C-Cbl, a ubiquitin E3 ligase that targets active ?-catenin: a novel layer of Wnt signaling regulation.

ABSTRACT: Regulation of transcriptionally active nuclear ?-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 ?-catenin during the Wnt-off phase, but little is known about the fate of active nuclear ?-catenin in the Wnt-on phase. We now describe ubiquitination of active ?-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 ?-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 ?-catenin. Deletion of the c-Cbl UBA domain abrogates its dimerization, binding to ?-catenin, Wnt-induced c-Cbl nuclear translocation, and ubiquitination of nuclear ?-catenin. c-Cbl activity inhibits pro-angiogenic Wnt targets IL-8 and VEGF levels and angiogenesis in a ?-catenin-dependent manner. This study defines for the first time c-Cbl as a ubiquitin E3 ligase that targets nuclearly active ?-catenin in the Wnt-on phase and uncovers a novel layer of regulation of Wnt signaling.

SUBMITTER: Chitalia V 

PROVIDER: S-EPMC4772756 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature