期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 20, 页码 12537-12546出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.616623
关键词
-
资金
- National Institutes of Health from NCI [RO1 CA175382]
- NHLBI [R01 GM49039, CA191970, R01EY017955, T32 HL007501]
- American Cancer Society [IRG-72-001-36]
- Sharon Anderson American Society of Nephrology Fellowship Award
- [R00CA134743]
Wnt signaling plays important roles in both the tumor-induced angiogenesis and tumorigenesis through the transcriptionally active nuclear beta-catenin. Recently, c-Cbl was identified as a unique E3 ubiquitin ligase targeting the active nuclear beta-catenin. However, little is known about the molecular mechanisms by which c-Cbl regulates ubiquitination and degradation of active beta-catenin. Here, we demonstrate that Wnt activation promotes the phosphorylation of c-Cbl at tyrosine 731(Tyr-731), which increases c-Cbl dimerization and binding to beta-catenin. Tyr-731 phosphorylation and dimerization mediate c-Cbl nuclear translocation and lead to the degradation of nuclearly active beta-catenin in the Wnt-on phase. c-Cbl activation also inhibits expression of the pro-angiogenic Wnt targets, IL-8 and VEGF. Phospho-Tyr-731-inactive mutant c-Cbl (Y731F) enhances and phosphomimetic mutant c-Cbl (Y731E) suppresses angiogenesis in zebrafish. Taken together, we have identified a novel mechanism for the regulation of active nuclear beta-catenin by c-Cbl and its critical role in angiogenesis. This mechanism can be further explored to modulate both the pathological angiogenesis and the tumorigenesis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据