The Notch signaling pathway is a conserved intercellular signaling mechanism that is essential for proper embryonic development in numerous metazoan organisms.

Members of the Notch gene family (NOTCHs) encode transmembrane receptors that are critical for various cell fate decisions. Multiple ligands that activate Notch and related receptors have been identified, including Serrate and Delta in Drosophila and JAG1 (MIM.601920) in vertebrates.

Four different Notch receptors (NOTCHs: NOTCH1 to NOTCH4) and five ligands (Jagged-1 (JAG1) and -2 (JAG2) and Delta-like [DLLs]: DLL1, DLL2 and DLL4) have been characterized in mammalian cells. These transmembrane receptors and ligands are expressed in different combinations in most, if not all, cell types.

The Notch pathway regulates cell fate determination of neighbouring cells through lateral inhibition, depending on their ability to express either the receptors or the ligands.

Notch signaling

Following ligand binding, NOTCHs are activated by a series of cleavages that releases its intracellular domain (NICD).

This processing requires the activity of two proteases, namely ADAM17 (tumour necrosis factor-? converting enzyme or TACE MIM.603369) and presenilin-1 (PSEN1 MIM.104311).

Nuclear translocation of NICD results in transcriptional activation of genes of the HESs family (Hes/E(spl) family) and HEYs family (Hesr/Hey family) through interaction of NICD with RBPSUH (or CBF1 MIM.147183), Su(H), and Lag-1, which is also known as the recombination signal sequence-binding protein (RBP)-j [also called Suppressor of Hairless, Su(H)].

The specificity of each ligand for a receptor and the subsequent specificity for downstream target activation are still poorly understood. However, studies on the spatial expression of Notch components have highlighted tissue-specific functions for these proteins.

NOTCH receptors participate in a signaling pathway that regulates many aspects of morphogenesis in multicellular animals through diverse effects on differentiation, proliferation, and cell survival. Overall, when activated, Notch signalling enables neighbouring cells to acquire distinct phenotypes, through a process named lateral inhibition.

The Notch receptor is pre-cleaved in the Golgi and is targeted subsequently to the plasma membrane where it interacts with ligands located on neighbouring cells.

Receptor?ligand interaction results in a conformational change in the receptor, thus enabling additional cleavages by TACE and the ?-secretase complex.

This proteolytic activity enables the Notch intracellular domain (NICD) to translocate to the nucleus where it activates the transcription of target genes (e.g. the Hes and Hey family of transcriptional repressors).

Monoubiquitylation (Ub) of the ligand by mindbomb (MIB) induces endocytosis of the ligand and the Notch extracellular domain (NECD) into the ligand cells where additional signalling might be initiated.

Notch receptors undergo acomplex set of proteolytic processing events in response to ligand activating, which eventuallyleads to release of the intracellular domain of the receptor.Signal transduction is normally initiated by binding to transmembrane ligands of the Serrate or Delta class, which induces proteolytic release of the intracellular NOTCH domain (NICD).

Free NICD translocates to the nucleus to form a short-lived complex with a Rel-like transcription factor, CSL, and Mastermind-like co-activators that activates lineage-specific programs of gene expression.

Thus, the NOTCH pathway provides a means for local environmental cues mediated through cell:cell interactions to direct or antagonize specific developmental programs.

Notch signalling in angiogenesis

Several components of the Notch pathway are present in the vasculature, both in the endothelium (Notch1, Notch4, Jagged-1, Dll-1 and -4, Hes1, Hey1 and Hey2) and in the surrounding mural cells (which also express Notch3).

At the cellular level, Notch signalling in ECs blocks cell proliferation and favours cell survival. Inhibition of proliferation is dependent on the down-regulation of p21cip1 and the inhibition of retinoblastoma protein phosphorylation by cyclin D-cdk4.

Owing to their location, ECs are under constant aggression from inflammatory cytokines and toxins from foreign organisms. Activation of Notch signalling protects ECs from this hostile environment through activation of Bcl-2 (BCL2). Altogether, these studies suggest that Notch signalling is required for the generation of a quiescent and mature vascular phenotype.

 Arterial?venous differentiation

Notch signalling is also crucial for arterial?venous differentiation. This process was thought previously to be governed by environmental cues, such as blood pressure. However, recent studies demonstrate that genetic predisposition is also important.

Mutation in gridlock, the zebrafish orthologue of Hey2, results in a loss of artery-specific markers, ectopic expression of venous markers and arterial?venous shunts in mutant animals. In addition, mice with deletions in Hey1 and Hey2 have decreased arterial makers.

Finally, venous differentiation is also programmed genetically and is dependent on active repression of Notch signalling by COUP-TFII, a member of the orphan nuclear receptor superfamily.

Functions

Recent data suggest NOTCH signals control hematopoietic development at multiple decision points through effects on differentiation and self-renewal.

Components:

 Notch1 (NOTCH1 MIM.190198)
 JAG1 (Jagged1), HES5 (MIM.607348)
 MASH1 (ASCL1 MIM.100790)
 presenilin-2 (PSEN2 MIM.600759)

Pathology

 Vascular diseases

The role of Notch signalling in vascular development is further emphasized in two human cardiovascular diseases: the cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) and Alagille disease, which result from mutations in genes coding for Notch3 (NOTCH3) and Jagged1 (JAG1), respectively.

Additionally, over-expression of an active form of Notch4 (NOTCH4) in the vasculature results in defective embryonic angiogenesis, thus implying that crucial levels of Notch signalling are necessary for appropriate angiogenesis.

 In hematopoietic cells

Withdrawal of NOTCH signals at particular decision points leads to hypoplasia of specific lymphoid subsets, whereas enforced NOTCH signaling skews lymphoid development in the opposite direction and causes certain leukemias, including a subset of T-cell acute lymphoblastic leukemias associated with a recurrent t(7;9) translocation involving human NOTCH1.

 In central nervous system

Notch signaling is also linked to twoforms of neurodegenerative disease. First, mutations in the Notch 3 receptor leads to the stroke anddementia syndrome CADASIL. Second, proteolytic processing of Notch is controlled by presenilins, which are frequently mutated in Alzheimer diesase.

Mouse models

In addition, mice lacking either Notch1, Jagged1 or the double knockout of Hey1 and Hey2 die during early embryonic development as a result of vascular plexus remodelling defects in the embryo and the yolk sac as well as defects in arterial venous differentiation.

Interestingly, Notch4 is expressed exclusively in the vasculature in embryonic mice but Notch4?/? mice are viable. However, Notch1 Notch4 double-knockout embryos show more pronounced vascular defects than Notch1 knockout embryos.

See also

 proteolyctic cleavage by notch receptors by presenilin.
 ubiquitination and turnover of the intracellular domain of the Notch receptor

References

 Miele L, Golde T, Osborne B. Notch signaling in cancer. Curr Mol Med. 2006 Dec;6(8):905-18. PMID: 17168741

 High FA, Epstein JA. The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet. 2008 Jan;9(1):49-61. PMID: 18071321

 Rampal R, Luther KB, Haltiwanger RS. Notch signaling in normal and disease States: possible therapies related to glycosylation. Curr Mol Med. 2007 Jun;7(4):427-45. PMID: 17584081

 Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatr Res. 2005 May;57(5 Pt 2):104R-109R. PMID: 15817497

 Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89. PMID: 16921404

 Sainson RC, Harris AL. Hypoxia-regulated differentiation: let?s step it up a Notch. Trends Mol Med. 2006 Apr;12(4):141-3. PMID: 16513423

 Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology. 2004 Dec;127(6):1775-86. PMID: 15578515

 Flynn DM, Nijjar S, Hubscher SG, de Goyet Jde V, Kelly DA, Strain AJ, Crosby HA. The role of Notch receptor expression in bile duct development and disease. J Pathol. 2004 Sep;204(1):55-64. PMID: 15307138

 Kadesch T. Notch signaling: the demise of elegant simplicity. Curr Opin Genet Dev. 2004 Oct;14(5):506-12. PMID: 15380241

 Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev. 2004 Feb;14(1):48-54. PMID: 15108805

 Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003 Oct;3(10):756-67. PMID: 14570040

 Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003 Jun;3(6):565-76. PMID: 12842085

 Gridley T. Notch signaling and inherited disease syndromes. Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R9-13. PMID: 12668592

 Screpanti I, Bellavia D, Campese AF, Frati L, Gulino A. Notch, a unifying target in T-cell acute lymphoblastic leukemia? Trends Mol Med. 2003 Jan;9(1):30-5. PMID: 12524208

 Joutel A, Tournier-Lasserve E. Notch signalling pathway and human diseases. Semin Cell Dev Biol. 1998 Dec;9(6):619-25. PMID: 10075489