NOTCH3

NOTCH3

NOTCH3

Protein-coding gene in the species Homo sapiens

Neurogenic locus notch homolog protein 3 (Notch 3) is a protein that in humans is encoded by the NOTCH3 gene.[5][6]

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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

Micrograph showing CADASIL with a Notch 3 immunostain.

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]

References

  1. [1]
    GRCh38: Ensembl release 89: ENSG00000074181 – Ensembl, May 2017
  2. [2]
    GRCm38: Ensembl release 89: ENSMUSG00000038146 – Ensembl, May 2017
  3. [3]
    "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. [4]
    "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. [5]
    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. PMID 7835890.
  6. [6]
    "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)".
  7. [7]
    Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, Dursun B, Bilgic B, Santana I, Hanagasi H, Gurvit H, Gibbs JR, Oliveira C, Emre M, Singleton A (2012). "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease". Neurobiol. Aging. 33 (5): 1008.e17–23. doi:10.1016/j.neurobiolaging.2011.10.009. PMC 3306507. PMID 22153900.
  8. [8]
    Rusanescu G, Mao J (2014). "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". J. Cell. Mol. Med. 18 (10): 2103–16. doi:10.1111/jcmm.12362. PMC 4244024. PMID 25164209.
  9. [9]
    Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K (2014). "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". Am. J. Med. Genet. A. 167A (2): 271–81. doi:10.1002/ajmg.a.36863. PMC 5589071. PMID 25394726.
  10. [10]
    Purow B (2012). "Notch Inhibition as a Promising New Approach to Cancer Therapy". Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology. Vol. 727. pp. 305–319. doi:10.1007/978-1-4614-0899-4_23. ISBN 978-1-4614-0898-7. PMC 3361718. PMID 22399357.
  11. [11]
    "Pfizer Oncology: ADC Development Overview (2016) » ADC Review".

Further reading
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