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Proteolytic Processing of Low Density Lipoprotein
Receptor-related Protein Mediates Regulated Release of Its
Intracellular Domain*
Petra
May,
Y. Krishna
Reddy§, and
Joachim
Herz¶
From the Departments of 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 interactsthrough its cytoplasmic tail with adaptor and
scaffold proteinsthat participate in cellular signaling. Its
extracellular domain,like that of the signaling receptor Notch and of
amyloid precursorprotein (APP), is proteolytically processed at
multiple positions.This similarity led us to investigate whether LRP,
like APP andNotch, might also be cleaved at a third, intramembranous
or cytoplasmicsite, resulting in the release of its intracellular
domain. Usingindependent experimental approaches we demonstrate that
the cytoplasmicdomain is released by a -secretase-like activity and
that thisevent is modulated by protein kinase C. Furthermore,
cytoplasmicadaptor proteins that bind to the LRP tail affect the
subcellularlocalization of the free intracellular domain and may
regulateputative signaling functions. Finally, we show that the
degradationof the free tail fragment is mediated by the proteasome.
Thesefindings suggest a novel role for the intracellular domain ofLRP
that may involve the subcellular translocation of preassembledsignaling complexes from the plasmamembrane.
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,
-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.
