The many facets of Notch ligands

Oncogene. 2008 Sep 1;27(38):5148-67. doi: 10.1038/onc.2008.229.


The Notch signaling pathway regulates a diverse array of cell types and cellular processes and is tightly regulated by ligand binding. Both canonical and noncanonical Notch ligands have been identified that may account for some of the pleiotropic nature associated with Notch signaling. This review focuses on the molecular mechanisms by which Notch ligands function as signaling agonists and antagonists, and discusses different modes of activating ligands as well as findings that support intrinsic ligand signaling activity independent of Notch. Post-translational modification, proteolytic processing, endocytosis and membrane trafficking, as well as interactions with the actin cytoskeleton may contribute to the recently appreciated multifunctionality of Notch ligands. The regulation of Notch ligand expression by other signaling pathways provides a mechanism to coordinate Notch signaling with multiple cellular and developmental cues. The association of Notch ligands with inherited human disorders and cancer highlights the importance of understanding the molecular nature and activities intrinsic to Notch ligands. Oncogene (2008) 27, 5148-5167; doi:10.1038/onc.2008.229.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis / physiology
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / physiology
  • Cell Communication / physiology
  • Cell Differentiation / physiology
  • Embryonic Development / physiology
  • Endocytosis / physiology
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / physiopathology
  • Glycosylation
  • Homeostasis / physiology
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Intercellular Signaling Peptides and Proteins / physiology
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins / chemistry
  • Membrane Proteins / physiology*
  • Neoplasms / genetics
  • Neoplasms / physiopathology
  • Peptide Hydrolases / physiology
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Receptors, Notch / genetics
  • Receptors, Notch / physiology*
  • Serrate-Jagged Proteins
  • Signal Transduction / physiology*
  • Stem Cells / physiology
  • Ubiquitination


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • delta protein
  • Peptide Hydrolases