WikiJournal Preprints/Notch signaling pathway

Introduction


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
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. Alleles of the two C. elegans Notch genes were identified based on developmental phenotypes: lin-12 and glp-1. The cloning and partial sequence of lin-12 were reported by Iva Greenwald.

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

Function
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

Angiogenesis
During angiogenesis, endothelial cells coordinate cellular actions using the Notch signaling pathway.

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

Pancreatic development
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
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
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.

Alagille syndrome
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). 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.

Cancer
At least 65% of T-ALL cases are caused by mutated aberrant Notch signaling. 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.

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

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

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. 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. 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
Many tumors involve Notch signaling; hence notch inhibitors, especially gamma-secretase inhibitors, are being studied as cancer therapy. 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.

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

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

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

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