[Frontiers in Bioscience 14, 2103-2114, January 1, 2009]

The collagen receptor uPARAP/Endo180

Lars H. Engelholm1,2, Signe Ingvarsen1, Henrik J. Jürgensen1, Thore Hillig1, Daniel H. Madsen1, Boye S. Nielsen1,3 and Niels Behrendt1

1The Finsen Laboratory, Rigshospitalet section 3735, Copenhagen Biocenter, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark, 2The Bartholin Institute, Rigshospitalet section 3731, Copenhagen Biocenter room, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark, 3Exiqon, Bygstubben 9, 2950 Vedbaek, Denmark

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Protein structure and molecular interactions
3.1. uPARAP belongs to an established protein family of endocytic receptors
3.2. The domains of uPARAR
3.3. The interaction of uPARAP with collagen
4. The cellular function of uPARAP
4.1. Collagen turnover
4.2. Interaction with pro-uPA and uPAR
dt>5. Tissue expression and physiological functions of uPARAP
5.1. Cellular and tissue specific expression
5.2. Expression of uPARAP in cancer
5.3. Physiological function of uPARAP and phenotype of uPARAP-deficient mice
5.4. Role in cancer
6. Conclusions and perspectives
7. Acknowledgement
8. References

1. ABSTRACT

The uPAR-associated protein (uPARAP/Endo180), a type-1 membrane protein belonging to the mannose receptor family, is an endocytic receptor for collagen. Through this endocytic function, the protein takes part in a previously unrecognized mechanism of collagen turnover. uPARAP/Endo180 can bind and internalize both intact and partially degraded collagens. In some turnover pathways, the function of the receptor probably involves an interplay with certain matrix-degrading proteases whereas, in other physiological processes, redundant mechanisms involving both endocytic and pericellular collagenolysis seem to operate in parallel. On certain cell types, uPARAP/Endo180 occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it seems to fulfill other functions in addition to collagenolysis. uPARAP/Endo180 is expressed on various mesenchymal cells, including subpopulations of fibroblasts, osteoblasts and chondrocytes, generally in conjunction with matrix turnover and collagenolysis. A striking expression is found in developing bone where the collagenolytic function of uPARAP/Endo180 is one of the rate-limiting steps in growth. In murine breast tumors, the endocytic function of the receptor in collagen breakdown seems to be involved in invasive tumor growth.