The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro.
Cell-surface heparan sulfate proteoglycans have been shown to participate in lipoprotein catabolism, but the roles of specific proteoglycan classes have not been examined previously. Here, we studied the involvement of the syndecan proteoglycan family. First, transfection of CHO cells with expression vectors for several syndecan core proteins produced parallel increases in the cell association and degradation of lipoproteins enriched in lipoprotein lipase, a heparan-binding protein. Second, a chimeric construct, FcR-Synd1, that consists of the ectodomain of the IgG Fc receptor Ia linked to the highly conserved transmembrane and cytoplasmic domains of syndecan-1 directly mediated efficient internalization, in a process triggered by ligand clustering. Third, internalization of lipase-enriched lipoproteins via syndecan-1 and of clustered IgGs via the chimera showed identical kinetics (t1/2 = 1 h) and identical dose-response sensitivities to cytochalasin B, which disrupts microfilaments, and to genistein, which inhibits tyrosine kinases. In contrast, internalization of the receptor-associated protein, which proceeds via coated pits, showed a t1/2 < 15 min, limited sensitivity to cytochalasin B, and complete insensitivity to genistein. Thus, syndecan proteoglycans can directly mediate ligand catabolism through a pathway with characteristics distinct from coated pits, and might act as receptors for atherogenic lipoproteins and other ligands in vivo.
Fuki
I V
IV
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Kuhn
K M
KM
Lomazov
I R
IR
Rothman
V L
VL
Tuszynski
G P
GP
Iozzo
R V
RV
Swenson
T L
TL
Fisher
E A
EA
Williams
K J
KJ
D000818:Animals; D016466:CHO Cells; D002738:Chloroquine / Q000494:pharmacology; D006224:Cricetinae; D003571:Cytochalasin B / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000493:pharmacokinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology; D011973:Receptors, LDL / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D053668:Syndecan-1; D053667:Syndecans; D019699:Thrombospondins / Q000494:pharmacology; D014162:Transfection
D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; C508241:SDC1 protein, human; C508243:Sdc1 protein, rat; D053668:Syndecan-1; D053667:Syndecans; D019699:Thrombospondins; D003571:Cytochalasin B; D002738:Chloroquine; D006493:Heparin; D019833:Genistein; D008071:Lipoprotein Lipase