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 γ-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 γ-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to TACE (TNFα-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.
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