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J. Biol. Chem., Vol. 279, Issue 33, 34302-34310, August 13, 2004
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¶
From the
Departments of Internal Medicine and Cellular and Molecular Physiology, School of Medicine, Yale University, New Haven, Connecticut 06520-8029
Megalin, a member of the low density lipoprotein receptor gene family, is required for efficient protein absorption in the proximal tubule. Recent studies have shown that the low density lipoprotein receptor-related protein, another member of this gene family, is proteolytically processed by 
-secretase implying a role for low density lipoprotein receptor-related protein in a Notchlike signaling pathway. This pathway has been shown to involve: 1) metalloprotease-mediated ectodomain shedding and -secretase-mediated intramembrane proteolysis of some receptors. Experiments were performed to determine whether megalin undergoes similar processing. By immunocytochemistry, immunoblotting, and a fluorogenic enzyme assay presenilin-1 (required for -secretase activity) and -secretase activity were found in the brush border of proximal kidney tubules where megalin is localized. Using a fluorogenic peptide containing an amyloid precursor protein -secretase cleavage site and Compound E, a specific -secretase inhibitor, we found high levels of -secretase activity in renal brush border membrane vesicles. Immunoblotting analysis of renal microsomes and opossum kidney proximal tubule (OKP) cells using antibodies directed to the cytosolic domain of megalin showed a 35–40-kDa, membrane-associated, carboxyl-terminal fragment of megalin (MCTF). When cells were incubated with 200 nM phorbol 12-myristate 13-acetate, the appearance of the MCTF increased 2.5-fold and was blocked by metalloprotease inhibitors. When the cells were incubated with -secretase inhibitor Compound E, it caused a 2-fold increase in MCTF. Finally, incubating the cells with 1 µM vitamin D-binding protein resulted in a 25% increase in the appearance of the MCTF. In summary, the MCTF is produced by protein kinase C regulated, metalloprotease-mediated ectodomain shedding and is the substrate for -secretase. We postulate that the enzymatic processing of megalin represents part of a novel ligand-dependent signaling pathway in the proximal tubule that links receptor-mediated endocytosis with cell signaling.
Received for publication, May 19, 2004 , and in revised form, June 3, 2004.
* This work was supported by National Institutes of Health Grant DK543933 (to D. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY627686
¶ To whom correspondence and reprint requests should be addressed: Section of Nephrology, Dept. of Internal Medicine, Yale University School of Medicine, 300 Cedar St., TAC S255, P. O. Box 208029, New Haven, CT 06520-8029. Tel.: 203-785-6739; Fax: 203-785-4904; E-mail: daniel.biemesderfer{at}yale.edu.
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