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1 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
2 Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
3 Gastroenterology, Vanderbilt University, Nashville, Tennessee, United States
4 Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee, United States; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
* To whom correspondence should be addressed. E-mail: d-brent.polk{at}vanderbilt.edu.
Regulated intestinal epithelial cell migration plays a key role in wound healing and maintenance of a healthy gastrointestinal tract. Epidermal growth factor (EGF) stimulates cell migration and wound closure in intestinal epithelial cells through incompletely understood mechanisms. In this study we investigated the role of the small GTPase Rac in EGF-induced cell migration using an in vitro wound healing assay. In mouse colonic epithelial (MCE) cell lines, EGF-stimulated wound closure was accompanied by a doubling of the number of cells containing lamellipodial extensions at the wound margin, increased Rac membrane translocation in cells at the wound margin, and rapid Rac activation. Either Rac1 siRNA or a Rac1 inhibitor completely blocked EGF-stimulated wound closure. While EGF failed to activate Rac in colon cells from EGF receptor (EGFR) knockout mice, stable expression of wild type EGFR restored EGF-stimulated Rac activation and migration. Pharmacological inhibition of either phosphatidylinositol 3-kinase (PI3K) or Src family kinases reduced EGF-stimulated Rac activation. Co-treatment of cells with both inhibitors completely blocked EGF stimulated Rac activation/localization to the leading edge of cells and lamellipodial extension. Our results present a novel mechanism by which the PI3K and Src signaling cascades cooperate to activate Rac and promote intestinal epithelial cell migration downstream of EGFR.
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