Model of the Notch signaling pathway. (a) The Notch signaling pathway is activated when a Notch ligand and a Notch receptor from adjacent cells bind to one another. (b) Binding of a Notch ligand and receptor initiates sequential cleavage steps, including extracellular ADAM protease followed by intracellular γ-secretase cleavage, of the Notch receptor. (c) An activated form of the receptor (NICD) is released and immediately translocates to the nucleus. (d) The NICD then binds to cofactors, including CSL, to initiate transcription of downstream targets, typically transcriptional repressors from the HES and HEY families. ADAM, a disintegrin and metalloprotease; CSL, CBF1/Suppressor of Hairless/LAG-1 family DNA-binding protein.