Abstract
Many different animal developmental and homeostatic processes rely on signalling via the highly conserved Notch pathway. Often Notch signalling has iterative roles during cell specification and differentiation, controlling not only the state of progenitor cells but also the fate and function of their progeny. Its roles continue throughout the lifespan of the organism, regulating normal tissue maintenance, as well as operating in response to damage. Consistent with such fundamental roles, the pathway has been associated with numerous diseases, including cancers. Understanding how Notch signalling is orchestrated to bring about different outcomes is challenging, given that it has many diverse functions. Classic models proposed that stochastic differences in cell states were important to polarise signalling during cell fate decisions. Subsequently, the importance of oscillatory Notch signalling was uncovered, and it became clear that it operates in different modalities depending on the regulatory inputs. With the advent of ever-more-sensitive live-imaging and quantitative approaches, it is becoming evident that differences in the dynamics, levels and architectures of Notch signalling are critical in shaping and maintaining tissues. This Review focuses on the cellular and molecular mechanisms involved in conferring different modalities on Notch pathway operations and how these enable different types of functional outcomes from pathway activation. We also discuss their dysregulation in cancer.
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Acknowledgements
We thank our research groups and our colleagues for inspiring discussions. We apologise that the brevity of the review means that we have had to select a few examples from the literature to illustrate the points made. Our research is supported by funding from UKRI Medical Research Council, Wellcome Trust, Instituto de Salud Carlos III, Instituto National de Investigacion, Agencia Estatal de Investigación (AEI) and AGAUR (Generalitat de Catalunya).
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Glossary
- Adaptor protein complexes
-
Multiprotein complexes that mediate vesicle formation and trafficking by linking cargo proteins to the vesicle coat.
- β-Catenin
-
A key intracellular component in the Wnt signalling pathway. Wnt binding to its receptor prevents β-catenin degradation, allowing it to regulate gene expression.
- Cell transformation
-
The process whereby normal cells become cancerous acquiring uncontrolled growth and division.
- Club cells
-
Non-ciliated epithelial cells in the airway that play a role in detoxification, secretion of protective proteins and airway regeneration.
- E3-ligase
-
An enzyme that tags proteins with ubiquitin altering their interactions with other adaptor proteins in the cell and in some cases targeting them for degradation by the proteasome.
- Enhancer decommissioning
-
The process of shutting down active enhancers, often by removing transcriptional machinery of histone modifications, to regulate gene expression.
- Exosomes
-
Small extracelluar vesicles released by cells to carry proteins, lipids and nucleic acids, important for cell communication in processes such as immune response and tumour progression.
- Extracellular matrix
-
A network of proteins and polysaccharides surrounding cells, providing structural support and signals for cell adhesion, migration or differentiation.
- Genetically mosaic tissues
-
Tissues composed of cells with different genetic makeups, often resulting from mutations, genetic recombination or experimental manipulation.
- IL-7R
-
Receptor protein for the cytokine interleukin 7 (IL-7). Binding of IL-7 activates other downstream pathways and regulates the development, proliferation and survival of immune T and B lymphocytes.
- Immunosuppressive tumour environments
-
A complex networks of cancer cells, immune cells and signalling molecules that suppresses immune activity, allowing tumours to evade immune.destruction. Key contributions include regulatory T cells, myeloid-derived suppressor cells and immunosuppressive cytokines.
- Lateral inhibition
-
A process in which a cell becomes selected from a group of equivalent cells and inhibits its neighbouring cells from adopting the same fate. Promotes the formation of distinct cell types in tissues.
- Mediator-associated kinase CDK8
-
(cyclin-dependent kinase 8). Regulatory subunit of the Mediator complex that regulates gene expression by phosphorylating transcription factors and RNA polymerase II. Linked to cancer progression.
- Mucociliary cell
-
Ciliated epithelial cells in the respiratory track that secrete mucus aiding in the clearance of particles and pathogens.
- Muscle satellite cells
-
Stem cells located beneath the basal lamina of muscle fibres, responsible for muscle growth, repair and regeneration.
- NFkB
-
(nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. Controls immune responses, inflammation, cell survival and proliferation. Activation leads to NFkB moving to the nucleus to induce inflammatory and survival genes. Chronic activation is linked to disease.
- Paraxial mesoderm
-
A region of the mesoderm located on either side of the neural tube that forms somites and contributes to the musculoskeletal system.
- PI3K
-
(phosphatidylinositol 3-kinase). Kinase enzyme that regulates cell growth, survival and metabolism. PI3K activation triggers protein kinase B (PKB, or Akt) signalling, which promotes cell survival and inhibits apoptosis. Dysregulated in cancer and metabolic diseases.
- Prolyl-isomerase Pin1
-
Peptidyl-prolyl isomerases are enzymes that regulate the stability, localization and activity of proteins. Pin1 recognizes and isomerises the phosphorylated serine/threonine–proline (pSer/Thr–Pro) motif.
- Somites
-
Segmented structures from the paraxial mesoderm that give rise to the vertebrae, skeletal, muscles and dermis.
- Translocation
-
Movement of a chromosome segment to a new location in the genome, within the same or a different chromosome, may be associated with cancer.
- Wing imaginal discs
-
The wing primordia, epithelial structures in insect larvae that develop into adult wings during metamorphosis.
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Bray, S.J., Bigas, A. Modes of Notch signalling in development and disease. Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-025-00835-2
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DOI: https://doi.org/10.1038/s41580-025-00835-2
