The c-Cbl ubiquitin ligase regulates nuclear β-catenin and angiogenesis by its tyrosine phosphorylation mediated through the Wnt signaling pathway.

The Journal of Biological Chemistry
Sowmya ShivannaVipul Chitalia

Abstract

Wnt signaling plays important roles in both the tumor-induced angiogenesis and tumorigenesis through the transcriptionally active nuclear β-catenin. Recently, c-Cbl was identified as a unique E3 ubiquitin ligase targeting the active nuclear β-catenin. However, little is known about the molecular mechanisms by which c-Cbl regulates ubiquitination and degradation of active β-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 β-catenin. Tyr-731 phosphorylation and dimerization mediate c-Cbl nuclear translocation and lead to the degradation of nuclearly active β-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 β-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.

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Citations

May 28, 2019·Cells·Chimera L LyleVipul C Chitalia
Apr 11, 2017·Oxidative Medicine and Cellular Longevity·Li JiangDan Meng
Apr 5, 2020·Bulletin of Experimental Biology and Medicine·E S KolegovaI V Kondakova
Dec 21, 2018·Journal of the American Heart Association·Maulin M PatelCristina Lupu
Jan 21, 2021·Biomolecules·Dina Aweida, Shenhav Cohen
May 15, 2021·Frontiers in Cell and Developmental Biology·Kim KobarJason N Berman

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