Notch after cleavage

Bray, Sarah; Gomez-Lamarca, Maria J.

doi:10.1016/j.ceb.2017.12.008

Cited by 70 publications

(69 citation statements)

References 63 publications

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“…As the active form of the Notch signal intracellular segment, NICD plays a crucial role in the conduction of Notch signaling [27]. In this study, we found that the expression of Notch1, Jagged1, and NICD in the AR group was significantly higher than that in the control group, which was in accordance with the experimental results of the AR patient serum.…”

Section: Discussionsupporting

confidence: 80%

Notch Signaling Promotes Development of Allergic Rhinitis by Suppressing Foxp3 Expression and Treg Cell Differentiation

Jiao

Wei

Kong

et al. 2018

Int Arch Allergy Immunol

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Background: The Notch signaling pathway plays an important role in regulating human immune function, but the relationship between allergic rhinitis (AR) and Notch signaling remains unclear. Objective: To investigate the role of Notch signaling in the pathogenesis of AR and its regulation on Foxp3-Treg cells. Method: The sera of 100 patients with AR and 50 controls were collected to assess the differences in Notch1, Jagged1, and DLL1 (Delta-like 1) expression. Experimental mice were divided into normal control, AR, Notch inhibitor, and dexamethasone groups. Allergic symptoms, total IgE levels, and the proportion of Treg cells in the peripheral blood were detected. Notch1, Jagged1, NICD (Notch intracellular domain, also known as ICN), and Foxp3 expression and Th1/Th2/Th17-related cytokines in the spleen were detected and compared between each group of mice. Results: Compared with the control group, the expression of Notch1 and Jagged1 in patients with AR was significantly elevated (p < 0.05). The expression of Notch1 and Jagged1 in patients with severe AR was higher than that observed in the mild to moderate AR patients and positively correlated with the levels of allergen sIgE (p < 0.05). The animal experiments revealed that compared with the normal control group, the expression of Notch1, Jagged1, and NICD in the AR group was increased, Foxp3 expression was decreased, and the proportion of Treg cells was decreased (p < 0.05). Compared with the AR group, allergic symptoms and total serum IgE levels and the expression of Notch1, Jagged1, and NICD were significantly decreased in the Notch inhibited group, whereas the expression of Foxp3 and the proportion of Treg cells were increased significantly (p < 0.05). The Th2-type immune responses were also enhanced and Th1-type immune responses decreased in the AR group, but the Th1/Th2 imbalance was reversed in the Notch inhibited group. Conclusion: Notch signaling downregulates Foxp3 expression and inhibits the differentiation of Treg cells to promote the development of AR. Blocking Notch signaling may be a potential treatment for AR.

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Section: Discussionsupporting

confidence: 80%

Notch Signaling Promotes Development of Allergic Rhinitis by Suppressing Foxp3 Expression and Treg Cell Differentiation

Jiao

Wei

Kong

et al. 2018

Int Arch Allergy Immunol

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“…Basic helix-loop-helix (bHLH) transcriptional repressors of the Enhancer of split [E(spl)] family proteins are representative examples of Notch signaling target genes that are evolutionarily conserved (Bray, 2006). To prevent constitutive activation of the pathway, NICD becomes phosphorylated and polyubiquitinated for proteasomal degradation through its carboxyl-terminal PEST (proline, glutamic acid, serine, and threonine-rich) domain (Bray & Gomez-Lamarca, 2018).…”

Section: Uni Que a S Pec Ts Of The Notch S Ig Naling Pathwaymentioning

confidence: 99%

“…Notch intracellular domain (NICD) consists of a single RAM (RBP-jκ Associated Molecule) domain, seven ankyrin (ANK) repeats, a transactivation domain (TAD) and a PEST sequence ( Figure 1) (Bray & Gomez-Lamarca, 2018 (Kopan, Nye, & Weintraub, 1994), as well as target sites for multiple post-translational modifications including phosphorylation (Espinosa, Ingles-Esteve, Aguilera, & Bigas, 2003;Ranganathan et al, 2011), acetylation (Guarani et al, 2011;Palermo et al, 2012), methylation (Hein et al, 2015), and ubiquitination (Fryer, White, & Jones, 2004). NICD released from the plasma membrane translocates into the nucleus via the NLS mediated nuclear import machinery (Huenniger et al, 2010;Sachan, Mishra, Mutsuddi, & Mukherjee, 2013).…”

Section: Notch Intracellular Domainmentioning

confidence: 99%

“…intracellular domain (NICD) consists of a single RAM (RBP-jκ Associated Molecule) domain, seven ankyrin (ANK) repeats, a transactivation domain (TAD) and a PEST sequence (Figure 1)(Bray & Gomez-Lamarca, 2018). In Drosophila, a poly-glutamine (Q)-rich domain called the OPA sequence is present within the TAD(Wharton, Yedvobnick, Finnerty, & Artavanis-Tsakonas, 1985) but this feature is not well conserved among mammalian…”

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confidence: 99%

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Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

Yamamoto

2020

Dev Growth Differ

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“…Presenilin 1 (PSEN1), the catalytic component of the γ‐secretase complex, is essential for cleavage function, which produces the intracellular domains (ICDs) of proteins by intramembranous proteolysis. Some ICDs of type I transmembrane proteins can travel to the cell nucleus and further play an important role, for example, the Notch1 ICD (NICD), which interacts with the RBPJ DNA‐binding protein and activates the expression of target genes, such as HES1 , HES5 , and SOX9 .…”

Section: Introductionmentioning

confidence: 99%

Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

Yong

Zhang

Liu

et al. 2019

The Journal of Pathology

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The γ‐secretase complex is a presenilin‐dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ‐secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ‐secretase complex inhibitor and CD147‐directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ‐secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Notch after cleavage

Cited by 70 publications

References 63 publications

Notch Signaling Promotes Development of Allergic Rhinitis by Suppressing Foxp3 Expression and Treg Cell Differentiation

Notch Signaling Promotes Development of Allergic Rhinitis by Suppressing Foxp3 Expression and Treg Cell Differentiation

Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

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