Notch intracellular pathway. Interaction of Notch receptors with their ligands, such as Delta-like or Jagged, leads to a cascade of proteolytic cleavages. The truncated receptor is then the substrate for a multiprotein complex formed by presenilin, nicastrin, Aph1 and Pen-2 with γ-secretase activity that cleaves Notch within its transmembrane domain, thus leading to the release of the intracellular domain (Notch-IC or NICD).⁹⁹  The first cleavage (S2) is mediated by ADAM-type metalloproteases, called TACE (TNF-α converting enzyme) in vertebrates or Kuzbanian in Drosophila, followed by a further cleavage at S3 within the transmembrane domain mediated by γ-secretase activity of presenilins, which liberates the cytoplasmic domain-Notch intracellular domain. The free Notch-IC enters the nucleus and binds to the transcription factor CSL, which displaces corepressors (CoR) and recruits coactivators (CoA), leading to transcriptional activation of downstream target genes.