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J. Biol. Chem., Vol. 282, Issue 37, 27037-27045, September 14, 2007

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Extracellular Collagenases and the Endocytic Receptor, Urokinase Plasminogen Activator Receptor-associated Protein/Endo180, Cooperate in Fibroblast-mediated Collagen Degradation^*

Daniel H. Madsen, Lars H. Engelholm, Signe Ingvarsen, Thore Hillig, Rebecca A. Wagenaar-Miller, Lars Kjøller¹, Henrik Gårdsvoll, Gunilla Høyer-Hansen, Kenn Holmbeck^¶, Thomas H. Bugge, and Niels Behrendt²

From the Finsen Laboratory, Rigshospitalet, Ole Maaløes Vej 5, Copenhagen N DK-2200, Denmark and the Oral & Pharyngeal Cancer Branch and ^¶Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892

The collagens of the extracellular matrix are the most abundant structural proteins in the mammalian body. In tissue remodeling and in the invasive growth of malignant tumors, collagens constitute an important barrier, and consequently, the turnover of collagen is a rate-limiting process in these events. A recently discovered turnover route with importance for tumor growth involves intracellular collagen degradation and is governed by the collagen receptor, urokinase plasminogen activator receptor-associated protein (uPARAP or Endo180). The interplay between this mechanism and extracellular collagenolysis is not known. In this report, we demonstrate the existence of a new, composite collagen breakdown pathway. Thus, fibroblast-mediated collagen degradation proceeds preferentially as a sequential mechanism in which extracellular collagenolysis is followed by uPARAP/Endo180-mediated endocytosis of large collagen fragments. First, we show that collagen that has been pre-cleaved by a mammalian collagenase is taken up much more efficiently than intact, native collagen by uPARAP/Endo180-positive cells. Second, we demonstrate that this preference is governed by the acquisition of a gelatin-like structure by the collagen, occurring upon collagenase-mediated cleavage under native conditions. Third, we demonstrate that the growth of uPARAP/Endo180-deficient fibroblasts on a native collagen matrix leads to substantial extracellular accumulation of well defined collagen fragments, whereas, wild-type fibroblasts possess the ability to direct an organized and complete degradation sequence comprising both the initial cleavage, the endocytic uptake, and the intracellular breakdown of collagen.

Received for publication, February 6, 2007 , and in revised form, July 2, 2007.

^* This work was supported by EU Contract LSHC-CT-2003-503297 and by grants from the Danish Cancer Society, the Danish Cancer Research Foundation, the Danish Medical Research Council, the National Institutes of Health Intramural Program and the Department of Defense (DAMD-17-02-1-0693). 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 Present address: LEO Pharma, Industriparken 55,0 Ballerup DK-275, Denmark.

² To whom correspondence should be addressed: Tel.: 45-354-56030; Fax: 45-354-53747; E-mail: niels.behrendt{at}finsenlab.dk.

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