Spatial Regulation and Generation of Diversity in Signaling Pathways
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Tyrosine Phosphorylation and Proteolytic Cleavage of Notch Are
© 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev151548. doi:10.1242/dev.151548 RESEARCH ARTICLE Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in Drosophila axon guidance Ramakrishnan Kannan1,*, Eric Cox1,‡, Lei Wang2,§, Irina Kuzina1,QunGu1 and Edward Giniger1,2,¶ ABSTRACT 2005) and the Akt pathway (Androutsellis-Theotokis et al., 2006; Notch signaling is required for the development and physiology of Perumalsamy et al., 2009), among others, that extend the menu of nearly every tissue in metazoans. Much of Notch signaling is molecular outcomes of Notch activation. The molecular events mediated by transcriptional regulation of downstream target genes, behind these alternative signaling mechanisms, however, are not well but Notch controls axon patterning in Drosophila by local modulation understood. of Abl tyrosine kinase signaling, via direct interactions with the Abl co- Perhaps the best-studied non-traditional function of Notch is its factors Disabled and Trio. Here, we show that Notch-Abl axonal regulation of axon patterning (comprising both axon growth and signaling requires both of the proteolytic cleavage events that initiate axon guidance) via interaction with the Abl tyrosine kinase canonical Notch signaling. We further show that some Notch protein signaling network (Crowner et al., 2003; Giniger, 1998; Kuzina is tyrosine phosphorylated in Drosophila, that this form of the protein et al., 2011; Le Gall et al., 2008). It has been demonstrated is selectively associated with Disabled and Trio, and that relevant biochemically, molecularly and genetically that, upon activation by tyrosines are essential for Notch-dependent axon patterning but not its ligand Delta, Notch promotes the growth and guidance of pioneer for canonical Notch-dependent regulation of cell fate. -
It's T-ALL About Notch
Oncogene (2008) 27, 5082–5091 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $30.00 www.nature.com/onc REVIEW It’s T-ALL about Notch RM Demarest1, F Ratti1 and AJ Capobianco Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA T-cell acute lymphoblastic leukemia (T-ALL) is an about T-ALL make it a more aggressive disease with a aggressive subset ofALL with poor clinical outcome poorer clinical outcome than B-ALL. T-ALL patients compared to B-ALL. Therefore, to improve treatment, it have a higher percentage of induction failure, and rate is imperative to delineate the molecular blueprint ofthis of relapse and invasion into the central nervous system disease. This review describes the central role that the (reviewed in Aifantis et al., 2008). The challenge to Notch pathway plays in T-ALL development. We also acquiring 100% remission in T-ALL treatment is the discuss the interactions between Notch and the tumor subset of patients (20–25%) whose disease is refractory suppressors Ikaros and p53. Loss ofIkaros, a direct to initial treatments or relapses after a short remission repressor ofNotch target genes, and suppression ofp53- period due to drug resistance. Therefore, it is imperative mediated apoptosis are essential for development of this to delineate the molecular blueprint that collectively neoplasm. In addition to the activating mutations of accounts for the variety of subtypes in T-ALL. This will Notch previously described, this review will outline allow for the development of targeted therapies that combinations ofmutations in pathways that contribute inhibit T-ALL growth by disrupting the critical path- to Notch signaling and appear to drive T-ALL develop- ways responsible for the neoplasm. -
Suppression of Notch Signaling Stimulates Progesterone Synthesis by Enhancing the Expression of NR5A2 and NR2F2 in Porcine Granulosa Cells
G C A T T A C G G C A T genes Article Suppression of Notch Signaling Stimulates Progesterone Synthesis by Enhancing the Expression of NR5A2 and NR2F2 in Porcine Granulosa Cells Rihong Guo 1,2, Fang Chen 2 and Zhendan Shi 1,2,* 1 Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China; [email protected] 2 Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China; [email protected] * Correspondence: [email protected] Received: 16 December 2019; Accepted: 18 January 2020; Published: 22 January 2020 Abstract: The conserved Notch pathway is reported to be involved in progesterone synthesis and secretion; however, the exact effects remain controversial. To determine the role and potential mechanisms of the Notch signaling pathway in progesterone biosynthesis in porcine granulosa cells (pGCs), we first used a pharmacological γ-secretase inhibitor, N-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl ester (DAPT), to block the Notch pathway in cultured pGCs and then evaluated the expression of genes in the progesterone biosynthesis pathway and key transcription factors (TFs) regulating steroidogenesis. We found that DAPT dose- and time-dependently increased progesterone secretion. The expression of steroidogenic proteins NPC1 and StAR and two TFs, NR5A2 and NR2F2, was significantly upregulated, while the expression of HSD3B was significantly downregulated. Furthermore, knockdown of both NR5A2 and NR2F2 with specific siRNAs blocked the upregulatory effects of DAPT on progesterone secretion and reversed the effects of DAPT on the expression of NPC1, StAR, and HSD3B. -
Notch-Jagged Signaling Complex Defined by an Interaction Mosaic
bioRxiv preprint doi: https://doi.org/10.1101/2021.02.19.432005; this version posted February 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Research Article Notch-Jagged signaling complex defined by an interaction mosaic Matthieu R. Zeronian1,4, Oleg Klykov2,3,4,5,Julia´ Portell i de Montserrat1,6, Maria J. Konijnenberg1, Anamika Gaur1,7, Richard A. Scheltema2,3* Bert J.C. Janssen1* Abstract The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoans, whereas dysfunction leads to debilitating developmental disorders and cancers. Other than a five-by-five domain complex, it is unclear how the 40 extracellular domains of the Notch1 receptor collectively engage the 19 domains of its canonical ligand Jagged1 to activate Notch1 signaling. Here, using cross-linking mass spectrometry (XL-MS), biophysical and structural techniques on the full extracellular complex and targeted sites,we identify five distinct regions, two on Notch1 and three on Jagged1, that form an interaction network.The Notch1 membrane-proximal regulatory region individually binds to the established Notch1 epidermal growth factor (EGF) 8-13 and Jagged1 C2-EGF3 activation sites, as well as to two additional Jagged1 regions, EGF 8-11 and cysteine-rich domain (CRD). XL-MS and quantitative interaction experiments show that the three Notch1 binding sites on Jagged1 also engage intramolecularly.These interactions, together with Notch1 and Jagged1 ectodomain dimensions and flexibility determined by small-angle X-ray scattering (SAXS), support the formation of backfolded architectures. -
Minireview Alzheimer's Disease
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Cell, Vol. 102, 271±273, August 4, 2000, Copyright 2000 by Cell Press Alzheimer's Disease: Minireview Neurodevelopment Converges with Neurodegeneration Mark Bothwell*³ and Edward Giniger² According to current models (D'Arcangelo et al., 1999; *Department of Physiology and Biophysics Hiesberger et al., 1999; Senzaki et al., 1999), Reelin acts University of Washington by binding to a complex of receptor proteins on the Seattle, Washington 98195 migrating neuron, which includes nonclassical cadher- ² Division of Basic Sciences ins (CNRs) and a pair of redundant receptors, the ApoE Program in Developmental Biology receptor 2 (ApoER2) and the VLDL receptor (VLDLR). Fred Hutchinson Cancer Research Center Binding of Reelin causes the ApoE and VLDL receptors Seattle, Washington 98109 to recruit an intracellular adaptor protein, Disabled (in mice called mDab1, but simply referred to as Dab hereaf- ter), and this becomes phosphorylated on tyrosine resi- dues, perhaps by a CNR-associated Src family protein Alzheimer's disease (AD) is the most common senile tyrosine kinase. Phosphorylation of Dab somehow dementia in the elderly. The disease is characterized causes the migrating neuron to cease migrating, release behaviorally by global cognitive decline, and defined from its substratum, the radial glial cell, and begin to histologically by two distinguishing pathologies: amy- differentiate. This picture is supported by the observa- loid plaques, which are extracellular deposits consisting tion that mutations in Dab or a double mutant in ApoER2 mainly of aggregated -amyloid peptide, and neurofibril- and VLDLR give phenotypes identical to that of Reelin lary tangles, which are intracellular deposits consisting mutants, and by biochemical analysis of Reelin signal- predominantly of hyperphosphorylated tau protein. -
Comparative Analysis of Notch1 and Notch2 Binding Sites in the Genome
Journal of Cancer 2017, Vol. 8 65 Ivyspring International Publisher Journal of Cancer 2017; 8(1): 65-73. doi: 10.7150/jca.16739 Research Paper Comparative analysis of Notch1 and Notch2 binding sites in the genome of BxPC3 pancreatic cancer cells Hao Liu1, Ping Zhou2, Hong Lan1, Jia Chen1, Yu-xiang Zhang1,3,4 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Fengtai District, Beijing, 100069 China. 2. Department of Bioinformatics and Computer Science, School of Biomedical Engineering, Capital Medical University, Beijing, China. 3. Cancer Institute of Capital Medical University, Beijing, China. 4. Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China. Corresponding author: Prof. Yu-xiang Zhang, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. Tel: 86-10-83950122; E-mail: [email protected]. © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2016.07.05; Accepted: 2016.09.26; Published: 2017.01.01 Abstract Notch signaling plays a key role in the development of pancreatic cancer. Among the four identified Notch receptors, Notch1 and Notch2 share the highest homology. Notch1 has been reported to be an oncogene but some reports indicate that Notch2, not Notch1, plays a key role in pancreatic carcinogenesis. As both are transcription factors, examination of their genomic binding sites might reveal interesting functional differences between them. -
JAG1 Gene Jagged 1
JAG1 gene jagged 1 Normal Function The JAG1 gene provides instructions for making a protein called Jagged-1, which is involved in an important pathway by which cells can signal to each other. The Jagged-1 protein is inserted into the membranes of certain cells. It connects with other proteins called Notch receptors, which are bound to the membranes of adjacent cells. These proteins fit together like a lock and its key. When a connection is made between the Jagged-1 and Notch proteins, it launches a series of signaling reactions (Notch signaling) affecting cell functions. Notch signaling controls how certain types of cells develop in a growing embryo, especially cells destined to be part of the heart, liver, eyes, ears, and spinal column. The Jagged-1 protein continues to play a role throughout life in the development of new blood cells. Health Conditions Related to Genetic Changes Alagille syndrome At least 226 mutations in the JAG1 gene have been identified in people with Alagille syndrome. Most of these mutations result in an abnormally short Jagged-1 protein that is missing the segment that normally spans the cell membrane (the transmembrane domain). Other mutations interfere with proper transport (trafficking) of the protein within the cell, preventing it from reaching the cell membrane. The loss of Jagged-1 protein at the cell membrane precludes its interaction with Notch proteins and prevents cell signaling. The lack of Notch signaling causes errors in development that result in missing or narrowed bile ducts in the liver, heart defects, distinctive facial features, and changes in other parts of the body. -
Two Novel Protein O-Glucosyltransferases That Modify Sites Distinct from POGLUT1 and Affect Notch Trafficking and Signaling
Two novel protein O-glucosyltransferases that modify sites distinct from POGLUT1 and affect Notch trafficking and signaling Hideyuki Takeuchia,1,2, Michael Schneiderb,1, Daniel B. Williamsona, Atsuko Itoa, Megumi Takeuchia, Penny A. Handfordc, and Robert S. Haltiwangera,b,3 aComplex Carbohydrate Research Center, The University of Georgia, Athens, GA 30602; bDepartment of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11795; and cDepartment of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom Edited by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, and approved July 20, 2018 (received for review March 6, 2018) The Notch-signaling pathway is normally activated by Notch–ligand present (Fig. 1A). Each EGF repeat has six conserved cysteine interactions. A recent structural analysis suggested that a novel O- residues that form three disulfide bonds in a distinct pattern that linked hexose modification on serine 435 of the mammalian NOTCH1 stabilize the 3D structure of EGF repeats. O-Glc is added to core ligand-binding domain lies at the interface with its ligands. This serine residues within the consensus sequence C1-X-S-X-(P/A)- serine occurs between conserved cysteines 3 and 4 of Epidermal C2 (where the modified amino acid is underlined, X represents Growth Factor-like (EGF) repeat 11 of NOTCH1, a site distinct from any amino acid, and C1 and C2 are the first and second cysteine those modified by protein O-glucosyltransferase 1 (POGLUT1), sug- residues of the EGF repeat) by protein O-glucosyltransferase 1 gesting that a different enzyme is responsible. Here, we identify (POGLUT1, Rumi in flies) (9, 10). -
Immobilization of Jagged1 Enhances Vascular Smooth Muscle Cells Maturation by Activating the Notch Pathway
cells Article Immobilization of Jagged1 Enhances Vascular Smooth Muscle Cells Maturation by Activating the Notch Pathway Kathleen Zohorsky 1, Shigang Lin 2 and Kibret Mequanint 1,2,* 1 School of Biomedical Engineering, University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B9, Canada; [email protected] 2 Department of Chemical and Biochemical Engineering, University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B9, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(519)-661-2111-X-88573 Abstract: In Notch signaling, the Jagged1-Notch3 ligand-receptor pairing is implicated for regulating the phenotype maturity of vascular smooth muscle cells. However, less is known about the role of Jagged1 presentation strategy in this regulation. In this study, we used bead-immobilized Jagged1 to direct phenotype control of primary human coronary artery smooth muscle cells (HCASMC), and to differentiate embryonic multipotent mesenchymal progenitor (10T1/2) cell towards a vascular lineage. This Jagged1 presentation strategy was sufficient to activate the Notch transcription factor HES1 and induce early-stage contractile markers, including smooth muscle α-actin and calponin in HCASMCs. Bead-bound Jagged1 was unable to regulate the late-stage markers myosin heavy chain and smoothelin; however, serum starvation and TGFβ1 were used to achieve a fully contractile smooth muscle cell. When progenitor 10T1/2 cells were used for Notch3 signaling, pre-differentiation with TGFβ1 was required for a robust Jagged1 specific response, suggesting a SMC lineage commit- ment was necessary to direct SMC differentiation and maturity. The presence of a magnetic tension Citation: Zohorsky, K.; Lin, S.; force to the ligand-receptor complex was evaluated for signaling efficacy. -
Targeting Notch Trafficking and Processing in Cancers
cells Review Targeting Notch Trafficking and Processing in Cancers Luca Pagliaro y, Claudia Sorrentino y and Giovanni Roti * Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; [email protected] (L.P.); [email protected] (C.S.) * Correspondence: [email protected]; Tel.: +39-0521-904062 These authors contributed equally to this work. y Received: 6 July 2020; Accepted: 8 September 2020; Published: 29 September 2020 Abstract: The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane γ-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known γ-secretase inhibitors. Keywords: NOTCH1; SERCA; T-cell acute lymphoblastic leukemia; thapsigargin; trafficking; CAD204520 1. Introduction In 1914, John S. Dexter described a heritable “perfect notched” phenotype in beaded Drosophila [1]. -
Role of Notch Signaling in Cell-Fate Determination of Human Mammary
Available online http://breast-cancer-research.com/content/6/6/R605 ResearchVol 6 No 6 article Open Access Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells Gabriela Dontu, Kyle W Jackson, Erin McNicholas, Mari J Kawamura, Wissam M Abdallah and Max S Wicha Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Corresponding author: Gabriela Dontu, [email protected] Received: 6 Apr 2004 Revisions requested: 10 May 2004 Revisions received: 28 Jun 2004 Accepted: 15 Jul 2004 Published: 16 Aug 2004 Breast Cancer Res 2004, 6:R605-R615 (DOI 10.1186/bcr920)http://breast-cancer-research.com/content/6/6/R605 © 2004 Dontu et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract Introduction Notch signaling has been implicated in the renewal and on early progenitor cells to promote their regulation of cell-fate decisions such as self-renewal of adult proliferation, as demonstrated by a 10-fold increase in stem cells and differentiation of progenitor cells along a secondary mammosphere formation upon addition of a Notch- particular lineage. Moreover, depending on the cellular and activating DSL peptide. In addition to acting on stem cells, developmental context, the Notch pathway acts as a regulator of Notch signaling is also able to act on multipotent progenitor cell survival and cell proliferation. Abnormal expression of Notch cells, facilitating myoepithelial lineage-specific commitment and receptors has been found in different types of epithelial proliferation. -
A Garden of Notch-Ly Delights Gerry Weinmaster and Raphael Kopan
CORRIGENDUM Development 133, 4793 (2006) doi:10.1242/dev.02713 A garden of Notch-ly delights Gerry Weinmaster and Raphael Kopan There was an error published in Development 133, 3277-3282. There was a mistake in the first paragraph of this meeting review, which should read as follows: Hosted by the Cantoblanco Workshops on Biology and organized by José Luis de la Pompa, Tom Gridley and Juan Carlos Izpisúa Belmonte, the meeting covered diverse aspects of this important signaling pathway. The authors apologize to readers for this mistake. MEETING REVIEW 3277 Development 133, 3277-3282 (2006) doi:10.1242/dev.02515 precedes Notch ubiquitination. Moreover, although ubiquitination A garden of Notch-ly of many proteins involves Lys48 in the formation of the ubiquitin chain, Israel reported that Notch1 and Deltex (one of the E3 ligases delights that regulates the level of cell surface Notch) are polyubiquitinated Gerry Weinmaster1,* and Raphael Kopan2 via the less commonly used Lys29. Israel’s finding suggests that levels of Deltex, and possibly of Notch, are regulated via their ubiquitination by the Itch/AIP4/Su(Dx) E3 ligase, followed by their Over the past decade, the Notch signaling pathway has been lysosomal degradation. These studies provide insight into how shown to be crucially important for normal metazoan ubiquitination regulates both the basal levels of Notch, as well as its development and to be associated with several human proteolytic activation for signaling. inherited and late onset diseases. The realization that altered Notch signaling contributes at various levels to human disease Notch proteins and their targets in normal and lead in May to the first meeting dedicated solely to Notch malignant T cells signaling in vertebrate development and disease in Madrid, The maturation of vertebrate Notch proteins involves its proteolytic Spain.