Perlecan heparan sulfate proteoglycan: a novel receptor that mediates a distinct pathway for ligand catabolism.
Cell surface heparan sulfate proteoglycans (HSPGs) participate in the catabolism of many physiologically important ligands. We previously reported that syndecan HSPGs directly mediate endocytosis, independent of coated pits. We now studied perlecan, a major cell surface HSPG genetically distinct from syndecans. Cells expressing perlecan but no other proteoglycans bound, internalized, and degraded atherogenic lipoproteins enriched in lipoprotein lipase. Binding was blocked by heparitinase, and degradation by chloroquine. Antibodies against beta(1) integrins reduced initial ligand binding, consistent with their roles as cell surface attachment sites for perlecan. By several criteria, catabolism via perlecan was distinct from either coated pits or the syndecan pathway. The kinetics of internalization (t(12) = 6 h) and degradation (t(12) approximately 18 h) were remarkably slow, unlike the other pathways. Blockade of the low density lipoprotein receptor-related protein did not slow perlecan-dependent internalization. Internalization via perlecan was inhibited by genistein but unaffected by cytochalasin D, a pattern distinct from coated pits or syndecan-mediated endocytosis. Finally, we examined cooperation between perlecan and low density lipoprotein receptors and found limited synergy. Our results demonstrate that perlecan mediates internalization and lysosomal delivery that is kinetically and biochemically distinct from other known uptake pathways and is consistent with a very slow component of HSPG-dependent ligand processing found in vitro and in vivo.
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Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, THomas Jefferson University, Philadelphia, PA 19107, USA.
Iozzo
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Williams
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D000818:Animals; D001158:Arteries / Q000378:metabolism; D016466:CHO Cells; D002417:Cattle; D002738:Chloroquine / Q000494:pharmacology; D006224:Cricetinae; D015638:Cytochalasin D / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008077:Lipoproteins, LDL / Q000097:blood; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008247:Lysosomes / Q000378:metabolism; D008892:Milk / Q000737:chemistry; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019812:Heparan Sulfate Proteoglycans; D008024:Ligands; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019384:Nucleic Acid Synthesis Inhibitors; D011971:Receptors, Immunologic; C071927:perlecan; D015638:Cytochalasin D; D002738:Chloroquine; D019833:Genistein; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase