The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism
TLDR
This Review highlights recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.About:
This article is published in Cell.The article was published on 2009-04-17 and is currently open access. It has received 3120 citations till now. The article focuses on the topics: Notch signaling pathway & Notch 1.read more
Citations
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Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures.
Krzysztof Glomski,Krzysztof Glomski,Sebastien Monette,Katia Manova,Bart De Strooper,Paul Saftig,Carl P. Blobel,Carl P. Blobel +7 more
TL;DR: It is reported that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling, supporting a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions.
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The Gamma Secretase Inhibitor MRK-003 Attenuates Pancreatic Cancer Growth in Preclinical Models
Masamichi Mizuma,Masamichi Mizuma,Zeshaan A. Rasheed,Shinichi Yabuuchi,Noriyuki Omura,Nathaniel R. Campbell,Roeland F. de Wilde,Elizabeth De Oliveira,Qing Zhang,Oscar Puig,William Matsui,Manuel Hidalgo,Anirban Maitra,N. V. Rajeshkumar +13 more
TL;DR: The rationale for small-molecule inhibition of Notch signaling as a therapeutic strategy in PDAC is strengthened, withGene expression analysis of untreated tumors indicated that upregulation of NF-κB pathway components was predictive of sensitivity to MRK-003, whereas upregulation in B-cell receptor signaling and nuclear factor erythroid-derived 2-like 2 pathway correlated with response to the combination of MRK -003 with gemcitabine.
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Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi).
Shakeel M. Thakurdas,Mario F. Lopez,Shinako Kakuda,Rodrigo Fernandez-Valdivia,Neda Zarrin-Khameh,Robert S. Haltiwanger,Hamed Jafar-Nejad +6 more
TL;DR: It is shown that on a C57BL/6 background, jagged1 heterozygous mice (Jag1+/−) exhibit impaired intrahepatic bile duct development, decreased SOX9 expression, and thinning of the periportal vascular smooth muscle cell (VSMC) layer, which is apparent at embryonic day 18 and the first postnatal week, and that Rumi opposes JAG1 function in the liver.
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Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase
Hideyuki Takeuchi,Rodrigo Fernandez-Valdivia,Devin S. Caswell,Aleksandra Nita-Lazar,Aleksandra Nita-Lazar,Nadia A. Rana,Thomas P. Garner,Thomas K. Weldeghiorghis,Megan A. Macnaughtan,Hamed Jafar-Nejad,Robert S. Haltiwanger +10 more
TL;DR: Dual substrate specificity for the glycosyltransferase Rumi is established and evidence that amino acid sequences of the recipient EGF repeat significantly influence which donor substrate (UDP-glucose or UDP-Xyl) is used is provided.
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The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage
Kameswaran Surendran,Scott Boyle,Hila Barak,Mijin Kim,Colin Stomberski,Brent McCright,Raphael Kopan +6 more
TL;DR: Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J-dependent manner, indicating that elevating Notch1 activity could improve renal functions in ALGS2 patients and suggesting temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients.
References
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Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Andrew P. Weng,Andrew P. Weng,Adolfo A. Ferrando,Adolfo A. Ferrando,Woojoong Lee,Woojoong Lee,John P. Morris,John P. Morris,Lewis B. Silverman,Lewis B. Silverman,Cheryll Sanchez-Irizarry,Cheryll Sanchez-Irizarry,Stephen C. Blacklow,Stephen C. Blacklow,A. Thomas Look,A. Thomas Look,Jon C. Aster,Jon C. Aster +17 more
TL;DR: These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
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Notch signalling: a simple pathway becomes complex
TL;DR: Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
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An Essential Role for Ectodomain Shedding in Mammalian Development
Jacques J. Peschon,Jennifer L. Slack,Pranitha Reddy,Kim L. Stocking,Susan W. Sunnarborg,David C. Lee,William E. Russell,Beverly J. Castner,Richard S. Johnson,Jeffrey N. Fitzner,Rogely W. Boyce,Nicole Nelson,Carl J. Kozlosky,Martin F. Wolfson,Charles Rauch,Douglas P. Cerretti,Raymond J. Paxton,Carl J. March,Roy A. Black +18 more
TL;DR: The phenotype of mice lacking TACE suggests an essential role for soluble TGFalpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.
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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.
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Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.
Johan H. van Es,Marielle E. van Gijn,Orbicia Riccio,Maaike van den Born,Marc Vooijs,Harry Begthel,Miranda Cozijnsen,Sylvie Robine,Doug J. Winton,Freddy Radtke,Hans Clevers +10 more
TL;DR: This work shows a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J and indicates that γ-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.
Related Papers (5)
Notch Signaling: Cell Fate Control and Signal Integration in Development
Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Andrew P. Weng,Andrew P. Weng,Adolfo A. Ferrando,Adolfo A. Ferrando,Woojoong Lee,Woojoong Lee,John P. Morris,John P. Morris,Lewis B. Silverman,Lewis B. Silverman,Cheryll Sanchez-Irizarry,Cheryll Sanchez-Irizarry,Stephen C. Blacklow,Stephen C. Blacklow,A. Thomas Look,A. Thomas Look,Jon C. Aster,Jon C. Aster +17 more