Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1.
Presenilin 1 (PS1), a polytopic membrane protein, is required for endoproteolytic processing at gamma-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 Notchl-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 gamma-secretase activity and Abeta 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.
Martys-Zage
J L
JL
Department of Neurobiology, Pharmacology, and Physiology, Howard Hughes Medical Institute, The University of Chicago, IL 60637, USA.
Kim
S H
SH
Berechid
B
B
Bingham
S J
SJ
Chu
S
S
Sklar
J
J
Nye
J
J
Sisodia
S S
SS
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002219:Carbamates; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed / Q000166:cytology / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004151:Dipeptides; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism; D005333:Fetus; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins; D007202:Indicators and Reagents / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D011480:Protease Inhibitors / Q000494:pharmacology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D002352:Carrier Proteins; D004151:Dipeptides; D007202:Indicators and Reagents; D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; C410009:L 685458; D008164:Luminescent Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse