Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates

The low density lipoprotein receptor (LDLR) family is composed of a class o f cell surface endocytic receptors that recognize extracellular ligands and internalize them for degradation by lysosomes, In addition to LDLR, mammal ian members of this family include the LDLR-related protein (LRP), the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor-2 (apoER2), and megalin. Herein we have analyzed the endocytic functions of t he cytoplasmic tails of these receptors using LRP minireceptors, its chimer ic receptor constructs, and full-length VLDLR and apoER2 stably expressed i n LRP-null Chinese hamster ovary cells. We find that the initial endocytosi s rates mediated by different cytoplasmic tails are significantly different , with half-times of ligand internalization ranging from less than 30 s to more than 8 min. The tail of LRP mediates the highest rate of endocytosis, whereas those of the VLDLR and apoER2 exhibit least endocytosis function. C ompared with the tail of LRP, the tails of the LDLR and megalin display sig nificantly lower levels of endocytosis rates. Ligand degradation analyses s trongly support differential endocytosis rates initiated by these receptors . Interestingly apoER2, which has recently been shown to mediate intracellu lar signal transduction, exhibited the lowest level of ligand degradation e fficiency. These results thus suggest that the endocytic functions of membe rs of the LDLR family are distinct and that certain receptors in this famil y may play their main roles in areas other than receptor-mediated endocytos is.