Cis-activation in the Notch signaling pathway

AbstractThe Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can in fact activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival and differentiation in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling “negative” signaling. These results establish cis-activation as a prevalent mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts.

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Cis-activation in the Notch signaling pathway

eLife ◽

10.7554/elife.37880 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 16

Author(s):

Nagarajan Nandagopal ◽

Leah A Santat ◽

Michael B Elowitz

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Single Cells ◽

Notch Pathway ◽

Cell Types ◽

Notch Signaling Pathway ◽

Activation Process ◽

Additional Mode ◽

Ligand Expression ◽

Multiple Ligand

The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can also activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling ‘negative’ (repressive) signaling. These results establish cis-activation as an additional mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts.

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Multifaceted regulation of Notch signaling by glycosylation

Glycobiology ◽

10.1093/glycob/cwaa049 ◽

2020 ◽

Author(s):

Ashutosh Pandey ◽

Nima Niknejad ◽

Hamed Jafar-Nejad

Keyword(s):

Notch Signaling ◽

Cell Biology ◽

Normal Development ◽

Notch Pathway ◽

Cell Types ◽

Notch Signaling Pathway ◽

Protein Glycosylation ◽

Notch Receptors ◽

Current Review ◽

Notch Activation

Abstract To build a complex body composed of various cell types and tissues and to maintain tissue homeostasis in the postembryonic period, animals use a small number of highly conserved intercellular communication pathways. Among these is the Notch signaling pathway, which is mediated via the interaction of transmembrane Notch receptors and ligands usually expressed by neighboring cells. Maintaining optimal Notch pathway activity is essential for normal development, as evidenced by various human diseases caused by decreased and increased Notch signaling. It is therefore not surprising that multiple mechanisms are used to control the activation of this pathway in time and space. Over the last 20 years, protein glycosylation has been recognized as a major regulatory mechanism for Notch signaling. In this review, we will provide a summary of the various types of glycan that have been shown to modulate Notch signaling. Building on recent advances in the biochemistry, structural biology, cell biology and genetics of Notch receptors and the glycosyltransferases that modify them, we will provide a detailed discussion on how various steps during Notch activation are regulated by glycans. Our hope is that the current review article will stimulate additional research in the field of Notch glycobiology and will potentially be of benefit to investigators examining the contribution of glycosylation to other developmental processes.

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Notch Signaling Activation as a Hallmark for Triple-Negative Breast Cancer Subtype

Journal of Oncology ◽

10.1155/2019/8707053 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 22

Author(s):

M. V. Giuli ◽

E. Giuliani ◽

I. Screpanti ◽

D. Bellavia ◽

S. Checquolo

Keyword(s):

Breast Cancer ◽

Notch Signaling ◽

Signaling Pathway ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Breast Cancer Subtype ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Notch Receptors ◽

Cancer Subtype

Triple-negative breast cancer (TNBC) is a subgroup of 15%-20% of diagnosed breast cancer patients. It is generally considered to be the most difficult breast cancer subtype to deal with, due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), which usually direct targeted therapies. In this scenario, the current treatments of TNBC-affected patients rely on tumor excision and conventional chemotherapy. As a result, the prognosis is overall poor. Thus, the identification and characterization of targets for novel therapies are urgently required. The Notch signaling pathway has emerged to act in the pathogenesis and tumor progression of TNBCs. Firstly, Notch receptors are associated with the regulation of tumor-initiating cells (TICs) behavior, as well as with the aetiology of TNBCs. Secondly, there is a strong evidence that Notch pathway is a relevant player in mammary cancer stem cells maintenance and expansion. Finally, Notch receptors expression and activation strongly correlate with the aggressive clinicopathological and biological phenotypes of breast cancer (e.g., invasiveness and chemoresistance), which are relevant characteristics of TNBC subtype. The purpose of this up-to-date review is to provide a detailed overview of the specific role of all four Notch receptors (Notch1, Notch2, Notch3, and Notch4) in TNBCs, thus identifying the Notch signaling pathway deregulation/activation as a pathognomonic feature of this breast cancer subtype. Furthermore, this review will also discuss recent information associated with different therapeutic options related to the four Notch receptors, which may be useful to evaluate prognostic or predictive indicators as well as to develop new therapies aimed at improving the clinical outcome of TNBC patients.

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The Notch Pathway in Breast Cancer Progression

The Scientific World JOURNAL ◽

10.1155/2018/2415489 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 20

Author(s):

Emmanuel N. Kontomanolis ◽

Sofia Kalagasidou ◽

Stamatia Pouliliou ◽

Xanthoula Anthoulaki ◽

Nikolaos Georgiou ◽

...

Keyword(s):

Breast Cancer ◽

Notch Signaling ◽

Signaling Pathway ◽

Cancer Progression ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Breast Cancer Progression ◽

Notch Receptors ◽

The Impact

Objective. Notch signaling pathway is a vital parameter of the mammalian vascular system. In this review, the authors summarize the current knowledge about the impact of the Notch signaling pathway in breast cancer progression and the therapeutic role of Notch’s inhibition.Methods. The available literature in MEDLINE, PubMed, and Scopus, regarding the role of the Notch pathway in breast cancer progression was searched for related articles from about 1973 to 2017 including terms such as “Notch,” “Breast Cancer,” and “Angiogenesis.”Results. Notch signaling controls the differentiation of breast epithelial cells during normal development. Studies confirm that the Notch pathway has a major participation in breast cancer progression through overexpression and/or abnormal genetic type expression of the notch receptors and ligands that determine angiogenesis. The cross-talk of Notch and estrogens, the effect of Notch in breast cancer stem cells formation, and the dependable Notch overexpression during breast tumorigenesis have been studied enough and undoubtedly linked to breast cancer development. The already applied therapeutic inhibition of Notch for breast cancer can drastically change the course of the disease.Conclusion. Current data prove that Notch pathway has a major participation and multiple roles during breast tumor progression. Inhibition of Notch receptors and ligands provides innovative therapeutic results and could become the therapy of choice in the next few years, even though further research is needed to reach safe conclusions.

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Mathematical analysis of the effect of portal vein cells on biliary epithelial cell differentiation through the Delta-Notch signaling pathway

BMC Research Notes ◽

10.1186/s13104-021-05656-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Masaharu Yoshihara ◽

Teppei Nishino ◽

Manoj Kumar Yadav ◽

Akihiro Kuno ◽

Takeshi Nagata ◽

...

Keyword(s):

Portal Vein ◽

Notch Signaling ◽

Signaling Pathway ◽

Target Genes ◽

Notch Signaling Pathway ◽

Epithelial Differentiation ◽

Production Rates ◽

Fine Grained ◽

Downstream Target ◽

Notch Receptors

Abstract Objective The Delta-Notch signaling pathway induces fine-grained patterns of differentiation from initially homogeneous progenitor cells in many biological contexts, including Drosophila bristle formation, where mathematical modeling reportedly suggests the importance of production rate of the components of this signaling pathway. In contrast, the epithelial differentiation of bile ducts in the developing liver is unique in that it occurs around the portal vein cells, which express extremely high amounts of Delta ligands and act as a disturbance for the amount of Delta ligands in the field by affecting the expression levels of downstream target genes in the cells nearby. In the present study, we mathematically examined the dynamics of the Delta-Notch signaling pathway components in disturbance-driven biliary differentiation, using the model for fine-grained patterns of differentiation. Results A portal vein cell induced a high Notch signal in its neighboring cells, which corresponded to epithelial differentiation, depending on the production rates of Delta ligands and Notch receptors. In addition, this epithelial differentiation tended to occur in conditions where fine-grained patterning was reported to be lacking. These results highlighted the potential importance of the stability towards homogeneity determined by the production rates in Delta ligands and Notch receptors, in a disturbance-dependent epithelial differentiation.

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Hairy/E(spl)-related(Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish

Development ◽

10.1242/dev.129.12.2929 ◽

2002 ◽

Vol 129 (12) ◽

pp. 2929-2946 ◽

Cited By ~ 13

Author(s):

Andrew C. Oates ◽

Robert K. Ho

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Central Component ◽

Mutant Genotype ◽

Her Family ◽

Somite Formation ◽

Anterior Segments ◽

Her Genes

We have examined the expression of a Hairy/E(spl)-related (Her) gene, her7, in the zebrafish and show that its expression in the PSM cycles similarly to her1 and deltaC. A decrease in her7 function generated by antisense oligonucleotides disrupts somite formation in the posterior trunk and tail, and disrupts the dynamic expression domains of her1 and deltaC, suggesting that her7 plays a role in coordinating the oscillations of neighboring cells in the presomitic mesoderm. This phenotype is reminiscent of zebrafish segmentation mutants with lesions in genes of the Delta/Notch signaling pathway, which also show a disruption of cyclic her7 expression. The interaction of HER genes with the Delta/Notch signaling system was investigated by introducing a loss of her7 function into mutant backgrounds. This leads to segmental defects more anterior than in either condition alone. Combining a decrease of her7 function with reduction of her1 function results in an enhanced phenotype that affects all the anterior segments, indicating that Her functions in the anterior segments are also partially redundant. In these animals, gene expression does not cycle at any time, suggesting that a complete loss of oscillator function had been achieved. Consistent with this, combining a reduction of her7 and her1 function with a Delta/Notch mutant genotype does not worsen the phenotype further. Thus, our results identify members of the Her family of transcription factors that together behave as a central component of the oscillator, and not as an output. This indicates, therefore, that the function of the segmentation oscillator is restricted to the positioning of segmental boundaries. Furthermore, our data suggest that redundancy between Her genes and genes of the Delta/Notch pathway is in part responsible for the robust formation of anterior somites in vertebrates.

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The Notch signalling pathway and breast cancer: The importance of balance and cellular self-control.

Current Signal Transduction Therapy ◽

10.2174/1574362414666190916120659 ◽

2019 ◽

Vol 14 ◽

Author(s):

Germán Saucedo-Correa ◽

Alejandro Bravo-Patiño ◽

Rosa Elvira Núñez-Anita ◽

Javier Oviedo-Boyso ◽

Juan José Valdez-Alarcón ◽

...

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Cross Talk ◽

Transcriptional Activation ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Self Control ◽

Design Strategies ◽

Notch Intracellular Domain ◽

The Cross

Notch is a cell-signaling pathway that is highly conserved in all metazoans and is responsible for cell differentiation and cross-talk communication with other signaling pathways such as WNT and Hh. In most cancers, the Notch signaling pathway is altered, causing atypical activity of vital processes such as cell cycle, differentiation and apoptosis, leading the cell to a carcinogenic state. Currently, the Notch signaling pathway has taken a special interest to design strategies in order to regulate the activity of this pathway since it is known that in the cancer molecular micro-environment the Notch pathway is over-expressed or presents an aberrant function, which, in consequence, corrupts the cross-talk communication with WNT and Hh pathways. Most of the existing strategies are focused on the systematic and whole inhibition of Notch pathway at the membrane level by the use of γ-secretases inhibitors. There are few strategies that act at the nuclear level inhibiting the activity of the transcriptional activation complex composed by the Notch intracellular domain, the transcriptional factor CSL and the Mastermind co-activator. In this review, by the fact that there are not any strategy focused to revert the over expression effect caused by the Notch pathway constitutive activity, we propose that the efforts to develop new strategies against cancer should be focused to understand the complexity of the cross-talk communication between Notch, WNT and Hh pathways to neutralize the gene aberrant activity characteristic of cancer cells which are responsible for those corrupted cross-talk communication.

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Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression

Cells ◽

10.3390/cells9081879 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1879 ◽

Cited By ~ 2

Author(s):

Christian T. Meisel ◽

Cristina Porcheri ◽

Thimios A. Mitsiadis

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Cell Fate ◽

Adult Life ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Fine Tuning ◽

Cell Fate Decisions

The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.

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Association between Notch signaling pathway and cancer

Acta medica Lituanica ◽

10.6001/actamedica.v19i4.2553 ◽

2013 ◽

Vol 19 (4) ◽

pp. 427-437

Author(s):

Nadežda Lachej ◽

Janina Didžiapetrienė ◽

Birutė Kazbarienė ◽

Daiva Kanopienė ◽

Violeta Jonušienė

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Notch Pathway ◽

Treatment Method ◽

Notch Signaling Pathway ◽

Published Data ◽

Undifferentiated Cells ◽

Oncologic Diseases ◽

Worse Prognosis

Background. The components of the Notch signaling pathway are important in maintaining the balance involved in cell proliferation, apoptosis and differentiation. Therefore, dysfunction of the Notch prevents differentiation, ultimately guiding undifferentiated cells toward malignant transformation. The aim of this article is to present recently published data concerning the role of the Notch signaling pathway components in development and prognosis of oncologic diseases, in occurrence of resistance to cytostatic agents and importance in creating of new cancer treatment approaches. Materials and methods. The Pubmed was the main source of looking for information for this article. Results. Recent investigations show that disorders of the Notch signaling pathway are associated with development of some human haematological and solid cancers. In different tissues and organs this active pathway can act as a tumor suppressor or an oncogene. Accordingly, the increased or decreased expression of its components is defined. Most of published data show that the increased expression of Notch pathway components correlates with a worse prognosis of cancer and a shorter survival. Recently, the Notch pathway has been reported to be involved in drug resistance. The modulation of the Notch signaling pathway could be helpful in treatment of some tumors with abnormal activity of this pathway’s components. Therefore changes in the expression of Notch components could become important predictive factors, helpful in selecting the proper treatment method. Conclusions. The results of recent studies are very important, since the detecting of the prognostic and predictive value of components of the Notch signaling pathway can allow creating new and improving already known methods of cancer diagnostic and treatment.

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