34 exons

7860 bp

This gene encodes a member of the Notch family. Members of this family are Type1 transmembrane receptors and share structural characteristics represented in the diagram. The conserved domains include 36 EGF repeats and 3 lin/Notch Repeats (LNR) in the extracellular domain, 7 Ankyrin repeats, 2 different nuclear localization domains and 1 OPA/PEST region conform the intracellular domain.
The Notch2 gene is transcribed and translated as a single inactive protein. This protein is cleaved by a furin-like convertase in the trans-golgi network before it reaches the plasma membrane to yield an active form. Cleavage results in a C-terminal fragment and a N-terminal fragment, linked by disulfide bridges. Following ligand binding, it is first cleaved by ADAM17 metallopeptidase to yield a membrane-associated intermediate fragment. This fragment is then cleaved by presenilin dependent gamma-secretase to release a Notch-derived peptide containing the intracellular domain from the membrane (see Notch activation diagram).
Protein modifications:

Phosphorylation: Different phosphorylation processes are important for regulating Notch2 activity. Only GSK3beta has been found to phosphorylate Notch2 in 32D-myeloid cells.

Glycosylation: fringe glycosyl-transferases modify the extracellular domain of Notch2 by glycosylation.

Expressed in the brain, heart, kidney, spleen (hematopoietic cells,T-cells, B-cells and mast cells), lung, intestine, skeletal muscle and liver (hepatic cells and bile duct cells), ameloblasts.

Type I membrane protein. Following proteolytical processing it is translocated to the nucleus.

Physiological receptor for membrane-bound ligands jagged1, jagged2 and delta1 to regulate cell-fate determination. Upon ligand activation, Notch intracellular domain forms a transcriptional activator complex with RBP-j kappa and Mastermind proteins and activates genes of the hairy/enhancer of split (hes) family. Notch2 behaves very similar to Notch1 at the biochemical level, and in fact, C-terminal intracellular region of Notch1 can functionally replace that of Notch2 in vivo. However specific functions, specific expression patterns and embryonic lethality of single mutant mice indicate that both proteins are not redundant.
Biological functions strictly associated to Notch2 are:

Development of kidney (proximal nephron structures: podocytes and proximal convoluted tubules).

B-cell differentiation: involved in the final stages of B-cell maturation at the marginal zone of the spleen and expression of CD23 in B-CLL (B-Cell Chronic Lymphoblastic leukaemia).

T-cell maturation: later stages of T cell development, induction of CD8+ cells.

Notch2 is also required for formation of the placental circulatory system.

Degree of amino acid identity between Notch1 and Notch2 proteins: overall, 56%; EGF-like repeats, 58%; LNR,58%; CDC10, 76% and PEST, 79%.

Two different mutations segregating in two families affected by Alagille syndrome: One mutation results in partial deletion of the intracellular domain including 4 ankyrin repeats, the second mutation affects EGF repeat 11.