Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs.

1. aberrantly expressed in the pathological tumour vascularization where it limits tumour angiogenesis through a pro-apoptotic activity PMID: 28719575
2. TGFbeta activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. PMID: 29170450
3. A novel NOTCH3 pathogenic variant (p.N1969 *) in the intracellular ankyrin repeat domain is detected in three CADASIL patients. PMID: 29980472
4. SIRT6 may suppress cell proliferation, migration, and invasion via inhibition of the NOTCH3 signaling pathway in glioma PMID: 29659670
5. hus Notch3 appears to be a promising target for gene therapy and DAPT is able to mediate a strong antitumor effect in nonsmall cell lung cancer (NSCLC) cells that overexpress Notch3. Further studies of a combined treatment regimen with DAPT and GEM are warranted and may provide greater efficacy and safety in the treatment of NSCLC patients PMID: 29781034
6. Adult-onset Mendelian leukodystrophy genes are not common factors implicated in Alzheimer's disease, but there is a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset Alzheimer's disease. PMID: 29544907
7. Vascular smooth muscle cells were cyclically stretched on flexible membranes. Expression of Jagged1, Notch3, and target genes was down-regulated with strain. Upon increasing thickness, the model predicted a switch-type behavior of Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain thickness. The Notch response to hemodynamics plays an important role in vascular homeostasis. PMID: 29610298
8. A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes Notch3-driven leukemia development. PMID: 27312418
9. We describe a CADASIL family with a novel R110C mutation in the NOTCH3 gene PMID: 29363903
10. The levels of markers related to PaSC activation, such as a-smooth muscle actin (alpha-SMA), collagen I and fibronectin, decreased in response to Notch3 knockdown, indicating that Notch3 plays an important role in PaSC activation. Furthermore, we confirmed that inhibition of PaSC activation via Notch3 siRNA reduced the proliferation and migration of PaSC-induced mouse pancreatic cancer (LTPA) cells. PMID: 29304760
11. The novel variant c.128G>C in exon 2 of NOTCH3 was identified in 2 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy PMID: 28867359
12. Temozolomide (TMZ)-mediated gene expression profiles and networks are involved in inducing glioblastoma cell death. Increased CHAC1 and reduced Notch3 levels are both also significantly involved in TMZ-mediated cytotoxicity. The TMZ-regulated CHAC1 pathway inhibits Notch3 activation, resulting in attenuation of Notch3-mediated signaling pathways. PMID: 27986595
13. These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients. PMID: 28710804
14. Our study also suggested the anti-neoplasm effect of mangiferin might be via the regulation of Notch3. Taken together, by targeting cell apoptosis pathways and enhancing the response to cisplatin treatment, mangiferin may represent a potential new drug for the treatment of human ovarian cancer. PMID: 28714011
15. Results found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome. These data suggested that Notch 3 overexpression promotes growth and chemoresistance in urothelial cancer. PMID: 28416766
16. Two heterozygous missense mutations in the NOTCH3 gene have been identified in two families affected with cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy PMID: 29188607
17. Results identified NOTCH3 as a direct target of MIR-613 which represses notch3 expression via targeting its 3'TUR. IN contrary, HOTAIR positively regulates the notch3 expression via acting as a competing endogenous RNA for miR-613 binding in pancreatic cancer. PMID: 28415631
18. The present study identified a novel variant (chr19:15288426A>C) in the NOTCH3 gene using whole exome sequencing and confirmed it using Sanger sequencing. With multiple in silico analyses and 3D structure simulation, it is suggested that this variant has mildly damaging effects on the function of NOTCH3 gene, but can decrease protein stability. PMID: 28440410
19. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt PMID: 27791012
20. we report a rare pathogenic mutation on exon 14 of the NOTCH3 gene in a Chinese family affected by CADASIL PMID: 27781952
21. The SNPs rs1044009 and rs1044006 in the NOTCH3 gene were associated with the risk of cerebral infarction disease in a Chinese Han agedness population. PMID: 27370894
22. Oligodendrocytes expressing mutant NOTCH3(R90C) (present in CADASIL disease), exhibited aberrant NOTCH3 proteolytic processing. These cells were less viable and had a higher rate of apoptosis. Cells with NOTCH3(R90C) had higher levels of intrinsic mitochondrial apoptosis, extrinsic death receptor path-related apoptosis, and autophagy compared with cells transfected with wild-type NOTCH3. PMID: 28601945
23. Novel variants in NOTCH3 associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. PMID: 27881154
24. NOTCH3 single-nucleotide polymorphisms role in susceptibility to non-small cell lung cancer PMID: 28968839
25. Single-nucleotide polymorphism in NOTCH3 gene is associated with breast cancers. PMID: 28775167
26. Reduced NOTCH3/NICD3 and NOTCH4/NICD4 in miR-96- and miR-183-expressing nasopharyngeal carcinoma (NPC) cells suggest the involvement of the NOTCH signaling pathway in their tumor suppressive function. PMID: 27431799
27. Low Notch3 expression is associated with left ventricle hypertrabeculation/non-compaction and Menetrier-like gastropathy. PMID: 28013292
28. High NOTCH3 expression is associated with basal breast cancer. PMID: 28108512
29. in in silico gene expression analysis of human T-ALL samples we observed a significant correlation between Pin1 and Notch3 expression levels, which may further suggest a key role of the newly identified Notch3-Pin1 axis in T-cell Acute Lymphoblastic Leukemia (T-ALL) aggressiveness and progression. Thus, combined suppression of Pin1 and Notch3 proteins may be exploited as an additional target therapy for T-ALL PMID: 26876201
30. MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3 pathway. PMID: 27887917
31. Specific Notch3 and Jag1 subcellular localization patterns may provide clues for the behavior of the corresponding tumors and could potentially be applied in the clinic for Jag1 targeting in triple-negative breast cancer patients PMID: 28476798
32. there is a cross-talk between Jagged1/Notch3 and VEGF in TNBC angiogenesis. Jagged1/Notch3 is expected to be an important signaling pathway for TNBC progression and a potential target for TNBC neovascularization therapy. PMID: 28625320
33. Mutations in NOTCH3 gene is associated with T-cell acute lymphoblastic leukemia. PMID: 27717083
34. Loss of Notch3 expression may be fundamental to the process of dedifferentiation that accompanies thyroid oncogenesis. Conversely, activation of Notch3 in thyroid cancer exerts an antiproliferative effect and restores elements of a differentiated phenotype PMID: 27861750
35. Notch3 and pS6 are significantly related to ovarian epithelial cancer development and prognosis, and their combination represents a potential biomarker and therapeutic target in ovarian tumor angiogenesis. PMID: 27445438
36. NOTCH3 381C>T and 1735T>C polymorphisms were associated with Ischemic Stroke and might be the risk factors for Ischemic Stroke development, but not NOTCH3 605C>T polymorphism. PMID: 27770607
37. This meta-analysis results did not show significant associations between polymorphisms of NOTCH3 genes and Ischemic stroke. PMID: 27266621
38. This study showed that CADASIL with Novel NOTCH3 Cys323Trp Mutation Presenting Border-Zone Infarcts. PMID: 27241575
39. Methylation of Notch3 modulates chemoresistance via P-glycoprotein PMID: 27780727
40. Notch3 gene expression is up-regulated by Hepatitis B virus X protein in liver cancer cells. PMID: 27840976
41. The mRNA and protein expression of NOTCH3 was significantly lower in cisplatin and astragaloside IV-treated cells. PMID: 28281965
42. About one third of oral squamous cell carcinomas showed NOTCH3 expression in cancer associated fibroblasts; this expression significantly correlated with tumor-size. PMID: 27124156
43. Overexpression of Notch3 significantly reversed the tumor-suppressive effects of miR491-5p. the present study reveals a mechanistic link between miR-491-5p and Notch3 in the pathogenesis of nasopharyngeal carcinoma. PMID: 27035429
44. Kaplan-Meier curves suggested that a high expression of Notch3 was a significant risk factor for shortened survival time. We also showed that inhibition of Notch3 had an antiinvasion role in PDAC cells. In vitro, the inhibition of Notch3 reduced the migration and invasion capabilities of PDAC cells PMID: 27633819
45. Data support a crucial role of Notch3 in the increase of stem-like property in NSCLC cells that might be associated with upregulation of ALDH1A1 and CD44 and activation of autophagy. PMID: 27035162
46. Jagged1 activation of Notch3 resulted in a significant decrease in cell proliferation while concomitantly promoting Hemangioma-pericyte maturation. PMID: 27941324
47. Results found new NOTCH3 missenses mutations in patients with pulmonary hypertension that were predicted to be likely pathogenic. PMID: 26894465
48. We present a Polish family with a previously unreported novel mutation in exon 12 c.1851C>C/G of the NOTCH3 gene and varying disease expression. One of the two family members with the confirmed mutation presented with all the main CADASIL symptoms; while, his affected father was nearly asymptomatic. PMID: 27375140
49. Overexpressing Notch3 protein upregulated Cdh1 expression and resulted in p27(Kip) accumulation by accelerating Skp2 degradation. PMID: 26694515
50. A rare 2182C>T mutation in exon 14 of the NOTCH3 gene was identified in all available cases PMID: 27455010

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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 1 (CADASIL1); Myofibromatosis, infantile 2 (IMF2); Lateral meningocele syndrome (LMNS)

Cell membrane; Single-pass type I membrane protein.; [Notch 3 intracellular domain]: Nucleus. Note=Following proteolytical processing NICD is translocated to the nucleus.

NOTCH family

Ubiquitously expressed in fetal and adult tissues.

HGNC: 7883

OMIM: 125310

KEGG: hsa:4854

STRING: 9606.ENSP00000263388

UniGene: Hs.8546