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. 2000 Feb;5(2):197-206.
doi: 10.1016/s1097-2765(00)80416-5.

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

J S Mumm  1 , E H Schroeter, M T Saxena, A Griesemer, X Tian, D J Pan, W J Ray, R Kopan
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Free article

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

J S Mumm et al. Mol Cell. 2000 Feb.
Free article

Abstract

Gamma-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 facilitates 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 gamma-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.

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