Journal ArticleDOI
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
Bart De Strooper,Wim Annaert,Philippe Cupers,Paul Saftig,Katleen Craessaerts,Jeff S. Mumm,Eric H. Schroeter,Vincent Schrijvers,Michael S. Wolfe,William J. Ray,Alison Goate,Raphael Kopan +11 more
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TLDR
It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.Abstract:
Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.read more
Citations
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Journal ArticleDOI
Crumbs is required to achieve proper organ size control during Drosophila head development
TL;DR: Overall, this work reveals a novel function for Crb in limiting ligand-dependent transactivation of the N receptor at the epithelial cell membrane at the apical epithelial plasma membrane.
Journal ArticleDOI
A Pathogenic Presenilin-1 Deletion Causes Abberrant Aβ42 Production in the Absence of Congophilic Amyloid Plaques
Harald Steiner,Tamas Revesz,Manuela Neumann,Helmut Romig,Melissa G. Grim,Brigitte Pesold,Hans A. Kretzschmar,John Hardy,Janice L. Holton,Ralf Baumeister,Henry Houlden,Christian Haass +11 more
TL;DR: The identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 ΔI83/ΔM84) is reported, which demonstrates that a small deletion of PS proteins can pathologically affect PS function in endoproteolysis of β-amyloid precursor protein and in Notch signaling.
Journal ArticleDOI
Suppressor role of activating transcription factor 2 (ATF2) in skin cancer
Anindita Bhoumik,Boris Fichtman,Charles DeRossi,Wolfgang Breitwieser,Harriet M. Kluger,Sean Davis,Antonio Subtil,Paul S. Meltzer,Stan Krajewski,Nic Jones,Ze'ev Ronai +10 more
TL;DR: The data reveal that loss of ATF2 transcriptional activity serves to promote skin tumor formation, thereby indicating a suppressor activity of ATF1 in skin tumors formation and reduction of nuclear ATF2 and increased β-catenin expression were seen in samples of squamous and basal cell carcinoma, as opposed to normal skin.
Journal ArticleDOI
The Role of Protease Activity in ErbB Biology
TL;DR: Roles of protease systems within the ErbB system of ligands and receptors are discussed, including the ADAM proteases, the gamma-secretase complex and the rhomboid proteases.
Journal ArticleDOI
γ-Secretase in biology and medicine
TL;DR: Inhibition of Notch signaling by gamma-secretase inhibitors, which is undesirable for the prevention or treatment of Alzheimer's disease, may be beneficial for the treatment of a variety of cancers.
References
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Journal ArticleDOI
The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor
TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
Journal ArticleDOI
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
Bart De Strooper,Paul Saftig,Paul Saftig,Katleen Craessaerts,Hugo Vanderstichele,Gundula Guhde,Wim Annaert,Kurt von Figura,Fred Van Leuven +8 more
TL;DR: The results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
Journal ArticleDOI
Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.
TL;DR: It is shown that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL.
Journal ArticleDOI
Skeletal and CNS defects in Presenilin-1-deficient mice.
TL;DR: Results show that PS1 is required for proper formation of the axial skeleton, normal neurogenesis, and neuronal survival.
Journal ArticleDOI
The Notch1 receptor is cleaved constitutively by a furin-like convertase
Frédérique Logeat,Christine Bessia,Christel Brou,Odile LeBail,Sophie Jarriault,Nabil G. Seidah,Alain Israël +6 more
TL;DR: The results confirm and extend recent reports indicating that the Notch receptor exists at the plasma membrane as a heterodimeric molecule, but disagree as to the nature of the protease that is responsible for the cleavage that takes place in the extracellular region.