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notch-4 (Drosophila) homolog protein (NOTCH4, INT3)
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
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)
Pathology:
- questionable association with schizophrenia [3,4]
General
ankyrin repeat domain protein (ANKRD)
glycoprotein
notch (Drosophila) homolog protein
Properties
SIZE: entity length = 2003 aa
MW = 210 kD
COMPARTMENT: cell nucleus
cellular membrane
MOTIF: signal sequence {1-23}
EGF domain {24-1171} (28)
Notch/Lin12 repeat {1170-1505} (3)
transmembrane domain {1448-1468}
arginine-rich region {1472-1476}
MOTIF: arginine residue (SEVERAL)
ankyrin repeat
NAME: ankyrin repeat
SITE: 1633-1665
ankyrin repeat
NAME: ankyrin repeat
SITE: 1666-1698
ankyrin repeat
NAME: ankyrin repeat
SITE: 1700-1732
ankyrin repeat
NAME: ankyrin repeat
SITE: 1733-1765
ankyrin repeat
NAME: ankyrin repeat
SITE: 1766-1798
Database Correlations
OMIM 164951
UniProt Q99466
PFAM correlations
Entrez Gene 4855
Kegg hsa:4855
References
- UniProt :accession Q99466
- OMIM :accession 164951
- Sklar P et al.
Association analysis of NOTCH4 loci in schizophrenia using
family and population-based controls.
Nature genetics 28:126-8 2001
PMID: 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: 11381258
- 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: 12627457