Journal of Molecular Neuroscience

, Volume 15, Issue 3, pp 189–204 | Cite as

Requirement for presenilin 1 in facilitating jagged 2-mediated endoproteolysis and signaling of notch 1

  • Jayme L. Martys-Zage
  • Seong-Hun Kim
  • Bridget Berechid
  • Sarah J. Bingham
  • Su Chu
  • Jeffrey Sklar
  • Jeff Nye
  • Sangram S. Sisodia
Article

Abstract

Presenilin 1 (PS1), a polytopic membrane protein, is required for endoproteolytic processing at γ-secretase site within the transmembrane domain of amyloid precursor proteins (APP). In addition, PS1 and its orthologues facilitate signaling of Notch family members, cell-surface receptors that specify cell fates during development. To clarify the mechanism(s) by which PS facilitates Notch signaling, we examined human Jagged-2-dependent metabolism and activity of a chimeric full-length Notch1-GFP molecule expressed in fibroblasts with heterozygous, or homozygous deletions of PS1. We demonstrate that PS1 is required for facilitating Jagged 2-mediated proteolysis and that translocation and accumulation of NICD in the nucleus correlates with signaling activity. Moreover, in a ligand-independent, Ca2+-depletion paradigm, we demonstrate that PS1 facilitates endoproteolysis of a plasma-membrane-associated, Notch1-GFP derivative. Finally, we report that NICD production is inhibited by L-685,458, a potent and selective inhibitor that blocks solubilized γ-secretase activity and Aβ production in cultured cells. These findings strongly suggest that intramembranous processing of APP and Notch 1 are mediated by similar, if not identical, proteases that require PS1 for their activation.

Index Entries

Presenilin Notch 1 Jagged 2 Alzheimer’s disease green fluorescent protein 

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Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • Jayme L. Martys-Zage
    • 1
  • Seong-Hun Kim
    • 1
  • Bridget Berechid
    • 2
  • Sarah J. Bingham
    • 3
  • Su Chu
    • 1
  • Jeffrey Sklar
    • 4
  • Jeff Nye
    • 2
  • Sangram S. Sisodia
    • 1
  1. 1.Departments of Neurobiology, Pharmacology, and Physiology, Howard Hughes Medical InstituteThe University of ChicagoChicago
  2. 2.Department of Molecular Pharmacology and Biological Chemistry and Department of PediatricsNorthwestern University Medical SchoolChicago
  3. 3.Kalamazoo CollegeKalamazoo
  4. 4.Department of PathologyHarvard Medical SchoolCambridge

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