A Novel Proteolytic Cleavage Involved in Notch Signaling: The Role of the Disintegrin-Metalloprotease TACE

Mol Cell. 2000 Feb;5(2):207-16. doi: 10.1016/s1097-2765(00)80417-7.

Abstract

The Notch1 receptor is presented at the cell membrane as a heterodimer after constitutive processing by a furin-like convertase. Ligand binding induces the proteolytic release of Notch intracellular domain by a gamma-secretase-like activity. This domain translocates to the nucleus and interacts with the DNA-binding protein CSL, resulting in transcriptional activation of target genes. Here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to TACE (TNFalpha-converting enzyme), a member of the ADAM (a disintegrin and metalloprotease domain) family of metalloproteases. Furthermore, experiments carried out on TACE-/- bone marrow-derived monocytic precursor cells suggest that this metalloprotease plays a prominent role in the activation of the Notch pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Amino Acid Sequence
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Calcium-Binding Proteins
  • Cell Differentiation
  • Disintegrins / metabolism*
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins / metabolism*
  • Metalloendopeptidases / metabolism*
  • Mice
  • Molecular Sequence Data
  • Monocytes / cytology
  • Monocytes / drug effects
  • Protein Biosynthesis
  • Protein Processing, Post-Translational
  • Proteins*
  • Receptor, Notch1
  • Receptors, Cell Surface / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors*

Substances

  • Calcium-Binding Proteins
  • Disintegrins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Notch1 protein, mouse
  • Proteins
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Serrate-Jagged Proteins
  • Transcription Factors
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • Adam17 protein, mouse
  • Tetradecanoylphorbol Acetate