F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of 
E3 ubiquitin ligase SCF(FBW7) (a complex of SKP1, cullin-1 and FBW7), plays 
important roles in various physiological and pathological processes. Although 
FBW7 is required for vascular development, its function in the endothelium 
remains to be investigated. In this study, we show that FBW7 is an important 
regulator of endothelial functions, including angiogenesis, leukocyte adhesion 
and the endothelial barrier integrity. Using RNA interference, we found that the 
depletion of FBW7 markedly impairs angiogenesis in vitro and in vivo. We 
identified the zinc finger transcription factor Krüppel-like factor 2 (KLF2) as 
a physiological target of FBW7 in endothelial cells. Knockdown of FBW7 
expression resulted in the accumulation of endogenous KLF2 protein in 
endothelial cells. FBW7-mediated KLF2 destruction was shown to depend on the 
phosphorylation of KLF2 via glycogen synthase kinase-3 (GSK3) at two conserved 
phosphodegrons. Mutating these phosphodegron motifs abolished the FBW7-mediated 
degradation and ubiquitination of KLF2. The siRNA-mediated knockdown of FBW7 
showed that KLF2 is an essential target of FBW7 in the regulation of endothelial 
functions. Moreover, FBW7-mediated KLF2 degradation was shown to be critical for 
angiogenesis in teratomas and in zebrafish development. Taken together, our 
study suggests a role for FBW7 in the processes of endothelial cell migration, 
angiogenesis, inflammation and barrier integrity, and provides novel insights 
into the regulation of KLF2 stability in vivo.