Notch ligand endocytosis: mechanistic basis of signaling activity

Semin Cell Dev Biol. 2012 Jun;23(4):429-36. doi: 10.1016/j.semcdb.2012.01.011. Epub 2012 Jan 24.

Abstract

Regulation of Notch signaling is critical to development and maintenance of most eukaryotic organisms. The Notch receptors and ligands are integral membrane proteins and direct cell-cell interactions are needed to activate signaling. Ligand-expressing cells activate Notch signaling through an unusual mechanism involving Notch proteolysis to release the intracellular domain from the membrane, allowing the Notch receptor to function directly as the downstream signal transducer. In the absence of ligand, the Notch receptor is maintained in an autoinhibited, protease resistant state. Genetic studies suggest that Notch ligands require ubiquitylation, epsin endocytic adaptors and dynamin-dependent endocytosis for signaling activity. Here we discuss potential models and supporting evidence to account for the absolute requirement for ligand endocytosis to activate signaling in Notch cells. Specifically, we focus on a role for ligand-mediated endocytic force to unfold Notch, override the autoinhibited state, and activate proteolysis to direct Notch-specific cellular responses.

Publication types

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

MeSH terms

  • Animals
  • Calcium-Binding Proteins / metabolism*
  • Calcium-Binding Proteins / physiology
  • Cell Communication
  • Endocytosis*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / physiology
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Ligands
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Protein Structure, Tertiary
  • Protein Transport
  • Protein Unfolding
  • Proteolysis
  • Receptors, Notch / chemistry
  • Receptors, Notch / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction*

Substances

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