The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis.
The human Notch family includes four receptors and five ligands. All four Notch receptors are synthesized as a single transmembrane polypeptide in the endoplasmic reticulum and transported to the cell surface trough the trans-Golgi network. Notch receptors are expressed as heterodimeric proteins with extracellular, transmembrane and intracellular domains .
When a ligand of the Delta/Serrate/LAG-2 family (located on the surface of neighboring cells) binds to the extracellular domain of the Notch receptor, it triggers proteolytic cleavage by a metalloprotease (a disintegrin and metalloprotease (ADAM)). ADAM cleavage produces a substrate for a second cleavage by the presenilin-containing γ-secretase complex, releasing the Notch intracellular domain (NICD). NCID corresponds to the activated form of Notch, which translocates to the nucleus and forms complexes with specific DNA-binding proteins (CBF1/Suppressor of Hairless/LAG-1 and Mastermind/SEL-8) and transcriptionally activates target genes . In the absence of receptor activation and NICD, CBF1 acts as a transcriptional repressor through interactions with the corepressors SMRT (silencing mediator of retinoid and thyroid receptors), KyoT2, CIR (CBF1-interacting corepressor) and SHARP (SMRT/HDAC1 (histone deacetylase 1)-associated repressor protein).
In addition to canonical intracellular signaling pathways, there are other types of noncanonical Notch signaling. The first one involves Notch ligation and translocation of activation signals independent of CBF1 (NICD-dependent), the second involves activation of Notch target genes that are independent of γ-secretase cleavage (NICD- and CBF1-independent) and the third involves CBF1-dependent gene activation without receptor cleavage and NICD release. Termination of Notch signaling can occur at or downstream of the Notch receptor. The Notch receptor can be degraded through the lysosomes by the ubiquitin ligase Itch/AIP4 or another ubiquitin ligase, Nedd4, which act together with Numb and Itch/AIP4 to stimulate endocytosis and lysosomal degradation of the Notch receptor . Finally, NICD1 phosphorylation by GSK3 regulates its interaction with the E3 ubiquitin ligase CDC4/FBW7, thereby controlling NICD1 ubiquitination and proteasome-mediated degradation . This multifaceted control of Notch expression underscores its critical functions in cellular homeostasis.
- D’Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010;92:73–129. [PMC free article] [PubMed]
- Kovall RA, Blacklow SC. Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol. 2010;92:31–71. [PubMed]
- Kopan R, Ilagan MXG. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–233. doi: 10.1016/j.cell.2009.03.045. [PMC free article] [PubMed] [Cross Ref]
- Bray S, Bernard F. Notch targets and their regulation. Curr Top Dev Biol. 2010;92:253–275. [PubMed]
- Fortini ME. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 2009;16:633–647. doi: 10.1016/j.devcel.2009.03.010. [PubMed] [Cross Ref]
- Chastagner P, Israël A, Brou C. AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One. 2008;3:e2735. doi: 10.1371/journal.pone.0002735. [PMC free article] [PubMed] [Cross Ref]
- Wilkin MB, Carbery AM, Fostier M, Aslam H, Mazaleyrat SL, Higgs J, Myat A, Evans DAP, Cornell M, Baron M. Regulation of Notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr Biol. 2004;14:2237–2244. doi: 10.1016/j.cub.2004.11.030. [PubMed] [Cross Ref]
- McGill MA, McGlade CJ. Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem. 2003;278:23196–23203. doi: 10.1074/jbc.M302827200. [PubMed] [Cross Ref]
- Fortini ME, Bilder D. Endocytic regulation of Notch signaling. Curr Opin Genet Dev. 2009;19:323–328. doi: 10.1016/j.gde.2009.04.005. [PMC free article] [PubMed] [Cross Ref]
- Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8:83–93. doi: 10.1038/nrc2290. [PubMed] [Cross Ref]
Images used in the article are copyright protected and owned by Joanna Pancewicz and Christophe P. Nicot.