Proteases of the ADAM (A disintegrin and metalloproteinase) family form a large group of metalloenzymes that function primarily to cleave (or shed) extracellular domains from plasma membrane bound signaling molecules. Whereas ADAM proteases are not thought to have strict cleavage site specificities, ADAM17 and ADAM10 have evolved distinct substrate preferences despite being the most closely related members of the family. ADAM17 is the principal sheddase of TNF-α and the majority of the EGFR-ligands (Blobel, 2005; Peschon et al., 1998), whereas ADAM10 is required for Notch and amyloid precursor protein (APP) shedding (Kuhn et al., 2010; van Tetering et al., 2009). The physiological importance of ADAM17 in EGFR-signaling is based on the striking phenotypic similarities between Adam17−/− and Egfr−/− mutant mice. Both die at birth due to multiple developmental defects involving the heart, lung, and skin (Blobel, 2005; Miettinen et al., 1995; Peschon et al., 1998).

Notch receptors are conserved membrane-anchored transcription regulators activated by proteolysis (Kopan and Ilagan, 2009; van Tetering and Vooijs, 2011). During maturation in the Golgi, Notch receptors are cleaved by furin-like convertases at site 1 (S1) located in a loop protruding from the negative regulatory region (NRR). When denatured for western blot analysis, the membrane–bound form of Notch1 (TMIC) migrates at~ 120 kDa. Ligand binding unfolds the Lin12-Notch repeat (LNR) module to expose and allow cleavage at