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J. Biol. Chem., Vol. 279, Issue 43, 44513-44521, October 22, 2004
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¶
From the
Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition and the Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2576
Members of the epidermal growth factor (EGF) family of ligands and their receptors regulate migration and growth of intestinal epithelial cells. However, our understanding of the signal transduction pathways determining these responses is incomplete. In this study we tested the hypothesis that p38 is required for EGF-stimulated intestinal epithelial monolayer restitution. EGF-stimulated migration in a wound closure model required continuous presence of ligand for several hours for maximal response, suggesting a requirement for sustained signal transduction pathway activation. In this regard, prolonged exposure of cells to EGF activated p38 for up to 5 h. Furthermore genetic or pharmacological blockade of p38 signaling inhibited the ability of EGF to accelerate wound closure. Interestingly p38 inhibition was associated with increased EGF-stimulated ERK1/ERK2 phosphorylation and cell proliferation, suggesting that p38 regulates the balance of proliferation/migration signaling in response to EGF receptor activity. Activation of p38 in intestinal epithelial cells through EGF receptor was abolished by blockade of Src family tyrosine kinase signaling but not inhibition of phosphatidylinositol 3-kinase or protein kinase C. Taken together, these data suggest that Src family kinase-dependent p38 activation is a key component of a signaling switch routing EGF-stimulated responses to epithelial cell migration/restitution rather than proliferation during wound closure.
Received for publication, June 4, 2004 , and in revised form, August 12, 2004.
* This work was supported by National Institutes of Health Awards DK07673 (to M. R. F.) and DK54993 (to D. B. P.) and by the Vanderbilt University Digestive Disease Research Center (National Institutes of Health Grant DK58404). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ To whom correspondence should be addressed. E-mail: d-brent.polk{at}vanderbilt.edu.
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