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
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Journal ArticleDOI
Signature Amyloid β Profiles Are Produced by Different γ-Secretase Complexes
Hermien Acx,Lucía Chávez-Gutiérrez,Lutgarde Serneels,Sam Lismont,Manasi Benurwar,Nadav Elad,Bart De Strooper,Bart De Strooper +7 more
TL;DR: It is found that the nature of the catalytic subunit in the complex affects both activities, and each γ-secretase complex produces a characteristic Aβ signature, which could be used to advance drug development in AD and other disorders.
Journal ArticleDOI
Notch-dependent control of myelopoiesis is regulated by fucosylation
Lan Zhou,Lebing Wei Li,Quanjian Yan,Bronisilawa Petryniak,Yunfang Man,Charles A. Su,Jeongsup Shim,Stephanie M. Chervin,John B. Lowe +8 more
TL;DR: Observations indicate that Notch-dependent signaling controls myelopoiesis in vivo and in vitro and identifies a requirement for Notch fucosylation in the expression of Notch ligand binding activity and Notch signaling efficiency in myeloid progenitors.
Journal ArticleDOI
Oncogenic NOTCH1 Control of MYC and PI3K: Challenges and Opportunities for Anti-NOTCH1 Therapy in T-Cell Acute Lymphoblastic Leukemias and Lymphomas
TL;DR: The identification of the downstream effector pathways controlled by NOTCH1 should pave the way for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL.
Journal ArticleDOI
Deletion of Presenilin 1 Hydrophilic Loop Sequence Leads to Impaired γ-Secretase Activity and Exacerbated Amyloid Pathology
Yu Deng,Leonid Tarassishin,Verena Kallhoff,Erica Peethumnongsin,Ling Wu,Yue-Ming Li,Hui Zheng +6 more
TL;DR: It is reported here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced γ-secretase cleavage at the Aβ40, but not the A β42, site, which supports a protective role of A β40 against amyloid pathology and raises the possibility that impaired ιsecretase activity could be the basis for AD pathogenesis in general.
Journal ArticleDOI
Notch and presenilins in vertebrates and invertebrates: implications for neuronal development and degeneration.
TL;DR: This finding establishes a specific biochemical role for presenilins in Notch signaling and interfaces with emerging evidence about how frizzled, disheveled and numerous other genes regulate the highly complex Notch pathway.
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.