Notch 4 Explained

Neurogenic locus notch homolog 4 (Notch 4) is a protein that in humans is encoded by the NOTCH4 gene located on chromosome 6.^[1]

Gene

An alternative splice variant of the NOTCH4 gene has been described, but its biological significance has not been determined.^[2]

Structure

The neurogenic locus notch homolog 4 protein is a member of the Notch family. Members of this type 1 transmembrane protein family share structural characteristics. These include an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain that consists of multiple, but different, domain types.

Function

Notch protein family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling pathway is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells

In Drosophila, notch interacts with its cell-bound ligands (delta and serrate), and establishes an intercellular signaling pathway that then plays a key role in development. Homologues of the notch-ligands have also been identified in humans, but precise interactions between these ligands and the human notch homologues remain to be determined. The notch protein is cleaved in the trans-Golgi network, and then presented on the cell surface as a heterodimer. The protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal, and hepatic development.^[2]

Clinical significance

Mutations in the notch4 gene may be associated with susceptibility to schizophrenia in a small portion of cases.^[3]

Further reading

• Artavanis-Tsakonas S, Rand MD, Lake RJ . Notch signaling: cell fate control and signal integration in development. . Science . 284 . 5415 . 770–6 . 1999 . 10221902 . 10.1126/science.284.5415.770 . 1999Sci...284..770A.
• Mumm JS, Kopan R . Notch signaling: from the outside in. . Dev. Biol. . 228 . 2 . 151–65 . 2001 . 11112321 . 10.1006/dbio.2000.9960 . free .
• Kojika S, Griffin JD . Notch receptors and hematopoiesis. . Exp. Hematol. . 29 . 9 . 1041–52 . 2001 . 11532344 . 10.1016/S0301-472X(01)00676-2 . free .
• Allenspach EJ, Maillard I, Aster JC, Pear WS . Notch signaling in cancer. . Cancer Biol. Ther. . 1 . 5 . 466–76 . 2003 . 12496471 . 10.4161/cbt.1.5.159. free .
• Wang Z, Wei J, Zhang X, etal . A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia. . Am. J. Med. Genet. B Neuropsychiatr. Genet. . 141 . 8 . 902–6 . 2007 . 16894623 . 10.1002/ajmg.b.30383 . 29260869 .
• Matsuno K, Diederich RJ, Go MJ, etal . Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. . Development . 121 . 8 . 2633–44 . 1995 . 10.1242/dev.121.8.2633 . 7671825 .
• Uyttendaele H, Marazzi G, Wu G, etal . Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. . Development . 122 . 7 . 2251–9 . 1996 . 10.1242/dev.122.7.2251 . 8681805 .
• Sugaya K, Sasanuma S, Nohata J, etal . Gene organization of human NOTCH4 and (CTG)n polymorphism in this human counterpart gene of mouse proto-oncogene Int3. . Gene . 189 . 2 . 235–44 . 1997 . 9168133 . 10.1016/S0378-1119(96)00857-8 .
• Uyttendaele H, Soriano JV, Montesano R, Kitajewski J . Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. . Dev. Biol. . 196 . 2 . 204–17 . 1998 . 9576833 . 10.1006/dbio.1998.8863 . free .
• Li L, Huang GM, Banta AB, etal . Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene. . Genomics . 51 . 1 . 45–58 . 1998 . 9693032 . 10.1006/geno.1998.5330 .
• Gray GE, Mann RS, Mitsiadis E, etal . Human ligands of the Notch receptor. . Am. J. Pathol. . 154 . 3 . 785–94 . 1999 . 10079256 . 10.1016/S0002-9440(10)65325-4. 1866435 .
• Imatani A, Callahan R . Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines. . Oncogene . 19 . 2 . 223–31 . 2000 . 10645000 . 10.1038/sj.onc.1203295 . free .
• Wei J, Hemmings GP . The NOTCH4 locus is associated with susceptibility to schizophrenia. . Nat. Genet. . 25 . 4 . 376–7 . 2000 . 10932176 . 10.1038/78044 . 34510337 .
• Suzuki T, Aoki D, Susumu N, etal . Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers. . Int. J. Oncol. . 17 . 6 . 1131–9 . 2001 . 11078798 . 10.3892/ijo.17.6.1131.
• Wu L, Aster JC, Blacklow SC, etal . MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. . Nat. Genet. . 26 . 4 . 484–9 . 2001 . 11101851 . 10.1038/82644 . 23335042 .
• Kusano S, Raab-Traub N . An Epstein-Barr virus protein interacts with Notch. . J. Virol. . 75 . 1 . 384–95 . 2001 . 11119607 . 10.1128/JVI.75.1.384-395.2001 . 113931 .
• Sklar P, Schwab SG, Williams NM, etal . Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls. . Nat. Genet. . 28 . 2 . 126–8 . 2001 . 11381257 . 10.1038/88836 . 41566662 .

Notes and References

1. Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T . Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3 . Genomics . 23 . 2 . 408–19 . Feb 1995 . 7835890 . 10.1006/geno.1994.1517 .
2. Web site: Entrez Gene: NOTCH4 Notch homolog 4 (Drosophila).
3. Shayevitz C, Cohen OS, Faraone SV, Glatt SJ . A re-review of the association between the NOTCH4 locus and schizophrenia . Am. J. Med. Genet. B Neuropsychiatr. Genet. . 159B . 5 . 477–83 . July 2012 . 22488909 . 10.1002/ajmg.b.32050 . 28027007 .