The Intracellular Domain of the β-Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner
Copyright policy )The Intracellular Domain of the β-Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner
The beta-amyloid precursor protein (APP) is a ubiquitous receptor-like molecule without a known function. However, the recent recognition that APP and Notch undergo highly similar proteolytic processing has suggested a potential signaling function for APP. After ligand binding, Notch is cleaved by the ADAM-17 metalloprotease followed by an intramembrane cleavage mediated by gamma-secretase. The gamma-secretase cut releases the Notch intracellular domain (NICD), which enters the nucleus and modulates transcription. Because APP is processed similarly by ADAM-17 and gamma-secretase, we reasoned that the APP intracellular domain (AICD) has a role analogous to the NICD. We therefore generated a plasmid encoding the AICD sequence and studied the subcellular localization of the expressed protein (C60). Our results demonstrate that the cytoplasmic domain of APP is a highly labile fragment that is stabilized by forming complexes with Fe65 and can then enter the nucleus in neurons and non-neural cells. These findings strongly support the hypothesis that APP signals in the nucleus in a manner analogous to the function of Notch.
- Harvard University United States
- Brigham and Women's Faulkner Hospital United States
Receptors, Notch, Active Transport, Cell Nucleus, Membrane Proteins, Metalloendopeptidases, Nuclear Proteins, Nerve Tissue Proteins, ADAM17 Protein, CREB-Binding Protein, Peptide Fragments, Repressor Proteins, ADAM Proteins, Amyloid beta-Protein Precursor, Endopeptidases, Aspartic Acid Endopeptidases, Drosophila Proteins, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational, Half-Life, Protein Binding, Signal Transduction
Receptors, Notch, Active Transport, Cell Nucleus, Membrane Proteins, Metalloendopeptidases, Nuclear Proteins, Nerve Tissue Proteins, ADAM17 Protein, CREB-Binding Protein, Peptide Fragments, Repressor Proteins, ADAM Proteins, Amyloid beta-Protein Precursor, Endopeptidases, Aspartic Acid Endopeptidases, Drosophila Proteins, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational, Half-Life, Protein Binding, Signal Transduction
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).412 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 0.1%
Citations provided by BIP!Popularity provided by BIP!