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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The cytotoxicity of γ-secretase inhibitor I to breast cancer cells is mediated by proteasome inhibition, not by γ-secretase inhibition
TL;DR: It is found that blocking γ-secretase activity by DAPT and L-685,458 had no effect on the survival and proliferation of a panel of six breast cancer cell lines while Z-LLNle-CHO could cause cell death even at concentrations that inhibitedγ- secretase activity less efficiently.
Journal ArticleDOI
Presenilin/γ-secretase activity regulates protein clearance from the endocytic recycling compartment
Mei Zhang,Annakaisa Haapasalo,Doo Yeon Kim,Laura A. MacKenzie Ingano,Warren H. Pettingell,Dora M. Kovacs +5 more
TL;DR: It is suggested that PS/γ‐secretase activity is required for normal endosomal recycling of soluble and membrane‐associated proteins through the ERC and a new mechanism by which impaired PS/ γ‐ secretase function may eventually contribute to neurodegeneration is proposed.
Journal ArticleDOI
Localization of presenilin–nicastrin complexes and γ‐secretase activity to the trans‐Golgi network
Robert Siman,Jamel Velji +1 more
TL;DR: The results resolve the apparent spatial paradox by demonstrating that presenilin–nicastrin complexes and presenILin‐dependent γ‐secretase activity are co‐localized to a late secretory compartment.
Journal ArticleDOI
Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls Notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase.
Jung-Soon Mo,Eun Jung Ann,Ji Hye Yoon,Jane Jung,Yun-Hee Choi,Hwa Young Kim,Ji Seon Ahn,Su Man Kim,Mi-Yeon Kim,Ji Ae Hong,Mi Sun Seo,Florian Lang,Eui Ju Choi,Hee Sae Park +13 more
TL;DR: It is reported that the serum- and glucocorticoid-inducible protein kinase SGK1 remarkably reduced the protein stability of the active form of Notch1 through Fbw7.
Journal ArticleDOI
Notch interferes with the scaffold function of JNK-interacting protein 1 to inhibit the JNK signaling pathway
Jin Woo Kim,Myung Jin Kim,Kwang Je Kim,Hee Jae Yun,Ji Soo Chae,Sang Gil Hwang,Tong Shin Chang,Hee Sae Park,Kang Woo Lee,Pyung Lim Han,Ssang-Goo Cho,Tae-Wan Kim,Eui Ju Choi +12 more
TL;DR: It is shown that Notch1-IC suppresses the scaffold activity of c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1) in the JNK signaling pathway by disrupting the scaffolding function of JIP1.
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.