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Dickkopf‐1 regulates epithelial cell migration by inhibiting directional orientation
Author(s) -
Koch Stefan,
Capaldo Christopher T,
Nava Porfirio,
Skerra Arne,
Sacks David B,
Parkos Charles A,
Nusrat Asma
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.359.5
Subject(s) - wnt signaling pathway , microbiology and biotechnology , cell polarity , motility , cell migration , phosphorylation , protein kinase c , chemistry , cell , cdc42 , golgi apparatus , signal transduction , biology , biochemistry , endoplasmic reticulum
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 shown to regulate tissue homeostasis in the intestine. In this report, we show that Dkk‐1 is secreted by migrating intestinal epithelial cells after wounding and during intestinal inflammation in vivo, and inhibits cell migration by attenuating directional orientation. We found that physiological concentrations of recombinant Dkk‐1 protein are sufficient to inhibit polarization of the microtubule organizing center and Golgi apparatus towards the leading edge of migrating epithelial cells. Cells exposed to Dkk‐1 exhibit a strong, mis‐localized activation of Cdc42, which coincides with an irregular localization of the polarity protein Par6 and increased phosphorylation of atypical PKC. In contrast, classical PKC phosphorylation is attenuated in the presence of Dkk‐1, suggesting that the observed effects on polarized cell migration might be mediated by inhibition of non‐canonical Wnt pathways. Taken together, these data demonstrate a previously undescribed role of Dkk‐1 in the establishment of directional polarity in epithelial cells, which contributes to the detrimental effects of Dkk‐1 in vivo. Supported by grants from the National Institutes of Health (DK72564, DK61379 and DK79392 to C.A.P., DK53202, DK55679, DK59888 to A.N.).