The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4 (NOTCH4 intracellular domain fragment), targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004). Notch4 level also increases when Fbxw7 is downregulated by RNA in mouse embryonic fibroblasts (Mao et al. 2004).