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J. Biol. Chem., Vol. 283, Issue 25, 17406-17415, June 20, 2008

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Decorin Regulates Endothelial Cell Motility on Collagen I through Activation of Insulin-like Growth Factor I Receptor and Modulation of 2β1 Integrin Activity^*

Lorna R. Fiedler¹, Elke Schönherr, Rachel Waddington, Stephan Niland, Daniela G. Seidler^¶, Daniel Aeschlimann²³, and Johannes A. Eble²

From the Matrix Biology and Tissue Repair Research Unit, School of Dentistry, Cardiff University, Heath Park, Cardiff, United Kingdom CF14 4XY, the Centre for Molecular Medicine, Excellence Cluster CardioPulmonary System, Vascular Matrix Biology, Frankfurt University Hospital, D-60590 Frankfurt, Germany and the ^¶Department of Physiological Chemistry and Pathobiochemistry, University Hospital of Muenster, D-48149 Muenster, Germany

The proteoglycan decorin is expressed by sprouting but not quiescent endothelial cells, and angiogenesis is dysregulated in its absence. Previously, we have shown that decorin core protein can bind to and activate insulin-like growth factor-I receptor (IGF-IR) in endothelial cells. In this study, we show that decorin promotes 2β1 integrin-dependent endothelial cell adhesion and migration on fibrillar collagen type I. We provide evidence that decorin modulates cell-matrix interaction in this context by stimulating cytoskeletal and focal adhesion reorganization through activation of the IGF-IR and the small GTPase Rac. Further, the glycosaminoglycan moiety of decorin interacts with 2β1, but not 1β1 integrin, at a site distinct from the collagen I-binding A-domain, to allosterically modulate collagen I-binding activity of the integrin. We propose that induction of decorin expression in angiogenic, as opposed to quiescent, endothelial cells promotes a motile phenotype in an interstitial collagen I-rich environment by both signaling through IGF-IR and influencing 2β1 integrin activity.

Received for publication, December 10, 2007 , and in revised form, April 9, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 293 and 492, SPP1086, and Eb177/5-1; NATO Grant CBP.NR.NRCLG 982113 (to D. A.); and a studentship from Cardiff University (to L. F.). 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 Fig. S1.

Deceased; to whose memory this paper is dedicated.

² Both authors contributed equally to this work.

¹ To whom correspondence may be addressed. Tel.: 44-2920-748420; Fax: 44-2920-744509; E-mail: fiedlerlr{at}cardiff.ac.uk. or Tel.: 44-2920-744240; Fax: 44-2920-744509; E-mail: AeschlimannDP{at}cardiff.ac.uk. ³ To whom correspondence may be addressed. Tel.: 44-2920-744240; Fax: 44-2920-744509; E-mail: AeschlimannDP{at}cardiff.ac.uk.

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