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
Reads0
Chats0
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
More filters
Journal ArticleDOI
Distinct roles of EGF repeats for the Notch signaling system.
TL;DR: It is demonstrated that Notch1 can form homodimers, which is achieved by its EGF motifs, implying that receptor homodimerization is an important initial step in Notch signal transduction.
Journal ArticleDOI
A novel substrate for analyzing Alzheimer's disease γ-secretase
TL;DR: This novel SPA4CT protein is processed by γ‐secretase in the same manner as APP‐derived A4CT and might be valuable for the generation of transgenic animals showing amyloid pathology.
Journal ArticleDOI
Notch in skeletal physiology and disease
TL;DR: Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease and controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders.
Journal ArticleDOI
Presenilin/γ-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with β-Catenin
Annakaisa Haapasalo,Doo Yeon Kim,Bryce W. Carey,Mari K. Turunen,Warren H. Pettingell,Dora M. Kovacs +5 more
TL;DR: Results show that PS/γ-secretase-mediated cleavage of LAR controls LAR-β-catenin interaction, suggesting an essential role for PS/ γ- secretase in the regulation of LAR signaling.
Journal ArticleDOI
Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner.
Naveen K. Neradugomma,Dharmalingam Subramaniam,Ossama Tawfik,Vincent Goffin,T. Rajendra Kumar,Roy A. Jensen,Shrikant Anant +6 more
TL;DR: The results demonstrate that cytokine signaling induced by PRL is active in colorectal cancers and may provide a novel target for therapeutic intervention.
References
More filters
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.