Fig 1 - uploaded by Matthew D Rand
Content may be subject to copyright.
![Elements of Notch signaling. A nonmechanistic schematic of various elements that have been shown to modulate Notch activity. Extracellular regions of Notch (N) and Delta (Dl) interact to activate the receptor. As a result of activation, the Supressor of Hairless [Su(H)] transcription factor eventually binds to regulatory sequences of the Enhancer of split [E(Spl)] complex genes, which encode bHLH proteins. bHLH products, together with Groucho, can repress the expression of the Achaete-Scute (Ac-Sc) proneural genes. Several additional factors that influence signaling through these core elements and that display molecular interactions are also shown. These include the ligand Serrate (Ser) and its negative regulator Fringe (Fng); the metalloprotease Kuzbanian (Kuz), which acts as a Delta-and potentially as a Notch-processing enzyme; the trans-Golgi convertase Furin, which cleaves Notch; Presenilin, which may cleave Notch in the membrane; and the Notch intracellular domain interacting proteins Deltex (Dx), Disheveled (Dsh), Disabled (Dab), and Numb; and in the nucleus, the two regulators Hairless (H) and Groucho (Gro). Structural elements of Notch and Delta are represented as follows: Purple and orange boxes represent EGF repeats, light-blue boxes represent EGF 11-12 of Notch, the yellow box represents the DSL domain, green ovals represent Notch and Lin-12 repeats, the red oval represents the six ankyrin repeats, and the brown box represents the pest sequence.](profile/Matthew-Rand/publication/13076358/figure/fig3/AS:667706139361281@1536204957019/Elements-of-Notch-signaling-A-nonmechanistic-schematic-of-various-elements-that-have.png)
Elements of Notch signaling. A nonmechanistic schematic of various elements that have been shown to modulate Notch activity. Extracellular regions of Notch (N) and Delta (Dl) interact to activate the receptor. As a result of activation, the Supressor of Hairless [Su(H)] transcription factor eventually binds to regulatory sequences of the Enhancer of split [E(Spl)] complex genes, which encode bHLH proteins. bHLH products, together with Groucho, can repress the expression of the Achaete-Scute (Ac-Sc) proneural genes. Several additional factors that influence signaling through these core elements and that display molecular interactions are also shown. These include the ligand Serrate (Ser) and its negative regulator Fringe (Fng); the metalloprotease Kuzbanian (Kuz), which acts as a Delta-and potentially as a Notch-processing enzyme; the trans-Golgi convertase Furin, which cleaves Notch; Presenilin, which may cleave Notch in the membrane; and the Notch intracellular domain interacting proteins Deltex (Dx), Disheveled (Dsh), Disabled (Dab), and Numb; and in the nucleus, the two regulators Hairless (H) and Groucho (Gro). Structural elements of Notch and Delta are represented as follows: Purple and orange boxes represent EGF repeats, light-blue boxes represent EGF 11-12 of Notch, the yellow box represents the DSL domain, green ovals represent Notch and Lin-12 repeats, the red oval represents the six ankyrin repeats, and the brown box represents the pest sequence.
Source publication
Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development.
Signals exchanged between neighboring cells through the Notch receptor can amplify and consolidate molecular differences,
which eventually dictate cell fates. Thus, Notch signals control how cells respond to intrinsi...
Context in source publication
Context 1
... and molecular interaction studies resulted in the identification of a number of proteins that may participate in transmitting or regulating Notch signals (Fig. 1). From this increasing array of proteins, whose direct rela- tion to Notch signaling is often unclear, a small group of elements emerges as forming the core of this signaling pathway. In Drosophila, the two single-pass transmembrane proteins, Delta and Serrate, have been identified as partially redundant Notch ligands (Delta and Jagged ...
Similar publications
Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising impo...
Of the 20 or so signal transduction pathways that orchestrate cell-cell interactions in metazoans, seven are involved during development. One of these is the Notch signalling pathway which regulates cellular identity, proliferation, differentiation and apoptosis via the developmental processes of lateral inhibition and boundary induction. In light...
Notch signaling plays a pivotal role in the regulation of many fundamental cellular processes, such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. At the molecular level, ligand binding induces the proteolytic cleavage of the Notch receptor. The intracellular domain of Notch translocates subseque...
In the canonical Notch signaling pathway, intramembrane cleavage by gamma-secretase serves to release an intracellular domain of Notch that has activity in the nucleus through binding to transcription factors. In addition, we showed that Notch also supplies signals to Delta, a major Notch ligand, to release the intracellular domain of Delta by gamm...
Delta and Notch are required for partitioning of vein and intervein cell fates within the provein during Drosophila metamorphosis. We find that partitioning of these fates is dependent on Delta-mediated signalling from 22 to 30 hours after puparium formation at 25 degrees C. Within the provein, Delta is expressed more highly in central provein cell...
Citations
... Of importance, our present findings demonstrated that stress augments the FeCl 3 -induced formation of thrombi, and this effect was rectified by CTSK knockout and its inhibitor. The ability of chronic stress to elevate the expression of CTSK is thus likely to have been involved in Notch signaling has been shown to control cell fates and signal integration in development [39]. Laboratory evidence indicates that among the Notch receptors, Notch1/ Hes1 signaling modulates not only cell proliferation but also apoptosis in the initiation and progression of tumors and cardiovascular diseases [26,40]. ...
Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis.
Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation.
CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.
... Notch signaling is an evolutionarily conserved mechanism [133] that functions in diverse developmental and physiological processes through cell-cell interactions [134], and is the key to maintain an undifferentiated state of HSCs [135] ( Fig. 4). In mammals, four Notch receptors (Notch1-4) and five Notch ligands (Dll1, Dll3, Dll4, Jagged-1, and Jagged-2) [136] have been found on hematopoietic precursors and BM stromal cells [137]. ...
Hematopoietic stem cells (HSCs) are an ideal source for the treatment of many hematological diseases and malignancies, as well as diseases of other systems, because of their two important features, self-renewal and multipotential differentiation, which have the ability to rebuild the blood system and immune system of the body. However, so far, the insufficient number of available HSCs, whether from bone marrow (BM), mobilized peripheral blood or umbilical cord blood, is still the main restricting factor for the clinical application. Therefore, strategies to expand HSCs numbers and maintain HSCs functions through ex vivo culture are urgently required. In this review, we outline the basic biology characteristics of HSCs, and focus on the regulatory factors in BM niche affecting the functions of HSCs. Then, we introduce several representative strategies used for HSCs from these three sources ex vivo expansion associated with BM niche. These findings have deepened our understanding of the mechanisms by which HSCs balance self-renewal and differentiation and provided a theoretical basis for the efficient clinical HSCs expansion.
... Receptors and ligands are Type Kappa j region, which is also known as CSL (CBF1/Suppressor of Hairless/LAG-1)) and coactivators (Mastermind-like (MAML) family members) to assemble the Notch transcription complex (NTC). The NTC binds enhancers and promoters to activate transcription of target genes [1][2][3][4][5][6]. NTCs can activate transcription via two type of DNA sites: independent CSL sites recruit monomeric NTCs, whereas two sites arranged in a head-to-head orientation 15-18 nucleotides apart (sequence-paired-sites or SPS) [7][8][9] recruit cooperative NTC dimers through a conserved Arginine (ARG) in the NICD ankyrin (ANK) domain [9,10]. ...
The Notch intracellular domain (NICD) regulates gene expression during development and homeostasis in a transcription factor complex that binds DNA either as monomer, or cooperatively as dimers. Mice expressing Notch dimerization-deficient (NDD) alleles of Notch1 and Notch2 have defects in multiple tissues that are sensitized to environmental insults. Here, we report that cardiac phenotypes and DSS (Dextran Sodium Sulfate) sensitivity in NDD mice can be ameliorated by housing mice under hypo-allergenic conditions (food/bedding). However, compound heterozygote NDD mice (N1RA/-; N2RA/-) in hypo-allergenic conditions subsequently develop severe hydrocephalus and hemorrhages. Further analysis revealed multiple vascular phenotypes in NDD mice including leakage, malformations of brain vasculature, and vasodilation in kidneys, leading to demise around P21. This mouse model is thus a hypomorphic allele useful to analyze vascular phenotypes and gene-environment interactions. The possibility of a non-canonical Notch signal regulating barrier formation in the gut, skin, and blood systems is discussed.
... Their fate and function are precisely regulated by the microenvironment in which they reside. Notch signaling, a key pathway akin to WNT signaling, plays a central role in dictating cell fate across various tissues (Artavanis-Tsakonas et al., 1999). ...
Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positioned where the body interfaces with the outside world. We review the many signaling pathways and mechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate with macrophages, Tregs and epithelial stem cells to mount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease.
... Notch signaling is an evolutionarily conserved pathway that plays a fundamental role in various developmental events like cell fate determination, proliferation, apoptosis, and stem cell maintenance [1][2][3][4]. Notch is synthesized as a 300 kDa precursor protein that is subjected to its first cleavage in the trans-Golgi network by furin-like convertases (S1 cleavage), resulting in a 180 kDa N-terminal extracellular domain NECD (Notch extracellular domain) and a 120 kDa C-terminal transmembrane intracellular domain, N™ [5]. This heterodimer of Notch receptor is targeted to the cell membrane where it interacts with ligands of the DSL family (Drosophila Delta and Serrate (Jagged in mammals) and C. elegans LAG-2). ...
The Notch pathway is an evolutionarily conserved signaling system that is intricately regulated at multiple levels and it influences different aspects of development. In an effort to identify novel components involved in Notch signaling and its regulation, we carried out protein interaction screens which identified non-muscle myosin II Zipper (Zip) as an interacting partner of Notch. Physical interaction between Notch and Zip was further validated by co-immunoprecipitation studies. Immunocytochemical analyses revealed that Notch and Zip co-localize within same cytoplasmic compartment. Different alleles of zip also showed strong genetic interactions with Notch pathway components. Downregulation of Zip resulted in wing phenotypes that were reminiscent of Notch loss-of-function phenotypes and a perturbed expression of Notch downstream targets, Cut and Deadpan. Further, synergistic interaction between Notch and Zip resulted in highly ectopic expression of these Notch targets. Activated Notch-induced tumorous phenotype of larval tissues was enhanced by over-expression of Zip. Notch-Zip synergy resulted in the activation of JNK pathway that consequently lead to MMP activation and proliferation. Taken together, our results suggest that Zip may play an important role in regulation of Notch signaling.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00018-024-05142-1.
... NICD enters the nucleus and binds to the hairless inhibitor (Su(H)), mediating changes in the expression of downstream target genes (e.g., Insects 2024, 15, 292 2 of 11 E(spl)) in specific tissues and developmental stages [2]. The Notch signaling pathway relies primarily on interactions between the Notch protein and various ligands to transmit signals between cells and plays a vital role in reproduction and development processes in insects [3]. In studies of the fruit fly Drosophila melanogaster, Notch was shown to mediate the functional differentiation of cells involved in various physiological activities, such as the formation of organ precursor cells [4], humoral and cellular immunity [5,6], cell proliferation [7], and the formation of germ cells in the testes and ovaries [8,9]. ...
Basilepta melanopus is a pest that severely affects oil tea plants, and the Notch signaling pathway plays a significant role in the early development of insect ovaries. In this study, we explored the function of the notch gene within the Notch signaling pathway in the reproductive system of B. melanopus. The functional domains and expression patterns of Bmnotch were analyzed. Bmnotch contains 45 epidermal growth factor-like (EGF-like) domains, one negative regulatory region, one NODP domain and one repeat-containing domain superfamily. The qPCR reveals heightened expression in early developmental stages and specific tissues like the head and ovaries. The RNA interference (RNAi)-based suppression of notch decreased its expression by 52.1%, exhibiting heightened sensitivity to dsNotch at lower concentrations. Phenotypic and mating experiments have demonstrated that dsNotch significantly impairs ovarian development, leading to reduced mating frequencies and egg production. This decline underscores the Notch pathway’s crucial role in fecundity. The findings advocate for RNAi-based, Notch-targeted pest control as an effective and sustainable strategy for managing B. melanopus populations, signifying a significant advancement in forest pest control endeavors.
... This control by heterodimer CBFβ-RUNX2 may contribute to the occurrence and development of OS [133]. Notch signal transduction is an old-fashioned cell interaction mechanism and an important regulator of the proliferation and differentiation of mouse chondrocytes [134,135]. Normally, Notch sig- Figure 4. Regulatory mechanisms of Runx2 in OS. The interaction between SOX9 and RUNX2 promotes the cell survival of OS [122]. ...
... The expression of Hes-1, a direct transcriptional target gene of Notch signaling [28], was detected at the mRNA and protein levels to evaluate the influence of DAPT on Notch signaling. Mice in the MC group showed enhanced Hes-1 mRNA expression ( Figure 2A, p < 0.01, vs. NC group). ...
Antarctic krill tropomyosin (AkTM) has been shown in mice to cause IgE-mediated food allergy. The objective of this work was to investigate the role of Notch signaling in AkTM-sensitized mice, as well as to determine the changes in gut microbiota composition and short-chain fatty acids (SCFAs) in the allergic mice. An AkTM-induced food allergy mouse model was built and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was used as an γ-secretase inhibitor to inhibit the activation of Notch signaling. Food allergy indices, some key transcription factors, histologic alterations in the small intestine, and changes in gut microbiota composition were examined. The results showed that DAPT inhibited Notch signaling, which reduced AkTM-specific IgE, suppressed mast cell degranulation, decreased IL-4 but increased IFN-γ production, and alleviated allergic symptoms. Quantitative real-time PCR and Western blotting analyses revealed that expressions of Hes-1, Gata3, and IL-4 were down-regulated after DAPT treatment, accompanied by increases in T-bet and IFN-γ, indicating that Notch signaling was active in AkTM-sensitized mice and blocking it could reverse the Th1/Th2 imbalance. Expressions of key transcription factors revealed that Notch signaling could promote Th2 cell differentiation in sensitized mice. Furthermore, 16S rRNA sequencing results revealed that AkTM could alter the diversity and composition of gut microbiota in mice, leading to increases in inflammation-inducing bacteria such as Enterococcus and Escherichia-Shigella. Correlation analysis indicated that reduced SCFA concentrations in AkTM-allergic mice may be related to decreases in certain SCFA-producing bacteria, such as Clostridia_UCG-014. The changes in gut microbiota and SCFAs could be partially restored by DAPT treatment. Our findings showed that inhibiting Notch signaling could alleviate AkTM-induced food allergy by correcting Th1/Th2 imbalance and modulating the gut microbiota.
... Важная роль в патогенезе T-ЛБЛ отводится сигнальному пути Notch. Это эволюционно консерва-тивный сигнальный путь, участвующий в регуляции таких фундаментальных клеточных процессов, как пролиферация, дифференцировка, апоптоз и выживание [16]. В частности, этот путь является необходимым для коммитирования гемопоэтических предшественников к развитию по Т-клеточному пути дифференцировки, а также для дальнейшего созревания Т-клеток [17]. ...
T-lymphoblastic lymphoma (T-LBL) is one of the most common non-Hodgkin lymphomas in children. According to the 2022 WHO classification, T-LBL and acute T-lymphoblastic leukemia are considered as a single disease since they both have T-cell precursors as a morphological substrate. In recent years, some progress has been made in the treatment of this disease, but the prognosis for relapses and refractory cases remains extremely unfavorable. One of the promising areas that can increase the effectiveness of therapy is the use of new treatment approaches that consider the molecular and biological features of this tumor. This review examines in detail the molecular aspects of the pathogenesis of T-LBL.
... Notch signaling has been studied extensively (Yamamoto et al. 2014) with its mechanism of signal transduction described in detail (Kopan and Ilagan 2009). Genetic studies indicate Notch's involvement in implementing a spectrum of fundamental processes across development, including regulating cell proliferation, apoptosis, cell fate specification, and activation of cell differentiation in a context-dependent manner (Artavanis-Tsakonas et al. 1999;Kopan and Ilagan 2009). Notch signaling integrates intrinsic and extrinsic developmental cues through its crosstalk with other critical signaling pathways, such as Wnt/β-catenin, NF-κB, and TGF-β/BMP signaling, to refine the developmental trajectory of organ formation and the whole organism (Artavanis-Tsakonas Collu et al. 2014;Guo and Wang 2009;Klüppel and Wrana 2005;Osipo et al. 2008). ...
A number of environmental toxicants are noted for their activity that leads to declined motor function. However, the role of muscle as a proximal toxicity target organ for environmental agents has received considerably less attention than the toxicity targets in the nervous system. Nonetheless, the effects of conventional neurotoxicants on processes of myogenesis and muscle maintenance are beginning to resolve a concerted role of muscle as a susceptible toxicity target. A large body of evidence from epidemiological, animal, and in vitro studies has established that methylmercury (MeHg) is a potent developmental toxicant, with the nervous system being a preferred target. Despite its well-recognized status as a neurotoxicant, there is accumulating evidence that MeHg also targets muscle and neuromuscular development as well as contributes to the etiology of motor defects with prenatal MeHg exposure. Here, we summarize evidence for targets of MeHg in the morphogenesis and maintenance of skeletal muscle that reveal effects on MeHg distribution, myogenesis, myotube formation, myotendinous junction formation, neuromuscular junction formation, and satellite cell-mediated muscle repair. We briefly recapitulate the molecular and cellular mechanisms of skeletal muscle development and highlight the pragmatic role of alternative model organisms, Drosophila and zebrafish, in delineating the molecular underpinnings of muscle development and MeHg-mediated myotoxicity. Finally, we discuss how toxicity targets in muscle development may inform the developmental origins of health and disease theory to explain the etiology of environmentally induced adult motor deficits and accelerated decline in muscle fitness with aging.
