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J. Biol. Chem., Vol. 283, Issue 25, 17341-17350, June 20, 2008

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The Human Hyaluronan Receptor for Endocytosis (HARE/Stabilin-2) Is a Systemic Clearance Receptor for Heparin^*

From the Department of Biochemistry and Molecular Biology, and The Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190

The hyaluronic acid receptor for endocytosis (HARE; also designated Stabilin-2) mediates systemic clearance of hyaluronan and chondroitin sulfates from the vascular and lymphatic circulations. The internalized glycosaminoglycans are degraded in lysosomes, thus completing their normal turnover process. Sinusoidal endothelial cells of human liver, lymph node, and spleen express two HARE isoforms of 315 and 190 kDa. Here we report that the 190- and 315-kDa HARE isoforms, expressed stably either in Flp-In 293 cell lines or as soluble ectodomains, specifically bind heparin (Hep). The K_d for Hep binding to purified 190- and 315-kDa HARE ectodomains was 17.2 ± 4.9 and 23.4 ± 5.3 nM, respectively. Cells expressing HARE readily and specifically internalized ¹²⁵I-streptavidin-biotin-Hep complexes, which was inhibited >70% by hyperosmolar conditions, confirming that uptake is mediated by the clathrin-coated pit pathway. Internalization of Hep occurred for many hours with an estimated HARE recycling time of 12 min. Internalized fluorescent streptavidin-biotin-Hep was present in a typical endocytic vesicular pattern and was delivered to lysosomes. We conclude that HARE in the sinusoidal endothelial cells of lymph nodes and liver likely mediates the efficient systemic clearance of Hep and many different Hep-binding protein complexes from the lymphatic and vascular circulations.

Received for publication, December 19, 2007 , and in revised form, April 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM69961 from NIGMS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 405-271-1288; Fax: 405-271-3092; E-mail: paul-weigel{at}ouhsc.edu.

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This article has been cited by other articles:

				E. N. Harris, B. A. Baggenstoss, and P. H. Weigel Rat and human HARE/stabilin-2 are clearance receptors for high- and low-molecular-weight heparins Am J Physiol Gastrointest Liver Physiol, June 1, 2009; 296(6): G1191 - G1199. [Abstract] [Full Text] [PDF]

				E. N. Harris and P. H. Weigel The ligand-binding profile of HARE: hyaluronan and chondroitin sulfates A, C, and D bind to overlapping sites distinct from the sites for heparin, acetylated low-density lipoprotein, dermatan sulfate, and CS-E Glycobiology, August 1, 2008; 18(8): 638 - 648. [Abstract] [Full Text] [PDF]

				M. S. Pandey, E. N. Harris, J. A. Weigel, and P. H. Weigel The Cytoplasmic Domain of the Hyaluronan Receptor for Endocytosis (HARE) Contains Multiple Endocytic Motifs Targeting Coated Pit-mediated Internalization J. Biol. Chem., August 1, 2008; 283(31): 21453 - 21461. [Abstract] [Full Text] [PDF]