notch-3 (Drosophila) homolog protein (NOTCH3)

^[1]^[2]^[3]

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 (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
interacts with MAML1, MAML2 & MAML3 which act as transcriptional coactivators for NOTCH3

defects in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
mutations affect highly conserved Cys within EGF domains