title: Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.
abstract: Oncogenic forms of Notch1, Notch2, and Notch4 appear to mimic signaling intermediates of Notch1 and suggest that the role of proteolysis in Notch signaling has been conserved. Here we demonstrate that extracellularly truncated Notch homologs are substrates for a presenilin-dependent gamma-secretase activity. Despite minimal conservation within the transmembrane domain, the requirement for a specific amino acid (P1' valine) and its position at the cleavage site relative to the cytosolic border of the transmembrane domain are preserved. Cleaved, untethered Notch intracellular domains from each receptor translocate to the nucleus and interact with the transcriptional regulatory protein CSL. All four Notch proteins display presenilin-dependent transactivating potential on a minimal promoter reporter. Thus, this study increases the number of biochemically characterized gamma-secretase substrates from two to five. Despite a high degree of structural homology and the presenilin-dependent activity of truncated Notch proteins, the extent that this reflects functional redundancy is unknown.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Saxena
authors.forename: E H
authors.initials: EH
authors.lastname: Schroeter
authors.forename: J S
authors.initials: JS
authors.lastname: Mumm
authors.forename: R
authors.initials: R
authors.lastname: Kopan
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D054407:Chemokine CCL4; D019742:Chemokines, CC; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins; D010450:Endopeptidases / Q000378:metabolism*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C066507:CCL4 protein, human; D054407:Chemokine CCL4; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; C497571:Rbpj protein, mouse; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C088731:Su(H) protein, Drosophila; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse