Perlecan heparan sulfate proteoglycan - A novel receptor that mediates a distinct pathway for ligand catabolism

Cell surface heparan sulfate proteoglycans (HSPGs) participate in the catab olism of many physiologically important ligands. We previously reported tha t syndecan HSPGs directly mediate endocytosis, independent of coated pits. We now studied perlecan, a major cell surface HSPG genetically distinct fro m syndecans. Cells expressing perlecan but no other proteoglycans bound, in ternalized, and degraded atherogenic lipoproteins enriched in lipoprotein l ipase. Binding was blocked by heparitinase, and degradation by chloroquine. Antibodies against beta(1) integrins reduced initial ligand binding, consi stent with their roles as cell surface attachment sites for perlecan. By se veral criteria, catabolism via perlecan was distinct from either coated pit s or the syndecan pathway. The kinetics of internalization (t(1/2) = 6 h) a nd degradation (t(1/2) similar to 18 h) were remarkably slow, unlike the ot her pathways. Blockade of the low density lipoprotein receptor-related prot ein did not slow perlecan-dependent internalization. Internalization via pe rlecan was inhibited by genistein but unaffected by cytochalasin D, a patte rn 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 biochemicall y distinct from other known uptake pathways and is consistent with a very s low component of HSPG-dependent ligand processing found in vitro and in viv o.