uPARAP/Endo180: a multifaceted protein of mesenchymal cells

Abstract

The urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) is already known to be a key collagen receptor involved in collagen internalization and degradation in mesenchymal cells and some macrophages. It is one of the four members of the mannose receptor family along with a macrophage mannose receptor (MMR), a phospholipase lipase receptor (PLA2R), and a dendritic receptor (DEC-205). As a clathrin-dependent endocytic receptor for collagen or large collagen fragments as well as through its association with urokinase (uPA) and its receptor (uPAR), uPARAP/Endo180 takes part in extracellular matrix (ECM) remodeling, cell chemotaxis and migration under physiological (tissue homeostasis and repair) and pathological (fibrosis, cancer) conditions. Recent advances that have shown an expanded contribution of this multifunctional protein across a broader range of biological processes, including vascular biology and innate immunity, are summarized in this paper. It has previously been demonstrated that uPARAP/Endo180 assists in lymphangiogenesis through its capacity to regulate the heterodimerization of vascular endothelial growth factor receptors (VEGFR-2 and VEGFR-3). Moreover, recent findings have demonstrated that it is also involved in the clearance of collectins and the regulation of the immune system, something which is currently being studied as a biomarker and a therapeutic target in a number of cancers.

Keywords: Cancer; Collagen; Endocytic receptor; MRC2; Tissue remodeling; uPARAP/Endo180.

Fig. 1

uPARAP/Endo180 belongs to the mannose receptor family. Schematic representation of the fourth members of the mannose receptor family. They share common domains from N-terminal to C-terminal including a Cysteine-rich domain (CRD), a Fibronectin type-II domain (FNII), several C-type lectin-like domains (CTLDs), a transmembrane domain and a cytosolic tail. uPARAP/Endo180 can interact with collagens, collectins and sugars or glycosylated proteins through the ligand-binding region (LBR composed of CRD, FNII, CTLD1 and CTLD2) and with EMMPRIN (CD147) through CTLD4. uPARAP/Endo180 contains two acidic residues (L1468 and V1469) responsible for its internalization and another one (E1464) controlling its trafficking

Fig. 2

The involvement of uPARAP/Endo180 in physiologic and pathological conditions. uPARAP is involved in various physiological processes such as bone development and wound healing. At the pathological level, uPARAP involvement is implied in fibrosis through collagen clearance, in cancer and in immunity

Fig. 3

The cellular functions of uPARAP/Endo180. uPARAP is involved in extracellular matrix (ECM) remodeling through direct binding of collagen to uPARAP. Collagen bound to CTLD2 is internalized by a clathrin-dependent endocytic process. Once in the early endosome, uPARAP is recycled to the membrane while the collagen is degraded in the lysosome. The uPARAP-uPA-uPAR complex enables the conversion of plasminogen to plasmin, which results in the degradation of ECM components. This trimolecular complex is also involved in cell motility via the activation of Rac1 and Cdc42, two small Ras GTPases. uPARAP prevents the heterodimerization of VEGFR-2/VEGFR-3 ensuring the maintenance and integrity of the lymphatic vasculature