Molecular and Cellular Biology of Plasminogen Activation

i034i
Interplay between MMPs and the Endocytic Collagen
Receptor, uPARAP/Endo180, in Collagen Degradation
Behrendt N* 1 , Madsen DH 1 , Ingvarsen S 1 , Hillig T 1 , Wagenaar-Miller R 2 , Kjøller L 1 , Gårdsvoll H 1 ,
Høyer-Hansen G 1 , Bugge TH 2 , Engelholm LH 1
1 The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark;
2Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH,
Bethesda, Maryland, USA
Presenting author e-mail: niels.behrendt@finsenlab.dk
The uPAR-associated protein (uPARAP/Endo180) is an endocytic cell surface receptor on
mesenchymal cells that is centrally engaged in the turnover of collagens of several subtypes. It
has recently become clear that uPARAP/Endo180-mediated collagen degradation takes place
both during bone development and in the invasive growth of malignant tumors. In this work, we
have focused on the interplay between this new mechanism and the more extensively studied,
extracellular routes of collagenolysis. In collagen internalization assays, 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, the growth of uPARAP/Endo180 deficient fibroblasts on a native
collagen matrix leads to a dramatic accumulation of large collagen fragments in the culture
supernatant. In contrast, wildtype fibroblasts possess the ability to direct a complete collagen
breakdown sequence, including both initial, extracellular cleavage, endocytic (uPARAP/Endo180
mediated) uptake of large, defined fragments and a final, intracellular degradation step. Thus,
our work shows that 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.
46 X I t h I n t e r n a t i o n a l W o r k s h o p o n