The endocytic collagen receptor, uPARAP/Endo180, is involved in the degradation of basement membrane and extracellular matrix collagen during invasive tumor growth (Curino, A. et al. (2005), J. Cell Biol. 169: 977–85). We have studied the interplay between uPARAP/Endo180-mediated endocytic collagen turnover and various extracellular routes of collagenolysis, mediated by matrix metalloproteases (MMPs). Whereas mice double-deficient for uPARAP/Endo180 and the membrane-associated MMP, MT1-MMP, have a highly compromised phenotype (Wagenaar-Miller, R. et al. (2007), Mol. Cell. Biol. 27: 6309–22), mice with combined deficiency for uPARAP/Endo180 and the soluble collagenase, MMP-13, have a phenotype close to that of mice deficient for either component alone. In a model system for studies on collagenolytic mechanisms in vitro, 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 (Madsen, D.M. et al. (2007), J. Biol. Chem. 282: 27037–45). In this system, 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. This preference is governed by the acquisition of a gelatin like structure of collagen, occurring upon collagenase-mediated cleavage under native conditions. Furthermore, a comparison of wildtype and uPARAP/Endo180-deficient fibroblasts showed that the latter cells, when grown on a native collagen matrix, display a dramatic accumulation of large collagen fragments in the culture supernatant. In contrast, wildtype fibroblasts possess the ability to direct a complete breakdown sequence, including the final intracellular degradation step after endocytosis of the initial collagen fragments. Thus, extracellular collagenolysis and endocytic collagen turnover can occur as an integrated mechanism in cultured fibroblasts and fibroblast-like cells. Most likely, a similar mechanism is operative in the stromal cell types that are responsible for collagenolysis during tumor invasion.
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Document Type: Abstract
Finsenlaboratoriet, Rigshospitalet, Ole Maaløes Vej 5, 2200 Kbh. N, Danmark
Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Publication date: May 1, 2008