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J. Biol. Chem., Vol. 280, Issue 16, 15767-15772, April 22, 2005

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Decorin, a Novel Player in the Insulin-like Growth Factor System^*

Elke Schönherr¶, Cord Sunderkötter||**, Renato V. Iozzo, and Liliana Schaefer

From the Matrix Biology and Tissue Repair Research Unit, Cardiff University Dental School, Cardiff CF14 4XY, United Kingdom, Institute of Physiological Chemistry and Pathobiochemistry, ^||Institute of Experimental Dermatology and Department of Dermatology, and the Department of Internal Medicine D, University and University Hospital of Münster, D-48149 Münster, Germany, the Department of Pathology, Anatomy, and Cell Biology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, and the ^**Department of Dermatology, University and University Hospital of Ulm, D-8901 Ulm, Germany

Decorin is a multifunctional proteoglycan that is expressed by sprouting endothelial cells. Its expression supports capillary formation and cell survival. Previously, it was shown that some effects of decorin are mediated by protein kinase B and the cyclin-dependent kinase inhibitor, p21. However, the cell surface receptor responsible for these effects was unknown. We demonstrate that decorin binds to the insulin-like growth factor-I (IGF-I) receptor on endothelial cells with an affinity in the nanomolar range (K_D = 18 nM), which is comparable with IGF-I (K_D = 1.2 nM). Furthermore, decorin can bind IGF-I itself, but with a lower affinity (K_D = 190 nM) than classical IGF-I-binding proteins. Decorin addition causes IGF-I receptor phosphorylation and activation, which is followed by receptor down-regulation. These effects are caused by the core protein of decorin, and the binding region could be mapped to the N terminus of the molecule. The physiological relevance of the decorin/IGF-I receptor interaction was corroborated in two animal models (e.g. inflammatory angiogenesis in the cornea and unilateral ureteral obstruction). In both models the IGF-I receptor was up-regulated in decorin-deficient mice compared with controls and the up-regulation could not compensate the decorin deficiency in the disease models. These data indicate that decorin is an important player in the IGF system and its loss cannot fully be compensated in different types of diseases.

Received for publication, January 13, 2005

^* This work was supported by the Deutsche Forschungsgemeinschaft (SFB 293, Project A7 (to E. S.), SFB 492 B10 (to L. S.), SFB 293, Project A8 (to C. S.)), by the Interdisciplinary Center for Clinical Research of the Medical Faculty of the University of Münster, Germany (Project D15 (to C. S.), D18 and Schae2/004/04 (to L. S.)), IMF SC 11 04 07 (to L. S.), BMBF Fk2 01 GM0310 (to C. S.), National Institutes of Health Grant RO1 CA-39481 (to R. V. I.). 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. Tel.: 44-29-2074-2595; Fax: 44-29-2074-4509; E-mail: schonherreh{at}cardiff.ac.uk.

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