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1 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
2 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Kidney Center, Nagaoka Red Cross Hospital, Nagaoka, Japan
3 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, University of California, San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: mfarquhar{at}ucsd.edu.
Megalin is the main endocytic receptor of the proximal tubule and is responsible for reabsorption of many filtered proteins. In contrast to other members of the low-density lipoprotein (LDL) receptor gene family it is expressed on the apical PM of polarized epithelial cells. To identify megalin's apical sorting signal we generated deletion mutants and chimeric minireceptors composed of complementary regions of megalin and LDL receptor related protein (LRP) and assessed the distribution of the mutants in MDCK cells by immunofluorescence and cell surface biotinylation. Megalin and LRP minireceptors are correctly targeted to the apical and basolateral PM, respectively, of Madin-Darby canine kidney (MDCK) cells. We found that the information that directs apical sorting is present in the cytoplasmic tail (CT) of megalin which contains three NPXY motifs, YXXØ, SH3, and di-leucine motifs, and a PDZ binding motif at its C-terminus. Deletion analysis established that aa107-136 of the megalin-CT containing the second NPXY-like motif is critical for apical sorting and targeting, whereas the regions containing the first and third NPXY motifs are required for efficient endocytosis. We conclude that the megalin-CT contains a novel apical sorting determinant and that cytoplasmic sorting machinery exists in MDCK cells for some apical transmembrane proteins.
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