Abstract
Since the discovery of a novel liver hyaluronan (HA) clearance receptor in 1981 by Laurent, Fraser and coworkers, 22 different ligands cleared by the renamed receptor (the Hyaluronan Receptor for Endocytosis (HARE); Stabilin-2 (Stab2)) were discovered over 37 years. Ligands fall into three groups: (1) 11 anionic polymers, (2) seven cleaved or modified proteins and (3) four types of cells. Seven synthetic ligands, not found normally in serum or tissues, likely mimic natural molecules cleared by the receptor. In 2002 we purified and cloned HARE, based on HA-binding activity, and two other groups cloned full-length receptor; FEEL-2 and Stab2. Macrophages likely require full-length Stab2 for efficient binding and phagocytosis of bacteria or apoptotic cells, since cell-binding domains are throughout the receptor. In contrast, all 16 known single-molecule binding sites are only within the C-terminal half (190HARE). The HARE isoform is generated by proteolysis, not mRNA splicing. The majority of circulating ligands is cleared by HARE, since sinusoidal endothelial cells of liver, spleen and lymph node express twice as many HARE half-receptors as full-length receptors. Based on their significant binding and functional differences, a modified receptor nomenclature is proposed that designates HARE as the C-terminal half-receptor isoform and Stab2 as the full-length receptor isoform.
Highlights
Since the discovery of a novel liver hyaluronan (HA) clearance receptor in 1981 by Laurent, Fraser and coworkers, 22 different ligands cleared by the renamed receptor (the Hyaluronan Receptor for Endocytosis (HARE); Stabilin-2 (Stab2)) were discovered over 37 years
The number of HA molecules bound per cell would decrease as the HA size increased. In this same 1986 study, Laurent et al [6] reported that the HA clearance receptor recognized chondroitin sulfate-A (CS-A), another member of the glycosaminoglycan (GAG) family of polysaccharides comprised of repeating disaccharide units with an uronic acid and an amino sugar
Based on the ability of CS-A and HA each to inhibit binding of the other ligand, they concluded that the receptor binding sites for both ligands must overlap
Summary
In a 1997 interview [1], Swedish scientist Torvard Laurent described the simple, unpretentious birth of what would eventually become the story of the hyaluronan receptor for endocytosis (HARE). Laurent was an expert in the biophysical and chemical properties of HA and Robert Fraser was an expert in mammalian physiology and anatomy Their collaboration provided an excellent combination of disciplines, perspectives and experimental techniques to perform a broad range of thorough and often elegant in vivo and in vitro studies over the five years to characterize this systemic HA clearance activity. The number of HA molecules bound per cell would decrease as the HA size (mass) increased In this same 1986 study, Laurent et al [6] reported that the HA clearance receptor recognized chondroitin sulfate-A (CS-A), another member of the glycosaminoglycan (GAG) family of polysaccharides comprised of repeating disaccharide units with an uronic acid and an amino sugar (as for HA). Based on the ability of CS-A and HA each to inhibit binding of the other ligand, they concluded that the receptor binding sites for both ligands must overlap
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