The Notch proteins

Abstract

What are they? The Notch proteins are transmembrane receptors that regulate differentiation in all types of tissues and organisms. The Notch family includes lin12 and glp1 from Caenorhabditis elegans, and mammalian Notch1 to Notch4. All the Notch proteins have extracellular EGF-like repeats for ligand binding, and intracellular RAM23 and ankyrin repeats for intracellular signalling.What are their known functions? They are best known for their role in ‘lateral inhibition’ in the developing fruitfly nervous system and in ‘lateral specification’ of several tissues in C. elegans. To put it simply, cells in a developing tissue communicate with one another through Notch receptors and their ligands. Those that receive a Notch signal assume one fate, whereas those that do not receive it assume another fate.How did they get that name? Notch, the founding member of the family, was first identified in the 1930s by means of a mutation in fruitflies that causes notched wings. Fruitfly embryos that completely lack Notch protein never develop properly; the embryonic nervous system is overgrown because of a lack of inhibitory regulation of neurogenesis.Who are their known associates? The transmembrane proteins of the DSL family (named after members Delta and Serrate from Drosophila and lag2 from C. elegans) are the ligands for the Notch family. They can act as either membrane-bound or diffusible ligands. The DSL family also includes the Jagged (Serrate-like) proteins.How do Notch proteins work? Notch proteins are probably cleaved three or four times, before and/or after ligand binding. One or more of the cleaved intracellular forms migrate(s) to the nucleus (see FigureFigure) where they regulate gene transcription together with proteins of the CSL family (named after the family members CBF, Suppressor of Hairless and lag1). But this is not the whole story; Notch signalling that is independent of Suppressor of Hairless has been shown in certain situations.Figure 1A model for Notch signal transduction. The Notch precursor molecule is cleaved in the endoplasmic reticulum by the Furin protease. The two fragments, NotchEC (blue) and NotchIC (pink) bind as a heterodimer to a DSL ligand (yellow), which might have been cleaved by the Kuzbanian protease. This binding triggers intracellular proteolysis and release of a cytoplasmic fragment, NotchICD, which translocates to the nucleus and associates with a CSL protein (green). The NotchICD-CSL heterodimer binds to DNA (orange) and activates gene transcription.View Large Image | View Hi-Res Image | Download PowerPoint SlideSo, do they have other functions? Notch binds both the Wingless and Dishevelled proteins in the Wnt/Wingless signalling pathway, which affects cell fates. Notch interacts with the Numb proteins, which participate in assymetrical cell divisions. It also interacts with the fringe proteins, and the Ras pathway.Any unusual cell biology? Notch and its ligand proteins seem to be transendocytosed: one finds Delta proteins from one cell transferred across cell membranes into cells expressing Notch proteins, and vice versa. This might reflect an unusual form of cell–cell communication.Can we do without them? No. Notch1 is required for the development of somites, truncations of the protein cause leukemia and it is overproduced in cases of cervical cancer. Mutations in the Notch4 gene cause breast cancer in mice. Point mutations in the Notch3 gene cause a stroke-like neurodegeneration (called CADASIL), and the Presenilin genes (mutations in which cause familial Alzheimer's disease) interact genetically with Notch genes. Mutations in Jagged1 cause foetal malformations (Alagille's syndrome), and mutations in Jagged2 (also known as Serrate2) cause synpolydactylism. And it can only be a matter of time before an immunological disorder is discovered involving Notch or DSL genes, because Notch signals also control development of the immune system at several stages.