Neurogenic locus notch homolog protein 3(Notch 3) is a
protein that in humans is encoded by the NOTCH3gene.[5][6]
Function
This gene encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein
notch. In Drosophila, 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.
Pathology
Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (
CADASIL).[6] Mutations in NOTCH3 have also been identified in families with Alzheimer's disease.[7] Adult Notch3 knock-out mice show incomplete neuronal maturation in the spinal cord dorsal horn, resulting in permanently increased nociceptive sensitivity.[8]
Mutations in
NOTCH3 are associated to
lateral meningocele syndrome.[9]
Pharmaceutical target
Notch3 is being investigated as a target for anti-cancer drugs, as it is overexpressed in several types of cancers.[10] Early clinical trials of
Pfizer's PF-06650808, an anti-Notch3 antibody linked to a cytotoxic drug, showed efficacy against solid tumors.[11]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (September 15, 1994). "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.
doi:
10.1006/geno.1994.1517.
PMID7835890.
Joutel A, Tournier-Lasserve E (2002). "[Molecular basis and physiopathogenic mechanisms of CADASIL: a model of small vessel diseases of the brain]". J. Soc. Biol. 196 (1): 109–15.
doi:
10.1051/jbio/2002196010109.
PMID12134625.
S2CID86151374.
Larsson C, Lardelli M, White I, Lendahl U (1994). "The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation". Genomics. 24 (2): 253–8.
doi:
10.1006/geno.1994.1613.
PMID7698746.
Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J (1993). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12". Nat. Genet. 3 (3): 256–9.
doi:
10.1038/ng0393-256.
PMID8485581.
S2CID13031278.
Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996). "Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia". Nature. 383 (6602): 707–10.
Bibcode:
1996Natur.383..707J.
doi:
10.1038/383707a0.
PMID8878478.
S2CID4351873.
Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E (1997). "Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients". Lancet. 350 (9090): 1511–5.
doi:
10.1016/S0140-6736(97)08083-5.
PMID9388399.
S2CID38044421.
Dichgans M, Herzog J, Gasser T (2001). "NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL". Neurology. 57 (9): 1714–7.
doi:
10.1212/wnl.57.9.1714.
PMID11706120.
S2CID21180235.