Ligand-mediated activation of Notch signaling. Notch expressed on the cell surface as a heterodimer is the mature, ligand-accessible form of the receptor. In the absence of ligand binding, heterodimeric Notch receptors are inactive. When Notch ligand binds to Notch receptor on an adjacent cell, a series of proteolytic cleavages occurs (referred to as S2 and S3 cleavages), resulting in release of the Notch intracellular domain (NotchIC) that subsequently translocates into the nucleus. In the absence of nuclear NotchIC, the transcription factor CBF1 binds to the DNA sequence 5′-(C/T)GTGGGAA-3′ within Notch target gene promoters and represses transcription. When Notch signaling is activated, nuclear NotchIC binds to CBF1 and, following recruitment of the nuclear protein MAML, results in the formation of a ternary complex that functions as a transcriptional activator. MAML recruits the histone acetyltransferase protein p300, resulting in histone acetylation and conversion of the local chromatin structure to a form amenable to active transcription, resulting in transcription of various Notch target genes including those belonging to the HES and HRT (HEY) families.