c-Cbl, a Ubiquitin E3 Ligase That Targets Active β-Catenin A NOVEL LAYER OF Wnt SIGNALING REGULATION

Regulation of transcriptionally active nuclear beta-catenin during the Wnt-on phase is crucial to ensure controlled induction of Wnt target genes. Several ubiquitin E3 ligases are known to regulate cytosolic beta-catenin during the Wnt-off phase, but little is known about the fate of active nuclear beta-catenin in the Wnt-on phase. We now describe ubiquitination of active beta-catenin in the Wnt-on phase by a RING finger ubiquitin E3 ligase, Casitas B-lineage lymphoma (c-Cbl) in endothelial cells. c-Cbl binds preferentially to nuclearly active beta-catenin in the Wnt-on phase via the armadillo repeat region. Wild-type c-Cbl suppresses and E3 ligase-deficient c-Cbl-70Z increases Wnt signaling. Wnt induces nuclear translocation of c-Cbl where it ubiquitinates nuclear beta-catenin. Deletion of the c-Cbl UBA domain abrogates its dimerization, binding to beta-catenin, Wnt-induced c-Cbl nuclear translocation, and ubiquitination of nuclear beta-catenin. c-Cbl activity inhibits pro-angiogenic Wnt targets IL-8 and VEGF levels and angiogenesis in a beta-catenin-dependent manner. This study defines for the first time c-Cbl as a ubiquitin E3 ligase that targets nuclearly active beta-catenin in the Wnt-on phase and uncovers a novel layer of regulation of Wnt signaling.