NEXT1 fragment of NOTCH1 is further cleaved at S3 by the presenilin-1 (PSEN1) containing gamma-secretase complex, which releases the intracellular domain NICD1 into the cytosol (Schroeter et al. 1998, De Strooper et al. 1999, Huppert et al. 2000, Fortini et al. 2002). PIN1, a prolyl isomerase, was recently found to bind phosphorylated Ser/Thr-Pro motifs in the cytoplasmic domain of NOTCH1 and potentiate NEXT1 cleavage by gamma-secretase. This generates a positive loop in NOTCH1 signaling since PIN1 is a transcriptional target of NICD1 (Rustighi et al. 2009).
|gamma-secretase complex||aspartic-type endopeptidase activity (0004190)|
|12209127||Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling||Nat Rev Mol Cell Biol||2002|
|10206645||A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain||Nature||1999|
|9620803||Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain||Nature||1998|
|10879540||Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1||Nature||2000|
|19151708||The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer||Nat Cell Biol||2009|