notch-4 (Drosophila) homolog protein (NOTCH4, INT3)
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Function
- receptor for membrane-bound ligands Jagged1, Jagged2 & delta1 to regulate cell-fate determination
- upon ligand activation through the released notch intracellular domain (NICD), it forms a transcriptional activator complex with RBP-J kappa & activates genes of the enhancer of split locus
- affects implementation of differentiation, proliferation & apoptotic programs
- may regulate branching morphogenesis in the developing vascular system (putative)
- synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form
- cleavage results in a C- terminal fragment N(TM) & a N-terminal fragment N(EC)
- following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane- associated intermediate fragment called notch extracellular truncation (NEXT)
- this fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (putative)
- phosphorylated (putative)
- heterodimer of a C-terminal fragment N(TM) & a N-terminal fragment N(EC) which are probably linked by disulfide bonds (putative)
- interacts with MAML1, MAML2 & MAML3 which act as transcriptional coactivators for NOTCH4
Structure
- belongs to the NOTCH family
- contains 5 ANK repeats
- contains 28 EGF-like domains
- contains 3 LNR (lin/notch) repeats
Compartment
- cell membrane; single-pass type 1 membrane protein
- notch 4 intracellular domain: nucleus
- following proteolytical processing NICD is translocated to the nucleus
Alternative splicing
named isoforms=3
Expression
- highly expressed in heart, moderately in lung & placenta & at low levels in the liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, bone marrow & fetal liver
- no expression was seen in adult brain or peripheral blood leukocytes
Pathology
- questionable association with schizophrenia[3][4]
Polymorphism
- the poly-Leu region of NOTCH4 (in the signal peptide) is polymorphic & the number of Leu varies in the population (from 6 to 12)
More general terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/Q99466.html
- ↑ OMIM https://mirror.omim.org/entry/164951
- ↑ 3.0 3.1 Sklar P et al. Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls. Nature genetics 28:126-8 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11381257
McGinnis RE, Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland. Nature genetics 28:128-9 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11381258 - ↑ 4.0 4.1 Skol AD et al Modest evidence for linkage and possible confirmation of association between NOTCH4 and schizophrenia in a large Veterans Affairs Cooperative Study sample. Am J Med Genet B Neuropsychiatr Genet. 2003 Apr 1;118B(1):8-15. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12627457