期刊
CELL RESEARCH
卷 23, 期 6, 页码 803-819出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2013.42
关键词
angiogenesis; FBW7; KLF2; ubiquitin; degradation; cell migration
类别
资金
- National Basic Research Program of China (973 program) [2010CB529704, 2012CB910404, 2013CB910900]
- National Natural Science Foundation of China [30800587, 30971521, 31171338, 31222037]
- Science and Technology Commission of Shanghai Municipality [11DZ2260300]
- Program for New Century Excellent Talents in University [NCET-10-0387]
- Shanghai Rising-Star Program from Science and Technology Commission of Shanghai Municipality [09QA1401900]
- Dawn Program of Shanghai Education Commission [11SG27]
F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCFFBW7 (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 Kruppel-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.
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