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251,252 In the canonical cascade, ligand binding (e.g., Jagged1/2, DLL1/3/4) to Notch receptors (Notch14) induces a two-step proteolytic cleavage, culminating in the release of the Notch intracellular domain (NICD), a cleaved cytoplasmic signaling domain that mediates intracellular signal transduction, by -secretase