Identification and characterization of presenilin-independent Notch signaling

J Biol Chem. 2002 Mar 8;277(10):8154-65. doi: 10.1074/jbc.M108238200. Epub 2001 Dec 26.


Presenilin (PS) proteins control the proteolytic cleavage that precedes nuclear access of the Notch intracellular domain. Here we observe that a partial activation of the HES1 promoter can be detected in PS1/PS2 (PS1/2) double null cells using Notch1 Delta E constructs or following Delta 1 stimulation, despite an apparent abolition of the production and nuclear accumulation of the Notch intracellular domain. PS1/2-independent Notch activation is sensitive to Numblike, a physiological inhibitor of Notch. PS1/2-independent Notch signaling is also inhibited by an active gamma-secretase inhibitor in the low micromolar range and is not inhibited by an inactive analogue, similar to PS-dependent Notch signaling. However, experiments using a Notch1-Gal4-VP16 fusion protein indicate that the PS1/2-independent activity does not release Gal4-VP16 and is therefore unlikely to proceed via an intramembranous cleavage. These data reveal that a novel PS1/2-independent mechanism plays a partial role in Notch signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Blotting, Northern
  • Blotting, Western
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism
  • DNA / metabolism
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Endopeptidases / metabolism
  • Etoposide / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Luciferases / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Microscopy, Fluorescence
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Precipitin Tests
  • Presenilin-1
  • Presenilin-2
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Notch
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Time Factors
  • Transcription, Genetic
  • Transfection


  • DNA, Complementary
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Numbl protein, mouse
  • Presenilin-1
  • Presenilin-2
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Etoposide
  • DNA
  • Luciferases
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse