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J. Biol. Chem., Vol. 282, Issue 42, 30785-30793, October 19, 2007

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Role of ADAM-9 Disintegrin-Cysteine-rich Domains in Human Keratinocyte Migration^*

Paola Zigrino¹, Julia Steiger, Jay W. Fox, Stefanie Löffek^¶, Alexander Schild, Roswitha Nischt, and Cornelia Mauch

From the Department of Dermatology and Center for Molecular Medicine, Kerpener Strasse 62, University of Cologne, 50937 Cologne, Germany, the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, and the ^¶Institute for Physiological Chemistry, University of Bonn, 53115 Bonn, Germany

ADAM-9 belongs to a family of transmembrane, disintegrin-containing metalloproteinases involved in protein ectodomain shedding and cell-cell and cell-matrix interactions. The aim of this study was to analyze the expression of ADAM-9 in skin and to assess the role of this proteolytic/adhesive protein in skin physiology. In normal skin, ADAM-9 expression was detected in both the epidermis and dermis and in vitro in keratinocytes and fibroblasts. Here we report that ADAM-9 functions as a cell adhesion molecule via its disintegrin-cysteine-rich domain. Using solid phase binding assays and antibody inhibition experiments, we demonstrated that the recombinant disintegrin-cysteine-rich domain of ADAM-9 specifically interacts with the 1 integrin subunit on keratinocytes. This was corroborated by co-immunoprecipitation. In addition, engagement of integrin receptors by the disintegrin-cysteine-rich domain resulted in ERK phosphorylation and increased MMP-9 synthesis. Treatment with the ERK inhibitor PD98059 inhibited MMP-9 induction. Furthermore, the presence of the soluble disintegrin-cysteine-rich domain did not interfere with cell migration on different substrates. However, keratinocytes adhering to the immobilized disintegrin-cysteine-rich domain showed increased motility, which was partially due to the induction of MMP-9 secretion. In summary, our results indicate that the ADAM-9 adhesive domain plays a role in regulating the motility of cells by interaction with 1 integrins and modulates MMP synthesis.

Received for publication, February 26, 2007 , and in revised form, August 14, 2007.

^* This work was supported by Wilhelm Sander-Stiftung Grant 1999.093.2 (to C. M. and R. N.), Center for Molecular Medicine, University of Cologne (BMFT/IDZ 10) Grant 01 GB 950/4, and by the Koeln Fortune Program of the Medical Faculty of the University of Cologne, Grant 10/2004 (to P. Z.). 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.

¹ To whom correspondence should be addressed: Dept. of Dermatology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel.: 49-221-478-5375; Fax: 49-221-478-5949; E-mail: Paola.Zigrino{at}uni-koeln.de.

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