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NOTCHs

Sunday 7 March 2004

Definition: Notch proteins are single-pass transmembrane receptors that regulate cell fate decisions during development.

See also : NOTCH signaling pathway

Notch receptors (NOTCHs) are highly conserved single-pass transmembrane proteins that regulate cellular differentiation and tissue homeostasis in a context-dependent manner and are implicated in normal development and in oncogenesis.

Upon interaction with Notch ligands on neighboring cells, signal transduction by Notch receptors occurs through a series of proteolytic cleavages.

The last of these is mediated by a [gamma]-secretase complex, which liberates the intracellular domain (ICD) of Notch to allow it to translocate to the nucleus and influence transcription of target genes. There are 4 Notch receptors (Notch 1 to 4) in mammals.

NOTCH1 is the best-characterized member and was initially discovered from cases of human T-LBL harboring t(7;9)(q34;q34.3), which juxtaposes the NOTCH1 gene on chromosome 9 to T-cell receptor [beta]-enhancer/promoter elements on chromosome 7.

Subsequent studies have shown a critical role for Notch1 in normal T-cell differentiation, being both necessary and sufficient for development from hematopoietic stem cells.

Notch receptors and their cognate ligands transduce crucial signals between cells in various tissues, and have been conserved across millions of years of evolution. Mutations in Notch signalling components result in congenital heart defects in humans and mice, demonstrating an essential role for Notch in cardiovascular development.

This signalling pathway is involved in many stages of heart development, and provide mechanistic insight into the vital functions of Notch in the aetiology of several common forms of paediatric and adult cardiac disease.

The Notch family includes 4 receptors: NOTCH1, NOTCH2 (MIM.600275), NOTCH3 (MIM.600276), and NOTCH4 (MIM.164951), whose ligands include the JAGs: JAG1 (MIM.601920), JAG2 (MIM.602570); and the DLLs: DLL1 (MIM.606582), DLL3 (MIM.602768), and DLL4 (MIM.605185).

All of the receptors have an extracellular domain containing multiple epidermal growth factor (EGF) (MIM.131530)-like repeats and an intracellular region containing the RAM domain, ankyrin repeats, and a C-terminal PEST domain.

Mammals possess 4 Notch receptors (Notch1‑4) and five ligands (Jagged1 and 2, and Delta-like 1, 3 and 4).

Notch receptors are expressed on the cell surface as heterodimeric proteins. They are composed of an extracellular domain containing up to 36 EGF‑like repeats followed by 3 cysteine rich LIN repeats and an intracellular domain containing multiple protein-protein interaction domains as well as a transactivation domain.

Notch signaling is triggered upon ligand-receptor interaction which induces two sequential proteolytic cleavages, the first in the extracellular domain mediated by metalloproteases of the ADAMs family, and the second within the transmembrane domain mediated by a g‑secretase (GS) activity of presenilins (PS).

This second cleavage allows the release and translocation of the intracellular domain of Notch (NICD) into the nucleus where it associates with CSL.

Binding of NICD to CSL leads to transcriptional activation by displacement of co-repressors (CoRs) and simultaneous recruitment of different coactivators (CoA) including mastermind like proteins (MAML) and p300.

Functions

Cell-to-cell communication is required for many biologic processes, including differentiation, proliferation, and homeostasis, and one system used by a wide range of eukaryotes is the Notch signaling pathway.

The Notch gene family consists of structurally conserved cell surface receptors that are activated by 1 or more membrane-bound ligands of the Delta/Serrate/Lag2 (DSL) gene family. Notch ligands are divided into 2 subclasses, the Delta family and the Serrate family.

All Notch ligands share some structural features, including EGF-like repeats, a characteristic DSL domain necessary for Notch binding, and a transmembrane region. However, an extracellular cysteine-rich domain and insertions that interrupt some EGF-like repeats are common only to the Serrate family. It is these structural differences that categorize a Notch ligand as a Delta or Serrate family member.

Members

|NOTCH1 |NOTCH2 |NOTCH3 |NOTCH4 |

Pathology

- MIR143-NOTCHs gene fusions in benign and malignant glomus tumors (23999936)

See also

- Notch signaling pathway

References

- 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

- 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

- 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

- 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

- Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565-97. PMID: 12730322