A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1

Jeffrey S. Mumm, Eric H. Schroeter, Meera T. Saxena, Adam Griesemer, Xiaolin Tian, D. J. Pan, William J. Ray, Raphael Kopan

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643 Scopus citations

Abstract

γ-secretase-like proteolysis at site 3 (S3), within the transmembrane domain, releases the Notch intracellular domain (NICD) and activates CSL-mediated Notch signaling. S3 processing occurs only in response to ligand binding; however, the molecular basis of this regulation is unknown. Here we demonstrate that ligand binding facilities cleavage at a novel site (S2), within the extracellular juxtamembrane region, which serves to release ectodomain repression of NICD production. Cleavage at S2 generates a transient intermediate peptide termed NEXT (Notch extracellular truncation). NEXT accumulates when NICD production is blocked by point mutations or γ-secretase inhibitors or by loss of presenilin 1, and inhibition of NEXT eliminates NICD production. Our data demonstrate that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to Notch activation.

Original languageEnglish (US)
Pages (from-to)197-206
Number of pages10
JournalMolecular cell
Volume5
Issue number2
DOIs
StatePublished - Jan 1 2000

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Mumm, J. S., Schroeter, E. H., Saxena, M. T., Griesemer, A., Tian, X., Pan, D. J., Ray, W. J., & Kopan, R. (2000). A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1. Molecular cell, 5(2), 197-206. https://doi.org/10.1016/S1097-2765(00)80416-5