| Note | 2321 amino acids with a predicted molecular mass of 243.66 Kd.
Single-pass type I membrane protein. Contain 1 signal peptide, 36 extracellular EGF repeats, 1 single transmembrane domain, and 2 PEST domains.
Synthesized in the endoplasmic reticulum as an inactive form, which is cleaved by a furin-like convertase in the trans-Golgi complex before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a transmembrane Notch subunit (NTM) and an extracellular Notch subunit (ECN). |
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| Description | Notch3 is a cell surface receptor for membrane-bound ligands including Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4. It is activated by ligand-receptor interaction, which triggers two successive proteolytic cleavages that release the active intracellular domain of Notch (NICD). The NICD translocates to the nucleus, where it interacts with CSL (CBF1/RBP-J kappa, Suppressor of Hairless, LAG-1). Binding of NICD to CSL displaces corepressor complexes and recruits coactivators, leading to transcription from promoters containing CSL-binding elements. The Notch3 target genes participate in wide spectrum of biological processes such as differentiation, proliferation and apoptosis. |
| Expression | Expressed in certain types of fetal and adult tissues. |
| Localisation | Mainly located at cell membrane. Following proteolytic events upon ligand binding, its intracellular domain is translocated into the nuclei. |
| Function | Notch3 is a membrane receptor that mediates cell-cell interactions to facilitate cell differentiation, growth and cell death. |
| Note | |
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| Entity | Non-small-cell lung cancer |
| Cytogenetics | t(15;19)(q11;p13) |
| Hybrid/Mutated Gene | A breakpoint was localized to the cosmid R31546. The breakpoint was found about 50 kilobases (kb) upstream of the Notch3 and within the 3' untranslated region of a putative gene, Hunk1, on 19p. Translocation of chromosome 19p was also found in several other chromosomes, including chromosomes 12q, 14q, 17q, 4q, and 6q. Overexpression of Notch3 full-length mRNA is associated with a 19p translocation. |
| Oncogenesis | The translocation is associated with Notch3 over-expression. Transgenic mouse study by constitutive expression of intracellular domain of Notch3 in lung epithelium using surfactant protein C promoter/enhancer resulted in inhibited differentiation of epithelial lung cell, altered lung morphology, and perinatal lethality in the transgenic mice. |
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| Entity | Ovarian cancer-serous type |
| Cytogenetics | Chromosome 19p13.12 amplification harboring the Notch3 gene is frequently identified in ovarian cancer. |
| Oncogenesis | In vitro study demonstrated that cell lines with Notch3 over-expression are more sensitive to the anti-proliferative effect of Notch3 signaling pathway inhibitors including gamma-secretase inhibitor and Notch3-specific siRNA. |
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| Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice. |
| Dang TP, Eichenberger S, Gonzalez A, Olson S, Carbone DP |
| Oncogene. 2003 ; 22 (13) : 1988-1997. |
| PMID 12673204 |
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| Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. |
| Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP |
| Journal of the National Cancer Institute. 2000 ; 92 (16) : 1355-1357. |
| PMID 10944559 |
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| Notch3 gene amplification in ovarian cancer. |
| Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM, Wang TL |
| Cancer research. 2006 ; 66 (12) : 6312-6318. |
| PMID 16778208 |
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