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Article information

Author: Sarmoko Sarmoko[a][i]  

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  1. ↑ Department of Pharmacy, Sumatera Institute of Technology, Lampung, Indonesia
  1. ↑ email@address.com

Abstract

The Notch signaling pathway is a highly conserved cell signaling system found in most animals. There are four distinct notch receptors in mammals, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region. During neurogenesis, Notch signaling promotes proliferative signaling, whereas Numb inhibits its activity to promote neural differentiation. It plays a major role in the regulation of embryonic development. Notch signaling is dysregulated in a number of cancers, and abnormal notch signaling has been linked to a number of diseases, including T-cell acute lymphoblastic leukemia (T-ALL), cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), multiple sclerosis, Tetralogy of Fallot, and Alagille syndrome. Notch signaling inhibition decreases T-cell acute lymphoblastic leukemia proliferation in both cultured cells and a mouse model.


Introduction

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Image caption text goes here (attribution: name of image creator, CC-BY 3.0)

The Notch protein is located both inside and outside of the cell membrane. When ligand proteins bind to the extracellular domain, they cause proteases to cleave and release the intracellular domain. The intracellular domain then enters the nucleus and changes gene expression.

The cleavage model was first proposed in 1993. It was based on work with the Notch gene in Drosophila and the lin-12 gene in C. elegans. It was also influenced by the first oncogenic mutation in a human Notch gene. Gary Struhl’s research in Drosophila and Raphael Kopan’s cell culture experiments in 1998 offered compelling evidence for this model. Although this model was initially disputed, by 2001 the supporting evidence was irrefutable.

Direct cell-to-cell contact activates the receptor by binding the notch receptor to the transmembrane proteins of the cells. The intercellular notch signal can turn off a trait in neighboring cells if one cell expresses it due to Notch binding. Thus, cell groupings form large structures. Therefore, Notch signaling requires lateral inhibition. Lin-12 and Notch determine binary cell fates, and lateral inhibition uses feedback mechanisms to amplify initial differences.

The Notch cascade includes intracellular proteins, ligands, and Notch. The Notch/Lin-12/Glp-1 receptor family specifies cell fates in Drosophila and C. elegans. The intracellular domain of Notch forms a complex with CBF1 and Mastermind to activate transcription of target genes. The structure of the complex has been determined.

Notch overview

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John S. Dexter identified a notch in Drosophila melanogaster wings in 1914. Thomas Hunt Morgan identified the gene’s alleles in 1917. Spyros Artavanis-Tsakonas and Michael W. Young separately sequenced and analyzed it in the 1980s.[1][2] Alleles of the two C. elegans Notch genes were identified based on developmental phenotypes: lin-12 and glp-1.[3][4] The cloning and partial sequence of lin-12 were reported by Iva Greenwald.[5]

The Notch pathway consists of four Notch receptors (Notch 1, 2, 3, and 4) and five typical DSL (Delta/Serrate/Lag-2) ligands: JAG-1 and 2 (Jagged 1 and 2), DLL-1, DLL-3, and DLL-4. Single-pass transmembrane protein ligands and receptors mediate cell-cell interactions.

The Jagged protein family—Jag1 and Jag2—is one of two Notch receptor ligand families. Delta-like proteins are the other family of ligands.

Signaling pathway

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Notch signaling starts when Notch receptors on the outside of a cell bind to ligands on the outside of the opposite cell.

Function

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The Notch signaling pathway regulates gene expression and cell differentiation during embryonic and adult life. Notch signaling also has a role in the following processes:

  • embryogenesis
  • im

Physiological role

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Embryogenesis

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Immune system

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Angiogenesis

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During angiogenesis, endothelial cells coordinate cellular actions using the Notch signaling pathway.[6]

Central nervous system development

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Neural progenitor cell (NPC) maintenance and self-renewal depended on the Notch signaling pathway. Glial cell specification, neurite formation, and learning and memory are other Notch pathway roles discovered recently.

Cardiac development

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Notch signal pathway plays a crucial role in at least three cardiac development processes: Atrioventricular canal, myocardial, and cardiac outflow tract (OFT).[7]

Pancreatic development

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Notch signaling recruits endocrine cell types from a common precursor via two pathways: lateral inhibition and suppressive maintenance. "Lateral inhibition" selects some cells for a primary fate and others for a secondary fate among cells with the same potential. Many cell fates require lateral inhibition. It may explain pancreatic epithelium's scattered endocrine cells. "Suppressive maintenance" describes Notch signaling in pancreatic differentiation. This activity may include fibroblast growth factor, although details are unclear.

Intestinal development

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Several studies suggest Notch signaling regulates intestine development. Mutations in Notch pathway components impact early intestinal cell fate decisions in zebrafish. Transcriptional analysis and gain of function experiments showed that Notch signaling targets Hes1 in the intestine and regulates adsorptive and secretory cell fates.

Bone development

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Early in vitro studies found the Notch signaling pathway downregulates osteoclastogenesis and osteoblastogenesis. During chondrogenesis, mesenchymal condensation and hypertrophic chondrocytes express Notch1. Notch signaling reduces BMP2-induced osteoblast differentiation. Notch signaling commits mesenchymal cells to the osteoblastic lineage and may be a bone regeneration therapy.

Clinical significance

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Alagille syndrome

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Rare genetic disorder Alagille syndrome (ALGS) affects the liver, heart, skeleton, eyes, and kidneys. Chronic cholestasis causes conjugated hyperbilirubinemia and jaundice in 95% of patients. Pruritus, growth failure, and xanthomas may occur. Ninety percent of ALGS patients have cardiovascular abnormalities. Most congenital cardiac disease involves the pulmonary outflow tract, with at least two-thirds of cases involving peripheral pulmonary stenosis (PPS).[8] Sixteen percent of complex structural anomalies are tetralogy of Fallot (TOF), a serious birth defect of the heart. TOF has been linked to mutations in the Notch gene.[9]

Cancer

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At least 65% of T-ALL cases are caused by mutated aberrant Notch signaling.[10] Mutations in Notch, FBXW7 (a negative regulator of Notch1), or t(7;9)(q34;q34.3) translocation can trigger Notch signaling. In T-ALL, Notch activation and oncogenic lesions like c-Myc stimulate anabolic pathways such as ribosome and protein synthesis to promote leukemia cell proliferation.[11]

Notch signaling regulates the tumor microenvironment, carcinogenesis, progression, angiogenesis, invasion, and metastasis of hepatocellular carcinoma (HCC).[12]

Notch acts as a tumor suppressor in the bladder, and its loss increases mesenchymal and invasive characteristics.[13]

Notch activity loss drives urothelial carcinoma. Over 40% of bladder carcinomas had mutations in components of the Notch pathway. Genetic Notch signaling inactivation causes Erk1/2 phosphorylation and urinary tract cancer in mice.[14] In one study, 90% of samples expressed Notch3, suggesting that Notch3 plays an important role in urothelial bladder cancer. High-grade tumors expressed more Notch3, and positive was linked to greater mortality.[15] Notch3 expression was also found to be a predictive immunohistochemistry marker for clinical follow-up of urothelial bladder cancer patients, allowing patients to have control cystoscopy sooner.

Notch inhibitors

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Many tumors involve Notch signaling; hence notch inhibitors, especially gamma-secretase inhibitors, are being studied as cancer therapy.[16] At least seven notch inhibitors were in clinical trials in 2013. MK-0752 performed well in an early breast cancer trial. In preclinical investigations, gamma-secretase inhibitors improved endometriosis, a disease with elevated notch pathway expression.[17][18]

LY3056480 is being studied to repair cochlear hair cells, which could treat hearing loss and tinnitus.[19][20]

Additional information

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Acknowledgements

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Any people, organisations, or funding sources that you would like to thank.

Competing interests

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Any conflicts of interest that you would like to declare. Otherwise, a statement that the authors have no competing interest.

Ethics statement

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An ethics statement, if appropriate, on any animal or human research performed should be included here or in the methods section.

References

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  1. ↑ Wharton, K. A.; Johansen, K. M.; Xu, T.; Artavanis-Tsakonas, S. (1985-12). "Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats". Cell 43 (3 Pt 2): 567–581. doi:10.1016/0092-8674(85)90229-6. ISSN 0092-8674. PMID 3935325. https://pubmed.ncbi.nlm.nih.gov/3935325. 
  2. ↑ Kidd, S.; Kelley, M. R.; Young, M. W. (1986-09). "Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors". Molecular and Cellular Biology 6 (9): 3094–3108. doi:10.1128/mcb.6.9.3094-3108.1986. ISSN 0270-7306. PMID 3097517. PMC PMC367044. https://pubmed.ncbi.nlm.nih.gov/3097517. 
  3. ↑ Austin, J.; Kimble, J. (1987-11-20). "glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans". Cell 51 (4): 589–599. doi:10.1016/0092-8674(87)90128-0. ISSN 0092-8674. PMID 3677168. https://pubmed.ncbi.nlm.nih.gov/3677168. 
  4. ↑ Priess, J. R.; Schnabel, H.; Schnabel, R. (1987-11-20). "The glp-1 locus and cellular interactions in early C. elegans embryos". Cell 51 (4): 601–611. doi:10.1016/0092-8674(87)90129-2. ISSN 0092-8674. PMID 3677169. https://pubmed.ncbi.nlm.nih.gov/3677169. 
  5. ↑ Greenwald, I. (1985-12). "lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor". Cell 43 (3 Pt 2): 583–590. doi:10.1016/0092-8674(85)90230-2. ISSN 0092-8674. PMID 3000611. https://pubmed.ncbi.nlm.nih.gov/3000611. 
  6. ↑ Antfolk, Daniel; Sjöqvist, Marika; Cheng, Fang; Isoniemi, Kimmo; Duran, Camille L.; Rivero-Muller, Adolfo; Antila, Christian; Niemi, Rasmus et al. (2017-06-06). "Selective regulation of Notch ligands during angiogenesis is mediated by vimentin". Proceedings of the National Academy of Sciences of the United States of America 114 (23): E4574–E4581. doi:10.1073/pnas.1703057114. ISSN 1091-6490. PMID 28533359. PMC 5468602. https://pubmed.ncbi.nlm.nih.gov/28533359. 
  7. ↑ Niessen, Kyle; Karsan, Aly (2008-05-23). "Notch signaling in cardiac development". Circulation Research 102 (10): 1169–1181. doi:10.1161/CIRCRESAHA.108.174318. ISSN 1524-4571. PMID 18497317. https://pubmed.ncbi.nlm.nih.gov/18497317. 
  8. ↑ Turnpenny, Peter D; Ellard, Sian (2012-03). "Alagille syndrome: pathogenesis, diagnosis and management". European Journal of Human Genetics 20 (3): 251–257. doi:10.1038/ejhg.2011.181. ISSN 1018-4813. PMID 21934706. PMC PMC3283172. http://www.nature.com/articles/ejhg2011181. 
  9. ↑ Kozyrev, Ivan; Dokshin, Pavel; Kostina, Aleksandra; Kiselev, Artem; Ignatieva, Elena; Golovkin, Alexey; Pervunina, Tatiana; Grekhov, Evgeny et al. (2020-07). "Dysregulation of Notch signaling in cardiac mesenchymal cells of patients with tetralogy of Fallot". Pediatric Research 88 (1): 38–47. doi:10.1038/s41390-020-0760-6. ISSN 1530-0447. PMID 31952074. https://pubmed.ncbi.nlm.nih.gov/31952074. 
  10. ↑ Weng, Andrew P.; Ferrando, Adolfo A.; Lee, Woojoong; Morris, John P.; Silverman, Lewis B.; Sanchez-Irizarry, Cheryll; Blacklow, Stephen C.; Look, A. Thomas et al. (2004-10-08). "Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia". Science (New York, N.Y.) 306 (5694): 269–271. doi:10.1126/science.1102160. ISSN 1095-9203. PMID 15472075. https://pubmed.ncbi.nlm.nih.gov/15472075. 
  11. ↑ Palomero, Teresa; Lim, Wei Keat; Odom, Duncan T.; Sulis, Maria Luisa; Real, Pedro J.; Margolin, Adam; Barnes, Kelly C.; O'Neil, Jennifer et al. (2006-11-28). "NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth". Proceedings of the National Academy of Sciences of the United States of America 103 (48): 18261–18266. doi:10.1073/pnas.0606108103. ISSN 0027-8424. PMID 17114293. PMC 1838740. https://pubmed.ncbi.nlm.nih.gov/17114293. 
  12. ↑ Huang, Qinfeng; Li, Junhong; Zheng, Jinghui; Wei, Ailing (2019). "The Carcinogenic Role of the Notch Signaling Pathway in the Development of Hepatocellular Carcinoma". Journal of Cancer 10 (6): 1570–1579. doi:10.7150/jca.26847. ISSN 1837-9664. PMID 31031867. PMC 6485212. https://pubmed.ncbi.nlm.nih.gov/31031867. 
  13. ↑ Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel et al. (2015-02). "NOTCH pathway inactivation promotes bladder cancer progression". The Journal of Clinical Investigation 125 (2): 824–830. doi:10.1172/JCI78185. ISSN 1558-8238. PMID 25574842. PMC 4319408. https://pubmed.ncbi.nlm.nih.gov/25574842. 
  14. ↑ Rampias, Theodoros; Vgenopoulou, Paraskevi; Avgeris, Margaritis; Polyzos, Alexander; Stravodimos, Konstantinos; Valavanis, Christos; Scorilas, Andreas; Klinakis, Apostolos (2014-10). "A new tumor suppressor role for the Notch pathway in bladder cancer". Nature Medicine 20 (10): 1199–1205. doi:10.1038/nm.3678. ISSN 1078-8956. http://www.nature.com/articles/nm.3678. 
  15. ↑ Ristic Petrovic, Ana; Stokanović, Dragana; Stojnev, Slavica; Potić Floranović, Milena; Krstić, Miljan; Djordjević, Ivana; Skakić, Aleksandar; Janković Veličković, Ljubinka (2022-01-24). "The Association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients". Bosnian Journal of Basic Medical Sciences. doi:10.17305/bjbms.2021.6767. ISSN 1840-4812. PMID 35073251. PMC PMC9392971. https://www.bjbms.org/ojs/index.php/bjbms/article/view/6767. 
  16. ↑ Purow, Benjamin (2012). "Notch inhibition as a promising new approach to cancer therapy". Advances in Experimental Medicine and Biology 727: 305–319. doi:10.1007/978-1-4614-0899-4_23. ISSN 0065-2598. PMID 22399357. PMC 3361718. https://pubmed.ncbi.nlm.nih.gov/22399357. 
  17. ↑ Schüring, Andreas N.; Dahlhues, Beatrice; Korte, Anna; Kiesel, Ludwig; Titze, Ulf; Heitkötter, Birthe; Ruckert, Christian; Götte, Martin (2018-03). "The endometrial stem cell markers notch-1 and numb are associated with endometriosis". Reproductive Biomedicine Online 36 (3): 294–301. doi:10.1016/j.rbmo.2017.11.010. ISSN 1472-6491. PMID 29398419. https://pubmed.ncbi.nlm.nih.gov/29398419. 
  18. ↑ Ramirez Williams, Laura; Brüggemann, Kathrin; Hubert, Marina; Achmad, Nurjannah; Kiesel, Ludwig; Schäfer, Sebastian D.; Greve, Burkhard; Götte, Martin (2019-12). "γ-Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells". Acta Obstetricia Et Gynecologica Scandinavica 98 (12): 1565–1574. doi:10.1111/aogs.13707. ISSN 1600-0412. PMID 31424097. https://pubmed.ncbi.nlm.nih.gov/31424097. 
  19. ↑ Erni, Silvia T.; Gill, John C.; Palaferri, Carlotta; Fernandes, Gabriella; Buri, Michelle; Lazarides, Katherine; Grandgirard, Denis; Edge, Albert S. B. et al. (2021). "Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors". Frontiers in Cell and Developmental Biology 9: 710159. doi:10.3389/fcell.2021.710159. ISSN 2296-634X. PMID 34485296. PMC 8414802. https://pubmed.ncbi.nlm.nih.gov/34485296. 
  20. ↑ Samarajeewa, Anshula; Jacques, Bonnie E.; Dabdoub, Alain (2019-05-08). "Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration". Molecular Therapy: The Journal of the American Society of Gene Therapy 27 (5): 904–911. doi:10.1016/j.ymthe.2019.03.017. ISSN 1525-0024. PMID 30982678. PMC 6520458. https://pubmed.ncbi.nlm.nih.gov/30982678. 
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