uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion

Abstract

The uptake and lysosomal degradation of collagen by fibroblasts constitute a major pathway in the turnover of connective tissue. However, the molecular mechanisms governing this pathway are poorly understood. Here, we show that the urokinase plasminogen activator receptor–associated protein (uPARAP)/Endo180, a novel mesenchymally expressed member of the macrophage mannose receptor family of endocytic receptors, is a key player in this process. Fibroblasts from mice with a targeted deletion in the uPARAP/Endo180 gene displayed a near to complete abrogation of collagen endocytosis. Furthermore, these cells had diminished initial adhesion to a range of different collagens, as well as impaired migration on fibrillar collagen. These studies identify a central function of uPARAP/Endo180 in cellular collagen interactions.

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

“…The importance of CTLD4 for the formation of the suppressive Endo180-CD147 complex in PECs was not uncovered in Endo180 DEx2-6/DEx2-6 mice that express a truncated form of the Endo180 receptor, including an intact CTLD4, and reach adulthood (32,33). Nevertheless, our analysis of prostate tissue from adult Endo180 DEx2-6/DEx2-6 mice has revealed that a significant architectural change occurs that closely recapitulates prostatic intraepithelial neoplasia, a common precursor for invasive prostate cancer (M. Rodriguez-Teja and colleagues; unpublished data).…”

Differential Regulation of Extracellular Tissue Inhibitor of Metalloproteinases-3 Levels by Cell Membrane-bound and Shed Low Density Lipoprotein Receptor-related Protein 1

“…Members belonging to the macrophage mannose receptor protein family may be possible candidates because they have been shown to internalize some LRP-1 ligands and play a crucial role in ECM turnover. For instance, urokinase plasminogen activator receptor-associated protein/endocytic recycling protein Endo180 is expressed in chondrocytes and fibroblasts and is involved in collagen internalization (40,41). TIMP-1 and TIMP-2 are also endocytosed by LRP-1 (42,43).…”

Endo180 Binds to the C-terminal Region of Type I Collagen

“…The interaction between various collagen types and Endo180 appears to play a role in cell-matrix adhesion, since Endo180-deficient cells have a 50% reduction in adhesion to type V collagen and also a reduced ability to bind to purified types I and IV collagen (54). To investigate whether the C-terminal glycine repeat region and C-prodomain of the ␣1 chain collagen mediate this adhesion to Endo180, we performed competition binding experiments.…”

“…The four receptors are type I transmembrane proteins with a highly conserved structure composed of an N-terminal cysteine-rich or ricin-type domain, a fibronectin type II domain, 8 or 10 C-type lectin-like domains (CTLDs), a single transmembrane domain, and a short cytoplasmic domain (51). Endo180 previously has been shown to act as a collagen receptor by binding to gelatin, type I, type II, type IV, and type V collagens and also mediates endocytosis and turnover of these extracellular matrix proteins (52)(53)(54)(55)(56). The fibronectin type II domain of Endo180 (which shares a highly conserved sequence with other collagen-binding fibronectin type II domains, such as fibronectin, MMP-2, and MMP-9 (49, 51, 52)) appears to be required for binding to these collagens.…”