The Notch Ligands, Jagged and Delta, Are Sequentially Processed by α-Secretase and Presenilin/γ-Secretase and Release Signaling Fragments*
By M. LaVoie, D. Selkoe. Journal of Biological Chemistry, 2003
339 citations recorded by the source corpus.
The cleavage of Notch by presenilin (PS)/γ-secretase is a salient example of regulated intramembrane proteolysis, an unusual mechanism of signal transduction. This cleavage is preceded by the binding of protein ligands to the Notch ectodomain, activating its shedding. We hypothesized that the Notch ligands, Delta and Jagged, themselves undergo PS-mediated regulated intramembrane proteolysis. Here, we show that the ectodomain of mammalian Jagged is cleaved by an A disintegrin and metalloprotease (ADAM) 17-like activity in cultured cells and in vivo, similar to the known cleavage of Drosophila Delta by Kuzbanian. The ectodomain shedding of ligand can be stimulated by Notch and yields membrane-tethered C-terminal fragments (CTFs) of Jagged and Delta that accumulate in cells expressing a dominant-negative form of PS or treated with γ-secretase inhibitors. PS forms stable complexes with Delta and Jagged and with their respective CTFs. PS/γ-secretase then mediates the cleavage of the latter to release the Delta and Jagged intracellular domains, a portion of which can enter the nucleus. The ligand CTFs compete with an activated form of Notch for cleavage by γ-secretase and can thus inhibit Notch signaling in vitro. The soluble Jagged intracellular domain can activate gene expression via the transcription factor AP1, and this effect is counteracted by the co-expression of the γ-secretase-cleaved product of Notch, Notch intracellular domain. We conclude that Delta and Jagged undergo ADAM-mediated ectodomain processing followed by PS-mediated intramembrane proteolysis to release signaling fragments. Thus, Notch and its cognate ligands are processed by the same molecular machinery and may antagonistically regulate each other's signaling.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/c3a50d2d6362889ecd9d6544de01b15997a748a3
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Citations in the corpus
- Notch signaling: simplicity in design, versatility in function (2011, background): “In endothelial cells, for example, Notch ICD can suppress the antiproliferative effect of Delta ICD (Kolev et al., 2005) and, conversely, the intracellular domain of Jag1 has been shown to suppress Notch ICD-induced transcription in COS cells (LaVoie and Selkoe, 2003).”
- Notch signaling: the core pathway and its posttranslational regulation. (2009, background): “…downregulation during lateral signaling or similar competitive signaling scenarios, or generates a soluble intracellular fragment from the ligand that translocates to the nucleus and performs a separate signaling function (Bland et al., 2003; Ikeuchi and Sisodia, 2003; LaVoie and Selkoe, 2003).”
- The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. (2009, neutral): “For the same reason, Jagged1 reverse signaling, a process that would involve ligand cleavage and release of a cytoplasmic, Notch-inhibiting fragment (LaVoie and Selkoe, 2003; Six et al., 2003) cannot explain our findings.”
- Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. (2004, background): “These deposits consist predominantly of Ab amyloid peptide and are derived from amyloid precursor protein (APP) by a series of proteolytic events, the last of which is responsible for an intramembranous COOH-terminal cleavage mediated by a multimeric complex called g-secretase. g-Secretase is an asp”