FBXW7 in the NOTCH1 pathway. (A) Under physiological conditions, upon binding with its ligand, NOTCH1 signaling is initiated by a series of proteolytic cleavages of the NOTCH1 receptor that lead to the translocation of the NICD into the nucleus. In the nucleus, NICD recruits RPBJ transcription factor and other coactivators to create an activation complex and to modify the expression of a number of target genes. FBXW7 promotes proteasomal degradation of NICD to limit NOTCH1 signaling. (B) If FBXW7 harbors mutations disrupting its ubiquitin ligase function, then NICD is prevented from being degraded and accumulates in the nucleus thereby sustaining NOTCH1 target gene expression. Professional illustration by Patrick Lane, ScEYEnce Studios.