Figure 1.

A model for SCF^FBW7-mediated KLF2 degradation to regulate endothelial functions. Tumor suppressor FBW7 is a substrate-recognizing subunit of SCF E3 ubiquitin ligase and promotes degradation of a) oncoproteins to regulate proliferation and survival; b) NF1 to modulate endothelial differentiation; and c) MED13/MED13L to regulate transcription. A new study reported in this issue of Cell Research revealed that KLF2, a transcription factor that negatively regulates endothelial functions, is also a substrate of SCF^FBW7 E3 ligase. Upon phosphorylation by GSK3 and likely other kinases under an undefined physiological trigger(s), KLF2 is recognized by FBW7 via two CPD motifs. Dimerization of SCF^FBW7 E3 ligase promotes KLF2 ubiquitylation and subsequent degradation by the 26S proteasome. Thus, by targeted degradation of KLF2, SCF^FBW7 activates endothelial functions, including migration, angiogenesis and the maintenance of endothelial barrier integrity.