A novel proteolytic cleavage involved in Notch signaling: The role of the disintegrin-metalloprotease TACE

The Notch1 receptor is presented at the cell membrane as a heterodimer afte r constitutive processing by a furin-like convertase. Ligand binding induce s the proteolytic release of Notch intracellular domain by a gamma-secretas e-like activity. This domain translocates to the nucleus and interacts with the DNA-binding protein CSL, resulting in transcriptional activation of ta rget genes. Here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secreta se-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to TACE (TNF alpha-converting enzyme), a mem ber of the ADAM (a disintegrin and metalloprotease domain) family of metall oproteases. Furthermore, experiments carried out on TACE(-/-) bone marrow-d erived monocytic precursor cells suggest that this metalloprotease plays a prominent role in the activation of the Notch pathway.