Targeting Notch Pathways
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
The discovery that activating mutations occur in over 50% of T-ALL patients has demonstrated the importance of this signaling pathway in the molecular pathogenesis of T-ALL. Inhibition of the Notch signaling pathway has opened up a new area for therapeutic intervention. γ-Secretase inhibitors hold promise as therapeutics for T-ALL and other malignances. These compounds will likely be most beneficial in combination with other drugs, either those currently used to treat T-ALL patients or other specific inhibitors of pathways downstream of Notch described in this chapter. Specific inhibitors of the Notch signaling pathway, such as antibodies or small molecules that specifically block Notchl signaling but not signaling by Notch 2–4, may be more effective and produce fewer side effects. The complexity of the Notch signaling pathway provides several additional points at which the pathway could be targeted including ligand binding, dimerization, proteolysis, and transcriptional activity.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Genetics: an autosomal recessive disorder. Four genes are associated with this condition and define different subtypes (1–4): DLL3 (delta-like 3), MESP2 (mesoderm posterior 2), LFNG (lunatic fringe), HES7 (hairy/enhancer of split, homolog of drosophila, 7). All these genes encode proteins involved in the notch-signalling pathway, crucial to normal somitogenesis. DLL3 is a notch ligand and is crucial in the cell-signalling processes which generate rostro–caudal somite boundary formation with a defined temporal periodicity driven by the molecular ‘segmentation clock’. MESP2 is a member of the basic helix-loop-helix (bHLH) family of transcriptional regulatory proteins. LFNG is a glycosyltransferase; it localises to the Golgi and post-translationally modifies the notch family receptors. Its expression is indirectly regulated by DLL3. HES7 encodes a bHLH-orange domain transcriptional repressor protein. In the mouse, HES genes are direct targets of notch and repress their own transcription through the interaction with their own promoters; due to their very short half-lives, cyclic waves of transcription are generated every 90–120 minutes. A rare form of SCD with autosomal dominant inheritance has been reported, the gene is still unknown.
Satellite cells and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
The Notch signalling pathway also plays a role in determining cell fate. Activation of the Notch pathway promotes myoblast proliferation and overexpression of the transmembrane receptor Notch-1 results in higher levels of Pax 7 in myoblasts and enhances satellite cell self-renewal (31, 32). By contrast, the Notch signalling inhibitor, Numb, promotes Myf-5 expression, myoblast differentiation and myotube formation (31). Numb is inherited asymmetrically when myoblast divide (31), potentially directing one daughter cell towards differentiation and another towards self-renewal. Numb localisation is also under the control of the Par complex (27), demonstrating how integrated cellular signalling can control satellite cell proliferation, differentiation and the return to quiescence.
Effects of Notch signalling pathway on the relationship between vascular endothelial dysfunction and endothelial stromal transformation in atherosclerosis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Notch signalling pathway was first discovered by Mohr in studying the gene function of Drosophila, which is a highly conserved intercellular communication pathway in biological evolution and plays an important role in many organ development processes [12]. The study found that there are four Notch receptors in mammals, Notch1, Notch2, Notch3 and Notch4, respectively. Notch ligands are Jagged1, Jagged2 and Delta1, Delta3, Delta4. All receptors and ligands are transmembrane proteins, and adjacent cells can pass through the binding of the receptor to the ligand. Notch1, Notch3, Notch4, Delta-like4, Jagged1 and Jagged2 were expressed on the arterial endothelium [13]. The Notch signalling pathway is a conserved and important signal transduction pathway that affects cell fate, which involves almost all cell proliferation and differentiation activities, and plays an important role in regulating cell differentiation, proliferation and apoptosis, and a series of physiological pathologies [14]. Notch signalling pathway family members include ligands, receptors, nuclear transcription factors, regulatory molecules and downstream target molecules and other components, which play a classic and conservative role in adult individuals and embryonic development process [15]. The results of this research mentioned above is related to embryonic development, tumorigenesis, degeneration of the immune system, immune system function regulation, bone marrow hematopoietic stem cell expansion, and other physiological and pathological processes.
Regulation of Notch Signaling Pathway to Innate Lymphoid Cells in Patients with Acute Myocardial Infarction
Published in Immunological Investigations, 2023
Haiwen Yu, Yongjie Wei, Yanyan Dong, Penglei Chen
The Notch signaling pathway is a cell signaling system that is conserved in a variety of eukaryotes (Castro et al. 2021) and controls a wide spectrum of developmental processes (Radtke et al. 2010; Yuan et al. 2010). Four Notch receptors (Notch1 ~ 4) and their ligands (such as Jagged1, Jagged2, and delta-like ligand 4) in mammals mediate cell-to-cell communication and proteolytic processing to promote signaling (Castro et al. 2021). Delta-like ligand negatively regulates angiogenic sprouting (Lobov et al. 2007). Whereas Jagged appears to have an opposing function by competing with delta-like ligand and participating in the recruitment of pericytes and sprouting (Qiu et al. 2016). Hairy and enhancer of split homolog 1 (Hes1) is one of the most important downstream target genes of Notch signaling and is widely expressed in human tissues, which are involved in immunoregulation both physiologically and pathologically, such as in cancers and inflammation (Rani et al. 2016; Wang et al. 2020). Notch signaling pathway plays important roles in various cellular mechanisms, such as cell fate determination, hematopoiesis, organ self-renewal, proliferation, and apoptosis (Castro et al. 2021). Notch signaling regulates atherosclerosis by controlling macrophage polarization and T-cell differentiation and activity (Vieceli Dalla Sega et al. 2019). However, the modulatory role of Notch signaling pathway in ACS is still not fully understood.
Potential signaling pathway through which Notch regulates oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose
Published in Journal of Receptors and Signal Transduction, 2021
Ziyang Jing, Langtao Hu, Yan Su, Gangqiang Ying, Chunyang Ma, Jiali Wei
The Notch gene was first recognized in Drosophila by Morgan, who named the gene for the marginal notch (Notch) of the wings Drosophila melanogaster, resulting in impaired function. The Notch protein family, a transmembrane receptor protein family, is widespread in vertebrates and invertebrates and highly conserved, can mediate interactions between cells, and plays an important role in determining cell fate. Moreover, Notch can be reactivated in disease states and can participate in the processes of apoptosis, regeneration, and tubule mesenchymal transition and can affect the occurrence and development of many kinds of kidney diseases through cross talk with other signaling pathways (across-talk). Upon the binding of the Notch signaling pathway ligand to the receptor, the Notch receptor undergoes conformational changes, mediating the release of the Notch intracellular domain (NICD) by gamma secretase. NICD is the activated form of Notch, which enters the nucleus to activate the downstream regulatory genes Hes and Hey and induce the differentiation of cells [10].
Related Knowledge Centers
- Animal
- Calcium
- Cell Signaling
- Conserved Sequence
- Oligomer
- Tetralogy of Fallot
- Notch Proteins
- Cell Surface Receptor
- Neurogenesis
- T-Lymphoblastic Leukemia/Lymphoma
- Tetralogy of Fallot