Murine Notch homologs (N1-4) undergo presenilin-dependent proteolysis

Oncogenic forms of Notch1, Notch2, and Notch4 appear to mimic signaling int ermediates of Notch1 and suggest that the role of proteolysis in Notch sign aling has been conserved. Here we demonstrate that extracellularly truncate d Notch homologs are substrates for a presenilin-dependent gamma -secretase activity. Despite minimal conservation within the transmembrane domain, th e requirement for a specific amino acid (P1' valine) and its position at th e cleavage site relative to the cytosolic border of the transmembrane domai n are preserved. Cleaved, untethered Notch intracellular domains from each receptor translocate to the nucleus and interact with the transcriptional r egulatory protein CSL. All four Notch proteins display presenilin-dependent transactivating potential on a minimal promoter reporter. Thus, this study increases the number of biochemically characterized gamma -secretase subst rates from two to five. Despite a high degree of structural homology and th e presenilin-dependent activity of truncated Notch proteins, the extent tha t this reflects functional redundancy is unknown.