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

J. Biol. Chem., 24 May 2002
Vol. 277, Issue 21, p. 18736-18743
DOI: 10.1074/jbc.M201979200

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

Abstract

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 γ-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.

  • Abbreviations:
    LDL
    low density lipoprotein
    LRP
    LDL receptor-related protein
    VLDL
    very low density lipoprotein
    apo-ER2
    apolipoprotein E receptor 2
    APP
    amyloid precursor protein
    ICD
    intracellular domain
    PKC
    protein kinase C
    PMA
    phorbol 12-myristate 13-acetate
    DAPT
    N-[N-(3,5,-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butyl ester
    VP16
    viral protein 16
    JNK
    c-Jun amino-terminal kinase
    DMEM
    Dulbecco's modified Eagle's medium
    FCS
    fetal calf serum
    MOPS
    4-morpholinepropanesulfonic acid
    PS1
    presenilin-1
    wt
    wild type
    PTB
    phosphotyrosine binding
    • Received February 27, 2002.
    • Revision received March 20, 2002.

    Citation:

    P. May, Y. K. Reddy, and J. Herz, Proteolytic Processing of Low Density Lipoprotein Receptor-related Protein Mediates Regulated Release of Its Intracellular Domain. J. Biol. Chem. 277, 18736-18743 (2002).

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