Notch4
Developmental stage
Highly expressed in endothelial cells during embryonic development from 9.0 dpc.
Function
Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). May regulate branching morphogenesis in the developing vascular system.
Involvement in disease
Loss of the extracellular domain causes constitutive activation of the Notch protein, which leads to hyperproliferation of glandular epithelial tissues and development of mammary carcinomas.
Post-translational modifications
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) and 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.
Phosphorylated.
Sequence Similarities
Belongs to the NOTCH family.
Tissue Specificity
Highly expressed in lung, moderately in heart kidney, and at lower levels in the ovary and skeletal muscle. A very low expression is seen in the brain, intestine, liver and testis.
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- Notch 4 intracellular domain
- Nucleus
- Following proteolytical processing NICD is translocated to the nucleus.
Alternative names
Int-3, Int3, Neurogenic locus notch homolog protein 4, Notch 4