The degradation of collagens, the most abundant proteins of the extracellular matrix, is involved in numerous physiological and pathological conditions including cancer invasion. An important turnover pathway involves cellular internalization and degradation of large, soluble collagen fragments, generated by initial cleavage of the insoluble collagen fibers. We have previously observed that in primary mouse fibroblasts, this endocytosis of collagen fragments is dependent on the receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180. Others have identified additional mechanisms of collagen uptake, with different associated receptors, in other cell types. These receptors include ␤1-integrins, being responsible for collagen phagocytosis, and the mannose receptor. We have now utilized a newly developed monoclonal antibody against uPARAP/Endo180, which down-regulates the receptor protein level on treated cells, to examine the role of uPARAP/Endo180 as a mediator of collagen internalization by a wide range of cultured cell types. With the exception of macrophages, all cells that proved capable of efficient collagen internalization were of mesenchymal origin and all of these utilized uPARAP/Endo180 for their collagen uptake process. Macrophages internalized collagen in a process mediated by the mannose receptor, a protein belonging to the same protein family as uPARAP/ Endo180. ␤1-Integrins were found not to be involved in the endocytosis of soluble collagen, irrespectively of whether this was mediated by uPARAP/Endo180 or the mannose receptor. This further distinguishes these pathways from the phagocytic uptake of particulate collagen.Remodeling of the extracellular matrix is required for a wide range of physiological and pathological conditions such as morphogenesis, organ growth, wound healing, arthritis, fibrosis and tumor growth, and metastasis (1-4). Collagens are the most abundant components of the extracellular matrix with collagen type I as the quantitatively dominating subtype. Thus, collagen constitutes about 25-30% of the dry weight of a human (5). The collagen in the body is undergoing continuous renewal and normally the collagen turnover rate is carefully controlled. Depending on the tissue type or extraneous events the collagen turnover rate can change dramatically. Therefore, highly efficient biological systems are needed in both the formation and degradation of collagen throughout life.In normal healthy tissue, collagen is fully hydroxylated and forms insoluble, cross-linked fibers and sheets of triple helical structures that are resistant to attack by most proteases (6). A number of proteases are nevertheless potentially capable of initiating the collagen degradation process through the cleavage of intact collagen fibers. These proteases are the matrix metalloproteinases (MMPs) 3 MMP-1, MMP-2, MMP-8, MMP-13, MMP-14, MMP-15, and MMP-16 and the cysteine protease cathepsin K (7-9). So far, most studies of collagen turnover have focused on the extracellular collagen degradat...

Background: Mannose receptor family members are candidate mediators of intracellular collagen degradation. Results: Despite common candidate collagen-binding domains and endocytic capacity throughout the family, only uPARAP/Endo180 and MR internalize collagens. Conclusion: A multi-domain interplay in the active receptors governs collagen endocytosis. Significance: Identification of the principal collagen receptors allows elucidation of the biological importance of intracellular collagen degradation.

Collagens make up the most abundant component of interstitial extracellular matrices and basement membranes. Collagen remodeling is a crucial process in many normal physiological events and in several pathological conditions. Some collagen subtypes contain specific carbohydrate side chains, the function of which is poorly known. The endocytic collagen receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 plays an important role in matrix remodeling through its ability to internalize collagen for lysosomal degradation. uPARAP/Endo180 is a member of the mannose receptor protein family. These proteins all include a fibronectin type II domain and a series of C-type lectin-like domains, of which only a minor part possess carbohydrate recognition activity. At least two of the family members, uPARAP/Endo180 and the mannose receptor, interact with collagens. The molecular basis for this interaction is known to involve the fibronectin type II domain but nothing is known about the function of the lectin domains in this respect. In this study, we have investigated a possible role of the single active lectin domain of uPARAP/ Endo180 in the interaction with collagens. By expressing truncated recombinant uPARAP/Endo180 proteins and analyzing their interaction with collagens with high and low levels of glycosylation we demonstrated that this lectin domain interacts directly with glycosylated collagens. This interaction is functionally important because it was found to modulate the endocytic efficiency of the receptor toward highly glycosylated collagens such as basement membrane collagen IV. Surprisingly, this property was not shared by the mannose receptor, which internalized glycosylated collagens independently of its lectin function. This role of modulating its uptake efficiency by a specific receptor is a previously unrecognized function of collagen glycosylation.The breakdown and remodeling of the extracellular matrix (ECM) 2 including the basement membrane are important steps in embryonic growth, tissue rearrangements in the healthy body, and invasive cancer growth (1-3). The ECM is composed of a range of different structural proteins, including collagens, laminins, fibronectin, and proteoglycans. The collagens make up by far the most abundant component. Collagens are trimeric proteins that form unique triple helices and assemble into large supramolecular structures such as fibers and sheets, enabling them to form the barriers and structures of the ECM (4).Collagens undergo a range of post-translational modifications, including extensive hydroxylation of prolyl and lysyl residues, N-and O-linked glycosylation, and processing of proforms (5). The hydroxylation of proline and lysine residues plays a role in triple helix stabilization and cross-linking of collagen molecules and the processing of proforms is important for the assembly of collagens into fibrillar structures (6). In contrast, the role of collagen glycosylation is poorly understood. Most is known about the O-linked glycosylation...

The collagen receptor uPARAP/Endo180, the product of the MRC2 gene, is a central component in the collagen turnover process governed by various mesenchymal cells. Through the endocytosis of collagen or large collagen fragments, this recycling receptor serves to direct basement membrane collagen as well as interstitial collagen to lysosomal degradation. This capacity, shared only with the mannose receptor from the same protein family, endows uPARAP/Endo180 with a critical role in development and homeostasis, as well as in pathological disruptions of the extracellular matrix structure. Important pathological functions of uPARAP/Endo180 have been identified in various cancers and in several fibrotic conditions. With a particular focus on matrix turnover in cancer, this review presents the necessary background for understanding the function of uPARAP/Endo180 at the molecular and cellular level, followed by an in-depth survey of the available knowledge of the expression and role of this receptor in various types of cancer and other degenerative diseases.