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Originally published In Press as doi:10.1074/jbc.M101589200 on February 21, 2001

J. Biol. Chem., Vol. 276, Issue 21, 18000-18006, May 25, 2001
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Differential Functions of Members of the Low Density Lipoprotein Receptor Family Suggested by Their Distinct Endocytosis Rates*

Yonghe LiDagger §, Wenyan LuDagger , Maria Paz Marzolo, and Guojun BuDagger ||

From the Dagger  Departments of Pediatrics and Cell Biology and Physiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110 and the  Department of Biology, University of Chile, Santiago, Chile

The low density lipoprotein receptor (LDLR) family is composed of a class of cell surface endocytic receptors that recognize extracellular ligands and internalize them for degradation by lysosomes. In addition to LDLR, mammalian 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 the cytoplasmic tails of these receptors using LRP minireceptors, its chimeric receptor constructs, and full-length VLDLR and apoER2 stably expressed in LRP-null Chinese hamster ovary cells. We find that the initial endocytosis 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. Compared with the tail of LRP, the tails of the LDLR and megalin display significantly lower levels of endocytosis rates. Ligand degradation analyses strongly support differential endocytosis rates initiated by these receptors. Interestingly apoER2, which has recently been shown to mediate intracellular signal transduction, exhibited the lowest level of ligand degradation efficiency. These results thus suggest that the endocytic functions of members of the LDLR family are distinct and that certain receptors in this family may play their main roles in areas other than receptor-mediated endocytosis.

* This work was supported in part by National Institutes of Health Grants NS37525, HL59150, and DK56783 (to G. B.) and by Fondecyt Grant 1990600, (to M. P. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a postdoctoral fellowship from the Heartland Affiliate of the American Heart Association.

|| Established Investigator of the American Heart Association. To whom correspondence should be addressed: Dept. of Pediatrics, Washington University School of Medicine, CB 8208, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-286-2860; Fax: 314-286-2894; E-mail: bu@kids.wustl.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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