PathwayStep516 PathwayStep515 PathwayStep518 PathwayStep517 Complex of NOTCH1 with its ligand is cleaved to produce NEXT1 Notch 2-ligand complex is cleaved to produce NEXT2 Notch 3-ligand complex is cleaved to produce NEXT3 Notch 4-ligand complex is cleaved to produce NEXT4 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor Authored: Jassal, B, 2004-12-17 11:53:55 GENE ONTOLOGYGO:0007220 Pubmed10693756 Pubmed10882062 Pubmed10882063 Reactome Database ID Release 43156988 Reactome, http://www.reactome.org ReactomeREACT_2001 Some transmembrane proteins such as the Notch receptor can be cleaved to release a cytosolic domain that translocates to the nucleus to control gene transcription. This is an example of a process called regulated intramembrane proteolysis (Rip). Rip is a control mechanism that is conserved from bacteria to humans and influences processes from cellular differentiation to lipid metabolism.<br>Once the ligand binds with the receptor, a proposed conformational change in the Notch receptor occurs which relieves an inhibition on the S2 protease cleavage site proximal to the plasma membrane. The S2 cleavage is catalyzed by an ADAM metalloprotease called TACE (TNF alpha converting enzyme). This enzyme is a homolog of the Drosophila Kuzbanian gene product which performs the same task. Cleavage at the S2 site generates a transient intermediate peptide termed NEXT (Notch EXtracellular Truncation). The remainder of the Notch receptor is still bound with the ligand at this point.