Evolution of Notch Transmembrane Receptors


Notch is the transmembrane receptor of a juxtacrine signalling pathway (Notch pathway) crucial for cell programming during animal development. The active Notch pathway is an innovation of the metazoan lineage: several major components of this molecular network are absent from other eukaryotes. The transmembrane multidomain protein Notch emerged through the assembly of both ancient and recent domains: some were probably already present in LUCA (Last Universal Common Ancestor) whereas others appeared during animal evolution. Data from a choanoflagellate genome suggest that the domain shuffling events which gave rise to the typical domain composition of Notch probably occurred before the emergence of animals. More genomic and functional experiments are needed to fully understand the evolution of the Notch receptor and the interactions with its ligands.

Key Concepts:

  • Multicellularity emerged independently several times during Life History.

  • Intercellular communication mechanisms can be performed either through direct cytoplasmic exchanges or through interactions involving membrane components.

  • Juxtacrine signalling requires physical contact between the two cells involved.

  • About 20 signalling pathways are involved in cell signalling in the metazoan (animal) lineage; among them, 7 are known to play major roles during animal development.

  • EGF repeats are known to be commonly used domains for protein–protein interactions in Eukaryota.

  • ANK repeats are one of the most common protein–protein interaction motifs in living beings.

  • The domain shuffling mechanism is important in genome evolution.

  • Gene duplication events represent a powerful tool for molecular and functional innovations.

  • Notch is the receptor of a juxtacrine signalling pathway crucial for cell programming during animal development.

Keywords: cell signalling; pathway; notch; delta; jagged; serrate; domain shuffling; metazoan evolution

Figure 1.

The four classically distinguished types of intercellular communication involving ligand–receptor interactions. (a) Autocrine: the same cell population produces both the ligand and the receptor, each cell regulates itself and its same‐type neighbours. (b) Paracrine: a cell produces a diffusible ligand, nearby cells having the receptor are the target. (c) Endocrine: the ligand synthesised by a cell will be conducted to target cells by the circulatory system (enabling long distances). (d) Juxtacrine: the interaction between ligand and receptor needs direct contact between cells, the ligand is not diffusible (case of Notch/Delta‐Jagged‐Serrate).

Figure 2.

Schematic representation of the Notch pathway in bilaterians (reproduced from Gazave et al., ). Both the Notch receptor and its ligands (Delta or Jagged/Serrate) are type I transmembrane proteins with a modular architecture. The Notch protein is synthesised as an inactive precursor that has to undergo various post‐translational modifications to become active: in the Golgi apparatus, the first cleavage (S1) is performed by the Furin protease and results in two fragments (NICD and NECD) which subsequently undergo O‐fucosylation (realised by O‐fucosyltransferase) and glycosylation (realised by Fringe). Notch is now an active transmembrane receptor. Upon ligand binding, the second cleavage (S2) occurs due to the metalloproteasesADAM10 and 17, followed by the final cleavage (S3) implicating the γ‐secretase complex (Presenilin‐Nicastrin‐APH1‐PEN2). These cleavages allow the NICD to be released into the cytoplasm and enable its translocation to the nucleus. In the nucleus, NICD interacts with the CSL (CBF1, Su(H), Lag‐1)/Ncor/SMRT/histone deacetylase (HDAC) transcriptional complex and recruits the co‐activator Mastermind and a histone acetylase (HAC), thus activating the transcription of target genes (in particular the HES/E(Spl) genes (Hairy/Enhancer of Split)) (Brou et al., ; Mumm and Kopan, ; Mumm et al., ; Fortini, ; Lieber et al., ).

Figure 3.

Arrangement of proteic domains in Notch (from Gazave et al., ): (a) a typical bilaterian Notch protein, with NOD and NODP domains; (b) a sponge Notch without NOD and NODP, (c) the Monosiga brevicollis ‘Notch‐like’ protein, with no NOD, NODP nor PEST domains and limited EGF repeats.



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How to Cite close
Gazave, Eve, and Renard, Emmanuelle(Nov 2010) Evolution of Notch Transmembrane Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022893]