GLYCOPROTEIN-330 LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN-2 MEDIATES ENDOCYTOSIS OF LOW-DENSITY LIPOPROTEINS VIA INTERACTION WITH APOLIPOPROTEIN B100
S. Stefansson et al., GLYCOPROTEIN-330 LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN-2 MEDIATES ENDOCYTOSIS OF LOW-DENSITY LIPOPROTEINS VIA INTERACTION WITH APOLIPOPROTEIN B100, The Journal of biological chemistry, 270(33), 1995, pp. 19417-19421
The ability of glycoprotein 330/low density lipoprotein receptor-relat
ed protein-2 (LRP-2) to function as a lipoprotein receptor was investi
gated using cultured mouse F9 teratocarcinoma cells. Treatment with re
tinoic acid and dibutyryl cyclic AMP, which induces F9 cells to differ
entiate into endoderm-like cells, produced a 50-fold increase in the e
xpression of LRP-2. Levels of the other members of the low density lip
oprotein (LDL) receptor (LDLR) family, including LDLR, the very low de
nsity lipoprotein receptor, and LRP-1, were reduced, When LDL cataboli
sm was examined in these cells, it was found that the treated cells en
docytosed and degraded at 10-fold higher levels than untreated cells.
The increased LDL uptake coincided with increased LRP-2 activity of th
e treated cells, as measured by uptake of both I-125-labeled monoclona
l LRP-2 antibody and the LRP-2 ligand prourokinase. The ability of LDL
to bind to LRP-2 was demonstrated by solid-phase binding assays. This
binding was inhibitable by LRP-2 antibodies, receptor-associated prot
ein (the antagonist of ligand binding for all members of the LDLR fami
ly), or antibodies to apoB100, the major apolipoprotein component of L
DL. In cell assays, LRP-2 antibodies blocked the elevated I-125-LDL in
ternalization and degradation observed in the retinoic acid/dibutyryl
cyclic AMP treated F9 cells. A low level of LDL endocytosis existed th
at was likely mediated by LDLR since it could not be inhibited by LRP-
2 antibodies, but was inhibited by excess LDL, receptor-associated pro
tein, or apoB100 antibody. The results indicate that LRP-2 can functio
n to mediate cellular endocytosis of LDL, leading to its degradation.
LRP-2 represents the second member of the LDLR family identified as fu
nctioning in the catabolism of LDL.