The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder

2008 ◽  
Vol 36 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Angela Bertagna ◽  
Dima Toptygin ◽  
Ludwig Brand ◽  
Doug Barrick
Keyword(s):  
Cell Fate ◽  
Tertiary Structure ◽  
Transmembrane Protein ◽  
Notch Signalling ◽  
Chain Model ◽  
Intracellular Domain ◽  
Cell Fate Decisions ◽  
Notch Intracellular Domain ◽  
Binding Regions ◽  
The Impact

Cell-fate decisions in metazoans are frequently guided by the Notch signalling pathway. Notch signalling is orchestrated by a type-1 transmembrane protein, which, upon interacting with extracellular ligands, is proteolytically cleaved to liberate a large intracellular domain [NICD (Notch intracellular domain)]. NICD enters the nucleus where it binds the transcription factor CSL (CBF1/suppressor of Hairless/Lag-1) and activates transcription of Notch-responsive genes. In the present paper, the interaction between the Drosophila NICD and CSL will be examined. This interaction involves two separate binding regions on NICD: the N-terminal tip of NICD {the RAM [RBP-Jκ (recombination signal-binding protein 1 for Jκ)-associated molecule] region} and an ankyrin domain ∼100 residues away. CD studies show that the RAM region of NICD lacks α-helical and β-sheet secondary structure, and also lacks rigid tertiary structure. Fluorescence studies show that the tryptophan residues in RAM are highly solvated and are quenched by solvent. To assess the impact of this apparent disorder on the bivalent binding of NICD to CSL, we modelled the region between the RAM and ANK (ankyrin repeat)-binding regions using polymer statistics. A WLC (wormlike chain) model shows that the most probable sequence separation between the two binding regions is ∼50 Å (1 Å=0.1 nm), matching the separation between these two sites in the complex. The WLC model predicts a substantial enhancement of ANK occupancy via effective concentration, and suggests that the linker length between the two binding regions is optimal for bivalent interaction.

HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage

2013 ◽  
Vol 451 (1) ◽  
pp. 123-134 ◽  
Author(s):  
Ji-hyun Ju ◽  
Wonseok Yang ◽  
Sunhwa Oh ◽  
KeeSoo Nam ◽  
Kyung-min Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Fate ◽  
Target Genes ◽  
Growth Factor Receptor ◽  
Cyclin B1 ◽  
Notch Signalling ◽  
Her2 Overexpression ◽  
Cell Fate Decisions ◽  
Notch Intracellular Domain ◽  
Notch Cleavage

In breast cancer, the HER2 (human epidermal growth factor receptor 2) receptor tyrosine kinase is associated with extremely poor prognosis and survival. Notch signalling has a key role in cell-fate decisions, especially in cancer-initiating cells. The Notch intracellular domain produced by Notch cleavage is translocated to the nucleus where it activates transcription of target genes. To determine the combinatory effect of HER2 and Notch signalling in breast cancer, we investigated the effect of HER2 on Notch-induced cellular phenomena. We found the down-regulation of Notch-dependent transcriptional activity by HER2 overexpression. Also, the HER2/ERK (extracellular-signal-regulated kinase) signal pathway down-regulated the activity of γ-secretase. When we examined the protein level of Notch target genes in HER2-overexpressing cells, we observed that the level of survivin, downstream of Notch, increased in HER2 cells. We found that activation of ERK resulted in a decrease in XAF1 [XIAP (X-linked inhibitor of apoptosis)-associated factor 1] which reduced the formation of the XIAP–XAF1 E3 ligase complex to ubiquitinate survivin. In addition, Thr34 of survivin was shown to be the most important residue in determining survivin stability upon phosphorylation after HER2/Akt/CDK1 (cyclin-dependent kinase 1)–cyclin B1 signalling. The results of the present study show the combinatorial effects of HER2 and Notch during breast oncogenesis.

scholarly journals SEL-5, A Serine/Threonine Kinase That Facilitates lin-12 Activity in Caenorhabditis elegans

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1641-1654 ◽  
Author(s):  
Hanna Fares ◽  
Iva Greenwald
Keyword(s):  
Cell Fate ◽  
Point Mutations ◽  
Kinase Domain ◽  
Terminal Region ◽  
Serine Threonine Kinase ◽  
Intracellular Domain ◽  
Cell Fate Decisions ◽  
Threonine Kinase ◽  
Amino Terminal ◽  
Fate Decision

Abstract Ligands present on neighboring cells activate receptors of the LIN-12/Notch family by inducing a proteolytic cleavage event that releases the intracellular domain. Mutations that appear to eliminate sel-5 activity are able to suppress constitutive activity of lin-12(d) mutations that are point mutations in the extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered intracellular domain. These results suggest that sel-5 acts prior to or during ligand-dependent release of the intracellular domain. In addition, sel-5 suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can suppress defects in the anchor cell/ventral uterine precursor cell fate decision and a sex myoblast/coelomocyte decision, but cannot suppress defects in two different ventral hypodermal cell fate decisions in hermaphrodites and males. sel-5 encodes at least two proteins, from alternatively spliced mRNAs, that share an amino-terminal region and differ in the carboxy-terminal region. The amino-terminal region contains the hallmarks of a serine/threonine kinase domain, which is most similar to mammalian GAK1 and yeast Pak1p.

Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽  
1997 ◽  
Vol 124 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
J.L. Pompa de la ◽  
A. Wakeham ◽  
K.M. Correia ◽  
E. Samper ◽  
S. Brown ◽  
...  
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Stem Cell Differentiation ◽  
Notch Signalling ◽  
Signalling Pathway ◽  
Notch Signalling Pathway ◽  
Altered Expression ◽  
Cell Fate Decisions ◽  
Targeted Mutation ◽  
Multiple Cell

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

scholarly journals Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julien Hurbain ◽  
Darka Labavić ◽  
Quentin Thommen ◽  
Benjamin Pfeuty
Keyword(s):  
Cell Fate ◽  
Stochastic Dynamics ◽  
Biochemical Networks ◽  
Stochastic Bifurcation ◽  
Modeling Framework ◽  
Life And Death ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Adaptation Response ◽  
The Impact

Abstract Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.

Dynamics of Notch signalling in the mouse oviduct and uterus during the oestrous cycle

2016 ◽  
Vol 28 (11) ◽  
pp. 1663 ◽  
Author(s):  
D. Murta ◽  
M. Batista ◽  
A. Trindade ◽  
E. Silva ◽  
L. Mateus ◽  
...  
Keyword(s):  
Real Time ◽  
Cell Fate ◽  
Expression Patterns ◽  
Cell Signalling ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Effector Proteins ◽  
Oestrous Cycle ◽  
Cell Fate Decisions ◽  
Effector Genes

The oviduct and uterus undergo extensive cellular remodelling during the oestrous cycle, requiring finely tuned intercellular communication. Notch is an evolutionarily conserved cell signalling pathway implicated in cell fate decisions in several tissues. In the present study we evaluated the quantitative real-time polymerase chain reaction (real-time qPCR) and expression (immunohistochemistry) patterns of Notch components (Notch1–4, Delta-like 1 (Dll1), Delta-like 4 (Dll4), Jagged1–2) and effector (hairy/enhancer of split (Hes) 1–2, Hes5 and Notch-Regulated Ankyrin Repeat-Containing Protein (Nrarp)) genes in the mouse oviduct and uterus throughout the oestrous cycle. Notch genes are differentially transcribed and expressed in the mouse oviduct and uterus throughout the oestrous cycle. The correlated transcription levels of Notch components and effector genes, and the nuclear detection of Notch effector proteins, indicate that Notch signalling is active. The correlation between transcription levels of Notch genes and progesterone concentrations, and the association between expression of Notch proteins and progesterone receptor (PR) activation, indicate direct progesterone regulation of Notch signalling. The expression patterns of Notch proteins are spatially and temporally specific, resulting in unique expression combinations of Notch receptor, ligand and effector genes in the oviduct luminal epithelium, uterus luminal and glandular epithelia and uterine stroma throughout the oestrous cycle. Together, the results of the present study imply a regulatory role for Notch signalling in oviduct and uterine cellular remodelling occurring throughout the oestrous cycle.

scholarly journals Quantifying the Stability of Coupled Genetic and Epigenetic Switches With Variational Methods

2021 ◽  
Vol 11 ◽  
Author(s):  
Amogh Sood ◽  
Bin Zhang
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Histone Modifications ◽  
Regulatory Networks ◽  
Variational Principles ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Fate Decisions ◽  
The Impact

The Waddington landscape provides an intuitive metaphor to view development as a ball rolling down the hill, with distinct phenotypes as basins and differentiation pathways as valleys. Since, at a molecular level, cell differentiation arises from interactions among the genes, a mathematical definition for the Waddington landscape can, in principle, be obtained by studying the gene regulatory networks. For eukaryotes, gene regulation is inextricably and intimately linked to histone modifications. However, the impact of such modifications on both landscape topography and stability of attractor states is not fully understood. In this work, we introduced a minimal kinetic model for gene regulation that combines the impact of both histone modifications and transcription factors. We further developed an approximation scheme based on variational principles to solve the corresponding master equation in a second quantized framework. By analyzing the steady-state solutions at various parameter regimes, we found that histone modification kinetics can significantly alter the behavior of a genetic network, resulting in qualitative changes in gene expression profiles. The emerging epigenetic landscape captures the delicate interplay between transcription factors and histone modifications in driving cell-fate decisions.

Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development

Development ◽  
1992 ◽  
Vol 115 (3) ◽  
pp. 737-744 ◽  
Author(s):  
F.F. Del Amo ◽  
D.E. Smith ◽  
P.J. Swiatek ◽  
M. Gendron-Maguire ◽  
R.J. Greenspan ◽  
...  
Keyword(s):  
Cell Fate ◽  
Mouse Embryo ◽  
Transmembrane Protein ◽  
Neuronal Cell ◽  
Cell Types ◽  
Drosophila Embryo ◽  
Mouse Development ◽  
Cell Fate Decisions ◽  
Early Mouse ◽  
Partial Cdna Clone

The Notch gene of Drosophila encodes a large transmembrane protein involved in cell-cell interactions and cell fate decisions in the Drosophila embryo. To determine if a gene homologous to Drosophila Notch plays a role in early mouse development, we screened a mouse embryo cDNA library with probes from the Xenopus Notch homolog, Xotch. A partial cDNA clone encoding the mouse Notch homolog, which we have termed Motch, was used to analyze expression of the Motch gene. Motch transcripts were detected in a wide variety of adult tissues, which included derivatives of all three germ layers. Differentiation of P19 embryonal carcinoma cells into neuronal cell types resulted in increased expression of Motch RNA. In the postimplantation mouse embryo Motch transcripts were first detected in mesoderm at 7.5 days post coitum (dpc). By 8.5 dpc, transcript levels were highest in presomitic mesoderm, mesenchyme and endothelial cells, while much lower levels were detected in neuroepithelium. In contrast, at 9.5 dpc, neuroepithelium was a major site of Motch expression. Transcripts were also abundant in cell types derived from neural crest. These data suggest that the Motch gene plays multiple roles in patterning and differentiation of the early postimplantation mouse embryo.

scholarly journals The Impact of Epigenetic Signatures on Amniotic Fluid Stem Cell Fate

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Daniela Di Tizio ◽  
Alessandra Di Serafino ◽  
Prabin Upadhyaya ◽  
Luca Sorino ◽  
Liborio Stuppia ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Amniotic Fluid ◽  
Cell Fate ◽  
Histone Modifications ◽  
Current Evidence ◽  
Cell Fate Decisions ◽  
Small Noncoding Rnas ◽  
Tight Correlation ◽  
The Impact

Epigenetic modifications play a significant role in determining the fate of stem cells and in directing the differentiation into multiple lineages. Current evidence indicates that mechanisms involved in chromatin regulation are essential for maintaining stable cell identities. There is a tight correlation among DNA methylation, histone modifications, and small noncoding RNAs during the epigenetic control of stem cells’ differentiation; however, to date, the precise mechanism is still not clear. In this context, amniotic fluid stem cells (AFSCs) represent an interesting model due to their unique features and the possible advantages of their use in regenerative medicine. Recent studies have elucidated epigenetic profiles involved in AFSCs’ lineage commitment and differentiation. In order to use these cells effectively for therapeutic purposes, it is necessary to understand the basis of multiple-lineage potential and elaborate in detail how cell fate decisions are made and memorized. The present review summarizes the most recent findings on epigenetic mechanisms of AFSCs with a focus on DNA methylation, histone modifications, and microRNAs (miRNAs) and addresses how their unique signatures contribute to lineage-specific differentiation.

scholarly journals High levels of Notch signaling down-regulate Numb and Numblike

2006 ◽  
Vol 175 (4) ◽  
pp. 535-540 ◽  
Author(s):  
Gavin Chapman ◽  
Lining Liu ◽  
Cecilia Sahlgren ◽  
Camilla Dahlqvist ◽  
Urban Lendahl
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Cultured Cells ◽  
Tumor Development ◽  
Proteasome Inhibitor Mg132 ◽  
Cell Fate Decisions ◽  
Protein Levels ◽  
Notch Intracellular Domain ◽  
Low Levels ◽  
Mediated Reduction

Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch, high levels of Notch signaling conversely led to a reduction of Numb and Numblike protein levels in cultured cells and in the developing chick central nervous system. The Notch intracellular domain but not the canonical Notch downstream proteins Hes 1 and Hey 1 caused a reduction of Numb and Numblike. The Notch-mediated reduction of Numblike required the PEST domain in the Numblike protein and was blocked by the proteasome inhibitor MG132. Collectively, these observations reveal a reciprocal negative regulation between Notch and Numb/Numblike, which may be of relevance for stabilizing asymmetric cell fate switches and for tumor development.

Phagocyte NADPH oxidase and specific immunity

2015 ◽  
Vol 128 (10) ◽  
pp. 635-648 ◽  
Author(s):  
Julien Cachat ◽  
Christine Deffert ◽  
Stephanie Hugues ◽  
Karl-Heinz Krause
Keyword(s):  
Dendritic Cells ◽  
Nadph Oxidase ◽  
Cell Fate ◽  
B Lymphocytes ◽  
Antigen Processing ◽  
Ros Generation ◽  
Cell Fate Decisions ◽  
Specific Immunity ◽  
Phagocyte Nadph Oxidase ◽  
The Impact

The phagocyte NADPH oxidase NOX2 produces reactive oxygen species (ROS) and is a well-known player in host defence. However, there is also increasing evidence for a regulatory role of NOX2 in adaptive immunity. Deficiency in phagocyte NADPH oxidase causes chronic granulomatous disease (CGD) in humans, a condition that can also be studied in CGD mice. Clinical observations in CGD patients suggest a higher susceptibility to autoimmune diseases, in particular lupus, idiopathic thrombocytopenic purpura and rheumatoid arthritis. In mice, a strong correlation exists between a polymorphism in a NOX2 subunit and the development of autoimmune arthritis. NOX2 deficiency in mice also favours lupus development. Both CGD patients and CGD mice exhibit increased levels of immunoglobulins, including autoantibodies. Despite these phenotypes suggesting a role for NOX2 in specific immunity, mechanistic explanations for the typical increase of CGD in autoimmune disease and antibody levels are still preliminary. NOX2-dependent ROS generation is well documented for dendritic cells and B-lymphocytes. It is unclear whether T-lymphocytes produce ROS themselves or whether they are exposed to ROS derived from dendritic cells during the process of antigen presentation. ROS are signalling molecules in virtually any cell type, including T- and B-lymphocytes. However, knowledge about the impact of ROS-dependent signalling on T- and B-lymphocyte phenotype and response is still limited. ROS might contribute to Th1/Th2/Th17 cell fate decisions during T-lymphocyte activation and might enhance immunoglobulin production by B-lymphocytes. In dendritic cells, NOX2-derived ROS might be important for antigen processing and cell activation.

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