File:Notch signaling, a highly conserved cell-cell signaling pathway, exerts an essential regulatory role in gene expression and controls cell fate determination, differentiation, and prolifer mouse.jpg
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| Description | Notch signaling, a highly conserved cell-cell signaling pathway, exerts an essential regulatory role in gene expression and controls cell fate determination, differentiation, and proliferation. Notch receptors and ligands, four and five respectively in mammals, are single transmembrane proteins connecting the cell-receiving and the cell-sending signal. The DSL domain of Dll/Jag ligands and the EGF-like repeats of Notch receptors mediate the interaction. The journey of Notch from transmembrane receptor to transcriptional regulator in the nucleus involves several processing events and it is heavily regulated. In the ER Notch is O-fucosylated on EGF-like repeats contain consensus O-fucose sites for Pofut1. Members of Fng can elongate the fucose modified residues by addition of N-acetylglycosamine. Glycosylation is important for proper Notch signaling in several ways but the underlying mechanisms remain to be elucidated. Notch is subject to a number of cleavage events designated S1 through S4. In the trans-Golgi during the secretion process, S1 is carried out by a furin-like convertase. The resulting heterodimeric Notch interacts with its ligand with subsequent shedding of the ectodomain and exposure of S2 site, target of ADAM/TACE. The gamma-secretase mediated S3/S4 events lead to release of NICD and translocation to the nucleus. In the absence of Notch, RBPJ (known as CSL) transcription factor recruits co-repressors that associate with histone deacetylase complexes and keep the chromatin in a transcriptional silent mode (different color, human gene) . NICD displaces the co-repressors to form a ternary complex, with RBPJ and members of Maml that recruits transcription factors to turn on the expression of Hes/Hey target and effector genes. It is important to note that members of Hes and Hey transcriptional regulators are the mediators of Notch downstream effects acting as transcriptional regulators, mostly repression. The mechanisms are not well understood; they are suspected to involve both DNA-dependent and independent events. Maml can also downregulate Notch by participating in the recruitment of kinases; phosphorylated NICD is target to ubiquitination and degradation. Ligands can also exert an inhibitory effect but the mechanisms are poorly understood. Proper Notch signaling is required for many aspects of development; alterations in Notch have been implicated in a number of conditions exemplified by congenital heart diseases, cerebral stroke and cancer. To see the ontology report for annotations, GViewer and download, click here [click to see associated GO term - GO:0007219, KEGG map map04330 and entry at Reactome - REACT_299.2]... |
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https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?acc_id=PW:0000204&species=Mouse 2022 updates to the Rat Genome Database: a Findable, Accessible, Interoperable, and Reusable (FAIR) resource. Vedi M, Smith JR, Hayman GT, Tutaj M, Brodie KC, De Pons JL, Demos WM, Gibson AC, Kaldunski ML, Lamers L, Laulederkind SJF, Thota J, Thorat K, Tutaj MA, Wang SJ, Zacher S, Dwinell MR, Kwitek AE. Genetics 2023. iyad042. doi: 10.3390/genes13122304. PMID: 36930729 |
| Author | Vedi M, Smith JR, Hayman GT, Tutaj M, Brodie KC, De Pons JL, Demos WM, Gibson AC, Kaldunski ML, Lamers L, Laulederkind SJF, Thota J, Thorat K, Tutaj MA, Wang SJ, Zacher S, Dwinell MR, Kwitek AE. |
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| current | 21:28, 30 April 2024 | | 1,119 × 942 (492 KB) | Rasbak (talk | contribs) | {{Information |description= Notch signaling, a highly conserved cell-cell signaling pathway, exerts an essential regulatory role in gene expression and controls cell fate determination, differentiation, and proliferation. Notch receptors and ligands, four and five respectively in mammals, are single transmembrane proteins connecting the cell-receiving and the cell-sending signal. The DSL domain of Dll/Jag ligands and the EGF-like repeats of Notch receptors mediate the interaction. The journey... |
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