The collagen receptor uPARAP/Endo180

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.

Collagen Type I as a Ligand for Receptor-Mediated Signaling

“…Such fragments can potentially activate the receptors of LRC, GPVI, LAIR-1, and G6b-B, as well as uPARAP/Endo180. Since LAIR-1 is expressed by osteoclasts [34] and uPARAP/Endo180 by osteoblasts [129], it is possible that such signals mediate temporal and spatial coordination of collagen matrix formation and degradation. In addition, formation of circulating fragments, such as those used as biomarkers of bone resorption [130], raises a possibility of long-distance signals generated during collagen degradation.…”

Mannose Receptor 2 Attenuates Renal Fibrosis

“…Remarkably, Mrc2 can internalize native as well as denatured collagens, although collagenase-mediated cleavage increases Mrc2 binding. 18,23 Mrc2 expression by either stromal cells or malignant cells has been associated with enhanced tumor invasion and metastasis. 25,[46][47][48] This study reveals that it also serves an important role in solid organ fibrosis by reducing the rate of interstitial collagen accumulation, resulting in protection of the surrounding parenchyma from fibrosis-associated destruction.…”

“…Current evidence indicates that Mrc2 serves primarily as an endocytic receptor that shuttles extracellular cargo to endolysosomes for degradation via a process that involves clathrincoated pits. 18 Once this process is complete, Mrc2 recycles back to the cell membrane-a cycle that may occur as often as 10 times per hour. 31 Extensive in vitro evidence, based primarily on studies in fibroblasts, suggests that collagens (I, III, IV, and likely others) are the major Mrc2 ligands.…”

“…22 Cultured Mrc2 +/+ fibroblasts were shown to internalize collagens I, VI, and V; it has been predicted that additional collagens may also be degraded via this pathway. 18,[23][24][25] Inhibition by E64d suggests that the collagenolytic lysosomal cathepsins are involved. [25][26][27] One physiologic function of Mrc2 seems to be in bone formation.…”

“…17 However, a series of in vitro studies published since 2000 report that the fibronectin type II domain of the mannose receptor 2 (Mrc2) functions as an endocytic receptor for soluble collagens using clathrin-coated pits to deliver collagen cargos to endolysosomes to be degraded. 18 Mrc2 is one of four members of the mannose receptor family, each a constitutive recycling receptor, but with distinct ligands. 19 The other members are mannose receptor 1, 20 the M-type phospholipase A2 receptor, 21 and dendritic cell DEC-205/LY75.…”