NOTCH3

Official Full Name

notch receptor 3

Organism

Homo sapiens

GeneID

4854

Background

This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

Synonyms

IMF2; LMNS; CASIL; CADASIL; CADASIL1;

Bio Chemical Class

Notch protein

Protein Sequence

MGPGARGRRRRRRPMSPPPPPPPVRALPLLLLLAGPGAAAPPCLDGSPCANGGRCTQLPSREAACLCPPGWVGERCQLEDPCHSGPCAGRGVCQSSVVAGTARFSCRCPRGFRGPDCSLPDPCLSSPCAHGARCSVGPDGRFLCSCPPGYQGRSCRSDVDECRVGEPCRHGGTCLNTPGSFRCQCPAGYTGPLCENPAVPCAPSPCRNGGTCRQSGDLTYDCACLPGFEGQNCEVNVDDCPGHRCLNGGTCVDGVNTYNCQCPPEWTGQFCTEDVDECQLQPNACHNGGTCFNTLGGHSCVCVNGWTGESCSQNIDDCATAVCFHGATCHDRVASFYCACPMGKTGLLCHLDDACVSNPCHEDAICDTNPVNGRAICTCPPGFTGGACDQDVDECSIGANPCEHLGRCVNTQGSFLCQCGRGYTGPRCETDVNECLSGPCRNQATCLDRIGQFTCICMAGFTGTYCEVDIDECQSSPCVNGGVCKDRVNGFSCTCPSGFSGSTCQLDVDECASTPCRNGAKCVDQPDGYECRCAEGFEGTLCDRNVDDCSPDPCHHGRCVDGIASFSCACAPGYTGTRCESQVDECRSQPCRHGGKCLDLVDKYLCRCPSGTTGVNCEVNIDDCASNPCTFGVCRDGINRYDCVCQPGFTGPLCNVEINECASSPCGEGGSCVDGENGFRCLCPPGSLPPLCLPPSHPCAHEPCSHGICYDAPGGFRCVCEPGWSGPRCSQSLARDACESQPCRAGGTCSSDGMGFHCTCPPGVQGRQCELLSPCTPNPCEHGGRCESAPGQLPVCSCPQGWQGPRCQQDVDECAGPAPCGPHGICTNLAGSFSCTCHGGYTGPSCDQDINDCDPNPCLNGGSCQDGVGSFSCSCLPGFAGPRCARDVDECLSNPCGPGTCTDHVASFTCTCPPGYGGFHCEQDLPDCSPSSCFNGGTCVDGVNSFSCLCRPGYTGAHCQHEADPCLSRPCLHGGVCSAAHPGFRCTCLESFTGPQCQTLVDWCSRQPCQNGGRCVQTGAYCLCPPGWSGRLCDIRSLPCREAAAQIGVRLEQLCQAGGQCVDEDSSHYCVCPEGRTGSHCEQEVDPCLAQPCQHGGTCRGYMGGYMCECLPGYNGDNCEDDVDECASQPCQHGGSCIDLVARYLCSCPPGTLGVLCEINEDDCGPGPPLDSGPRCLHNGTCVDLVGGFRCTCPPGYTGLRCEADINECRSGACHAAHTRDCLQDPGGGFRCLCHAGFSGPRCQTVLSPCESQPCQHGGQCRPSPGPGGGLTFTCHCAQPFWGPRCERVARSCRELQCPVGVPCQQTPRGPRCACPPGLSGPSCRSFPGSPPGASNASCAAAPCLHGGSCRPAPLAPFFRCACAQGWTGPRCEAPAAAPEVSEEPRCPRAACQAKRGDQRCDRECNSPGCGWDGGDCSLSVGDPWRQCEALQCWRLFNNSRCDPACSSPACLYDNFDCHAGGRERTCNPVYEKYCADHFADGRCDQGCNTEECGWDGLDCASEVPALLARGVLVLTVLLPPEELLRSSADFLQRLSAILRTSLRFRLDAHGQAMVFPYHRPSPGSEPRARRELAPEVIGSVVMLEIDNRLCLQSPENDHCFPDAQSAADYLGALSAVERLDFPYPLRDVRGEPLEPPEPSVPLLPLLVAGAVLLLVILVLGVMVARRKREHSTLWFPEGFSLHKDVASGHKGRREPVGQDALGMKNMAKGESLMGEVATDWMDTECPEAKRLKVEEPGMGAEEAVDCRQWTQHHLVAADIRVAPAMALTPPQGDADADGMDVNVRGPDGFTPLMLASFCGGALEPMPTEEDEADDTSASIISDLICQGAQLGARTDRTGETALHLAARYARADAAKRLLDAGADTNAQDHSGRTPLHTAVTADAQGVFQILIRNRSTDLDARMADGSTALILAARLAVEGMVEELIASHADVNAVDELGKSALHWAAAVNNVEATLALLKNGANKDMQDSKEETPLFLAAREGSYEAAKLLLDHFANREITDHLDRLPRDVAQERLHQDIVRLLDQPSGPRSPPGPHGLGPLLCPPGAFLPGLKAAQSGSKKSRRPPGKAGLGPQGPRGRGKKLTLACPGPLADSSVTLSPVDSLDSPRPFGGPPASPGGFPLEGPYAAATATAVSLAQLGGPGRAGLGRQPPGGCVLSLGLLNPVAVPLDWARLPPPAPPGPSFLLPLAPGPQLLNPGTPVSPQERPPPYLAVPGHGEEYPAAGAHSSPPKARFLRVPSEHPYLTPSPESPEHWASPSPPSLSDWSESTPSPATATGAMATTTGALPAQPLPLSVPSSLAQAQTQLGPQPEVTPKRQVLA

Open

Disease

Lung cancer, Pancreatic cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

Notch3 is an important member of the Notch family of cells. It is highly conserved in evolution and can be activated by binding to ligands of neighboring cells. It maintains the balance between cell proliferation, differentiation, and apoptosis by regulating downstream genes, and plays a decisive role in the fate of cells.

The Notch3 signaling pathway consists of its ligand and receptor. The ligand is the single-span membrane protein described above. It is a precursor with a relative molecular mass of 280 kD when it is initially synthesized, and then forms a mature homolog under the action of proteolytic enzymes. The source dimer transmembrane receptor consists of an extracellular domain and a non-covalently bound transmembrane and intracellular domain. The Noch pathway interacts with other signaling pathways such as NF-κB, TGF-β, JAK-STAT, Ras, and Wnt / β-catenin pathways. Many regulatory factors affect each other and make the Noch signal-regulating network more and more extensive. Notch3 signaling pathway has many functions, which are important for the development and maturation of cells, the normality and integrity of vascular structures, and the development of the central nervous system.

Figure 1. Notch3 promotes anoikis resistance in ovarian cancer. (Brown, C. W., et al. 2015)

Noch3 and Liver Cancer

In hepatocellular carcinoma, the expression of Noch3 is elevated, and the high expression of Noch3 is related to the proliferation, differentiation, metastasis and invasion of liver cancer. Studies have shown that in hepatocellular carcinoma, Noch is activated and induces tumor formation in rats. The high expression of Noch3 in hepatocellular carcinoma tissues is related to tumor size. Pathological indicators combined with patient prognosis analysis show that the high expression of Noch3 is significantly positively correlated with tumor aggressiveness and short survival time.

The interference of γ-secretase inhibitors or small hairpin RNA to silence Noch3 in hepatocellular carcinoma cells can regulate the expression of downstream target genes, and can change the response of hepatocellular carcinoma cells to different chemoradiation factors through the regulation of other signaling pathways. In hepatocellular carcinoma, down-regulation of Noch1 and Noch3 caused Hes1 down-regulation, CDKN1C/P57 up-regulated and inhibited cell growth, while CDKN1C/P57 was a target gene for the transcriptional suppression of Notch effector Hes1. Studies have shown that loss of Notch3 can increase p53 expression, increase tumor cell DNA damage and impede the cell cycle progression of liver cancer cells. There is a corresponding relationship between the high expression of Noch3 in liver cancer and tumor metastasis, vascular invasion, and satellite foci. Noch3 down-regulates MMP-1 and MMP-9 through the Erk1/2 pathway to reduce the invasion ability of hepatocellular carcinoma cells.

Notch3 and Other Tumors

In ovarian cancer cells, the Notch3 gene is overexpressed. Inactivation of Noch3 over-expressed cell lines through Noch3 receptor inhibitors or Notch3 specific sirNA can significantly inhibit Noch3 proliferation and induce apoptosis. Jagged1 plays an important role in the regulation of ovarian cancer. The Jagged1/Notch3 interaction constitutes a near-circulation cycle that promotes the proliferation and spread of ovarian cancer cells in the peritoneal cavity. The expression of Jagged1 is regulated by the Notch3 and Wnt/β-catenin signaling pathways. The regulation of the Wnt/Notch pathway affects the stem maintenance of tumor cells. The new natural drug dracolide A can down-regulate the proteins Notch1, Notch3, CDC-25c, Akt, p-Akt, and bcl-2, which in turn causes apoptosis and cell cycle arrest, and inhibits the growth and clonal formation of CaOV3 and SKOV3 cells. Experiments have shown that toxicin A is a potential natural drug that targets Noch3 by targeting, and has potential research value.

References:

Brown, C. W. , Brodsky, A. S. , & Freiman, R. N. . (2015). Notch3 overexpression promotes anoikis resistance in epithelial ovarian cancer via upregulation of col4a2. Molecular Cancer Research, 13(1), 78-85.
Zviadi, Aburjania, Samuel, Jang, Jason, & Whitt, et al. (2018). The role of notch3 in cancer. The oncologist.
Joon T Park, Mei Li, Kentaro Nakayama, Tsui-Lien Mao, & Tian-Li Wang. (2006). Notch3 gene amplification in ovarian cancer. Cancer Research, 66(12), 6312-6318.

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