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Notch signalling: a simple pathway becomes complex

Key Points

  • Notch is the receptor in a highly conserved signalling pathway that is crucial in development and implicated in malignant transformation. The basic paradigm of Notch signalling is simple, and involves proteolytic cleavage to release an intracellular fragment (Nicd) that functions to regulate transcription.

  • In the nucleus, Nicd displaces a repression complex and, with the DNA-binding CSL (CBF1, Su(H) and LAG-1) protein, recruits the co-activator Mastermind. Additional epigenetic cofactors are implicated and recruitment of kinases and ubiquitin ligases probably contribute to rapid turnover of the activator complex.

  • Activity of the receptor is also regulated post-translationally. A number of different auxiliary components are implicated, including several ubiquitin ligases and proteins, such as Numb, that have direct links to the endocytic machinery.

  • Notch ligands are transmembrane proteins and they require E3 ubiquitin ligases for their activity. The mechanisms whereby the ligands become competent to signal are not yet known, but probably entail endocytosis. Localization and cleavage of ligands might also contribute to their regulation.

  • In many developmental processes, feedback mechanisms operate to amplify or restrict the activity of the Notch pathway. These include transcriptional regulation of auxiliary factors that in turn influence ligand or receptor activity and microRNAs.

Abstract

A small number of signalling pathways are used iteratively to regulate cell fates, cell proliferation and cell death in development. Notch is the receptor in one such pathway, and is unusual in that most of its ligands are also transmembrane proteins; therefore signalling is restricted to neighbouring cells. Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.

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Figure 1: The core Notch pathway.
Figure 2: Ligand activation entails ubiquitylation.
Figure 3: Processing and trafficking regulate Notch-receptor activity.
Figure 4: Nuclear cycle of CSL.

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Acknowledgements

My apologies to all those colleagues whose important contributions have not been acknowledged due to the space constraints of this Review. My thanks to A. Krejci, M. Glittenberg, A. Djiane and the reviewers for helpful comments, and to F. Wirtz-Peitz and J. Knoblich (Institute of Molecular Biotechnology, Vienna, Austria) for the beautiful image of SOPs in Box 2. Work on Notch signalling in my laboratory is currently supported by grants from the Medical Research Council, the Wellcome Trust and the Association for International Cancer Research.

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Glossary

ADAM-family metalloproteases

Transmembrane disintegrins and metalloproteases that proteolytically cleave the juxtamembrane region of cellular transmembrane proteins and detach their extracellular regions — this process is known as ectodomain shedding.

γ-secretase complex

Presenilin, a multispan membrane protein, is the catalytic subunit, and the transmembrane proteins nicastrin and APH1 stabilize the presenilin holoprotein. PEN2, a two-pass transmembrane protein, induces endoproteolysis of presenilin and maturation of the γ-secretase complex.

E3 ubiquitin ligase

An adaptor protein that links ubiquitin-conjugating E2 enzymes with substrates and contributes to the catalytic transfer of ubiquitin onto the substrate.

Epsin

A clathrin and phosphatidylinositol-4,5-bisphosphate-binding protein that contains ubiquitin-interaction motifs. It is thought to facilitate endocytosis of ubiquitylated cargo proteins.

Auxilin

A J-domain-containing protein that is implicated in the disassembly of clathrin from clathrin-coated vesicles.

Recycling endosome

A compartment that sorts transmembrane proteins that are recycled to the plasma membrane following endocytosis.

Exocyst

A heteromeric protein complex that is required for polarized exocytosis of post-Golgi secretory vesicles.

Bearded-related proteins

Short polypeptides that were identified in insects and contain an N-terminal amphipathic helix and 2 or 3 conserved motifs.

Adherens junction

A cell–cell junction that mediates adhesion through cadherins and regulates and/or links to the actin cytoskeleton.

PDZ-binding motif

A motif at the C terminus of a protein that is recognized by a PDZ-domain-containing protein. PDZ-domains are conserved 80–90-residue domains that fold into a β-sandwich and are found in many scaffold and signalling proteins.

Fringe

A Golgi-resident glycosyl-transferase that was first identified in D. melanogaster and has three homologues in mammals: Lunatic Fringe, Radical Fringe and Manic Fringe.

RAB GTPases

Members of the Ras superfamily of small GTPases, RAB proteins regulate vesicle budding, fusion and motility.

HRS/VPS27

A protein that contains ubiquitin-interaction motifs and is important for sorting ubiquitylated endosomal cargoes.

Syntaxin I

Integral membrane protein with sequence similarity to t-SNAREs that is involved in vesicle docking and vesicle fusion.

β-arrestin

Also known as non-visual arrestin, it is a cytoplasmic protein that promotes endocytosis of G-protein-coupled receptors and is present in coated vesicles.

ESCRT

(Endosomal sorting complex required for transport). Three heteromeric protein complexes, ESCRTI, ESCRTII and ESCRTIII, function sequentially in the sorting of membrane proteins into the multivesicular body.

AP2 complex

A heterotetrameric trafficking adaptor complex that comprises two large, one medium and one small subunit. It interacts with clathrin and also, through the appendage domain of a large subunit, binds to accessory proteins, including Epsins.

Rel family

Also known as nuclear factor (NF)-κB proteins, this family of transcription factors contains a conserved domain (the Rel-homology domain (RHD)) that is required for DNA binding and dimerization. These proteins are important in defence against infectious diseases and cellular stress.

Somitogenesis

The development of somites, the segmental blocks of mesoderm that give rise to the axial skeleton, muscles and dermis.

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Bray, S. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7, 678–689 (2006). https://doi.org/10.1038/nrm2009

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