PathwayStep2823 PathwayStep2819 PathwayStep518 Notch 4-ligand complex is cleaved to produce NEXT4 PathwayStep5556 Notch 4 heterodimer binds with a Notch ligand in the extracellular space NEXT4 is cleaved to produce NICD4 NICD4 traffics to the nucleus Signaling by NOTCH4 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: Orlic-Milacic, M, 2012-02-10 GENE ONTOLOGYGO:0007219 Reactome Database ID Release 431980150 Reactome, http://www.reactome.org ReactomeREACT_118636 Reviewed: Joutel, A, 2004-12-15 Similar to NOTCH1, NOTCH4 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH4, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH4, NICD4, into the cytosol. NICD4 subsequently traffics to the nucleus where it acts as a transcriptional regulator.