Notch Signaling: Cell Fate Control and Signal Integration in Development

Artavanis‐Tsakonas, Spyros; Rand, Matthew D.; Lake, Robert J.

doi:10.1126/science.284.5415.770

Cited by 5,387 publications

(4,354 citation statements)

References 105 publications

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“…Notch signalling is an evolutionarily conserved mechanism to control cells’ response to intrinsic or extrinsic developmental cues that are obligatory to unfold specific developmental programs 9. The Notch activity involves in the process of differentiation, proliferation, and apoptotic programs in all stages of development of the organisms.…”

Section: Discussionmentioning

confidence: 99%

“…The evolutionarily conserved Notch signalling pathway has been identified to be critical in regulating cell differentiation, proliferation, apoptosis and cell‐cell communication 9, 10. The Notch signalling pathway consists of four Notch receptors (Notch1‐4) and five ligands (Delta‐like1, Delta‐like3, Delta‐like4, Jagged1 and Jagged2) in mammals 11, 12, 13, 14.…”

Section: Introductionmentioning

confidence: 99%

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Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

Cheng

Dai

et al. 2018

J Cellular Molecular Medi

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To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07‐1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16‐2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose‐dependent manner (P trend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r 2 = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

Cheng

Dai

et al. 2018

J Cellular Molecular Medi

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“…Activation of Notch signaling by shear has recently been shown in zebrafish 11 , so to investigate whether Notch signaling was involved here in shear-induced barrier function, we treated hEMVs with DAPT ( N -[ N -(3,5-difluorophenacetyl)-L-alanyl]- S -phenylglycine t -butylester), an inhibitor of γ-Secretase 4 , which cleaves Notch to release the transcriptionally active Notch intracellular domain (ICD, Extended Data Fig. 3a) 12 . Notch1 ICD cleavage increases with flow (Fig.…”

mentioning

confidence: 99%

A non-canonical Notch complex regulates adherens junctions and vascular barrier function

Polacheck

Kutys

Yang

et al. 2017

Nature

275

315

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The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and hemostasis1. Hemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signaling mechanism that drives adherens junction assembly. Shear stress triggers Dll4-dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain – the key domain that mediates barrier establishment. Expression of the Notch1 transmembrane domain is sufficient to rescue Notch1 knockout-induced defects in barrier function, and does so by catalyzing the formation of a novel receptor complex in the plasma membrane consisting of VE-cadherin, the transmembrane protein tyrosine phosphatase LAR, and the Rac1 GEF Trio. This complex activates Rac1 to drive adherens junction assembly and establish barrier function. Canonical Notch transcriptional signaling is highly conserved throughout metazoans and is required for many processes in vascular development, including arterial-venous differentiation3, angiogenesis4, and remodeling5; here, we establish the existence of a previously unappreciated non-canonical cortical signaling pathway for Notch1 that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling.

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“…The Notch signalling cascade is important in the development of several tissues, including the peripheral and central nervous systems (Artavanis-Tsakonas et al, 1999). Notch signalling is controlled by local cell -cell interactions based on the expression of Notch receptors and ligands on neighbouring cells that activate the cascade.…”

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confidence: 99%

Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

et al. 2005

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Neuroblastoma (NB), a sympathetically derived childhood tumour, shows characteristics of neuronal precursor cells, suggesting a halted differentiation process. We have previously shown that the Notch signalling cascade, a key player during normal neurogenesis, also might be involved in NB differentiation. Valproic acid (VPA), a well-tolerated antiepileptic drug, has been shown to induce differentiation and cell death of NB cells, possibly associated with its recently described HDAC inhibiting activity. Stimulation of NB cells with VPA led to increased cell death and phenotypic changes associated with differentiation, that is, neurite extension and upregulation of neuronal markers. VPA treatment also led to an activated Notch signalling cascade as shown by increased levels of intracellular Notch-1 and Hes-1, mimicking the initial phase of induced differentiation. These results reinforce that VPA potentially could be used in differentiation therapy of NB and that the effects in part could be a consequence of interference with the Notch signalling cascade.

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Notch Signaling: Cell Fate Control and Signal Integration in Development

Cited by 5,387 publications

References 105 publications

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

A non-canonical Notch complex regulates adherens junctions and vascular barrier function

Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

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