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J. Biol. Chem. 277 (21): 18736-18743

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Proteolytic Processing of Low Density Lipoprotein Receptor-related Protein Mediates Regulated Release of Its Intracellular Domain*

Petra MayDagger , Y. Krishna Reddy§, and Joachim HerzDagger

From the Departments of Dagger  Molecular Genetics and § Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The low density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional cell surface receptor that interacts through its cytoplasmic tail with adaptor and scaffold proteins that participate in cellular signaling. Its extracellular domain, like that of the signaling receptor Notch and of amyloid precursor protein (APP), is proteolytically processed at multiple positions. This similarity led us to investigate whether LRP, like APP and Notch, might also be cleaved at a third, intramembranous or cytoplasmic site, resulting in the release of its intracellular domain. Using independent experimental approaches we demonstrate that the cytoplasmic domain is released by a gamma -secretase-like activity and that this event is modulated by protein kinase C. Furthermore, cytoplasmic adaptor proteins that bind to the LRP tail affect the subcellular localization of the free intracellular domain and may regulate putative signaling functions. Finally, we show that the degradation of the free tail fragment is mediated by the proteasome. These findings suggest a novel role for the intracellular domain of LRP that may involve the subcellular translocation of preassembled signaling complexes from the plasma membrane.


* This work was supported in part by National Institutes of Health Grants HL20948, HL63762, and NS43408, the Deutsche Forschungsgemeinschaft (to P. M.), by the Alzheimer Association, and by the Perot Family Foundation.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.

An Established Investigator of the American Heart Association and Parke Davis and recipient of a Wolfgang-Paul Award from the Humboldt Foundation. To whom correspondence should be addressed: Dept. of Molecular Genetics, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390-9046. Tel.: 214-648-5633; Fax: 214-648-8804; E-mail: Joachim.Herz@UTSouthwestern.edu.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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