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The Notch pathway is a contact-dependent signaling pathway that controls cell-fate decisions, differentiation, proliferation, and tissue patterning through interactions between membrane-bound Notch receptors and membrane-bound ligands on neighboring cells. Canonical Notch signaling is activated when ligand engagement triggers proteolytic release of the Notch intracellular domain, which enters the nucleus and regulates transcription together with DNA-binding transcriptional complexes. In the canonical mechanism, ligand-dependent Notch activation leads to release of the intracellular Notch domain, and presenilin-dependent γ-secretase activity is required for production of the active intracellular signaling fragment. The released intracellular domain functions as a nuclear signal that converts Notch receptor activation at the membrane into transcriptional regulation of target programs such as HES/HEY-family genes and other context-dependent downstream targets. The literature links Notch p