Once bound to FBXW7, phosphorylated NICD1 is ubiquitinated, which leads to degradation of NICD1 and downregulation of NOTCH1 signaling. FBXW7-mediated ubiquitination and degradation of NOTCH1 depend on the C-terminally located PEST domain of NOTCH1 (Fryer et al. 2004, Oberg et al. 2001, Wu et al. 2001). The PEST domain in NOTCH1 and the substrate binding WD40 domain in FBXW7 are frequent targets of mutations in T-cell acute lymphoblastic leukemia - T-ALL (Welcker and Clurman 2008).