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J. Biol. Chem., Vol. 283, Issue 27, 18812-18820, July 4, 2008

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Krüppel-like Factor 5 Controls Keratinocyte Migration via the Integrin-linked Kinase^*

From the Department of Medicine, Gastroenterology Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Migration of epithelial cells is critical for normal homeostasis in gut and skin, but the factors regulating this process are not completely understood. The zinc finger transcription factor Klf5 (IKLF; BTEB2) is highly expressed in proliferating cells of esophagus, skin, and other organs. We hypothesized that Klf5 regulates keratinocyte migration via the integrin-linked kinase (ILK), which, like Klf5, is localized to basal keratinocytes. We stably transduced mouse primary esophageal keratinocytes to overexpress Klf5 or small interfering RNA against Klf5. Klf5 overexpression in keratinocytes increased migration and correlated directly with ILK expression and activation. ILK expression restored migratory capacity in keratinocytes with suppression of Klf5, whereas ILK small interfering RNA blocked the increased migration resulting from Klf5 overexpression. By chromatin immunoprecipitation, electromobility shift assay, and luciferase reporter assays, we confirmed that ILK was a direct target for Klf5. In addition, Klf5 induced the activation of the ILK targets Cdc42 and myosin light chain, which are critical for cell migration and motility but not Rac1, AKT, or GSK3β. Overall, these results demonstrate that Klf5 is a key regulator of cell migration via ILK and provide new insight into the regulation of epithelial cell migration.

Received for publication, February 21, 2008 , and in revised form, April 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R21 DK073888 from NIDDK, P30 DK050306 from NIDDK (to the University of Pennsylvania Center for Molecular Studies in Digestive and Liver Disease) through the Morphology Core and the Molecular Biology Core, and P01 A098101 from NCI ("Mechanisms of Esophageal Carcinogenesis"). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

¹ To whom correspondence should be addressed: 600 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6144. Tel.: 215-746-7780; Fax: 215-573-2024; E-mail: jpkatz{at}mail.med.upenn.edu.

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