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).