title: Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling.
abstract: Notch signaling requires a series of proteolytic cleavage events to release the Notch intracellular domain (NICD) that functions directly in signal transduction. The Notch receptor is locked down in a protease-resistant state by a negative regulatory region (NRR) that protects an ADAM (a disintegrin and metalloprotease) cleavage site. Engagement with ligand-bearing cells induces global conformational movements in Notch that unfold the NRR structure to expose the ADAM cleavage site and initiate proteolytic activation. Although both ADAM10 and ADAM17 have been reported to cleave Notch to facilitate NICD release by gamma-secretase, the relevant ADAM has remained controversial. Our study provides new insight into this conflict, as we find that although Notch1 (N1) is a substrate for both ADAM10 and ADAM17, the particular ADAM required for receptor activation is context dependent. Specifically, ADAM10 was absolutely required for N1 signaling induced by ligands, while signaling independent of ligands required ADAM17. In contrast to the strict and differential use of ADAM10 and ADAM17 in normal and dysregulated signaling, respectively, both proteases participated in signaling intrinsic to N1 mutations associated with leukemia. We propose that in addition to exposing the ADAM cleavage site, activating N1 conformational changes facilitate selective cleavage by specific proteases.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA.
authors.forename: Esra Cagavi
authors.initials: EC
authors.lastname: Bozkulak
authors.forename: Gerry
authors.initials: G
authors.lastname: Weinmaster
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
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