Volume 23, No 6, Jun 2013
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 23 Issue 6, June 2013: 803-819
ORIGINAL ARTICLES
FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation
Rui Wang1,3,*, Yan Wang1,*, Ning Liu1,4,*, Chunguang Ren2,*, Cong Jiang1, Kai Zhang1, Su Yu1, Yunfei Chen1, Hui Tang1, Qi Deng1, Cong Fu2, Yingcong Wang1, Rong Li1, Mingyao Liu1, Weijun Pan2 and Ping Wang1
1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
2Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China
3College of Pharmacy, Liaocheng University, Liaocheng, Shandong 252059, China
4Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China
Correspondence:
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 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.
10.1038/cr.2013.42
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