 20
SP - 4816
EP - 4825
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 22
ER -