title: c-Cbl, a ubiquitin E3 ligase that targets active β-catenin: a novel layer of Wnt signaling regulation.
abstract: Regulation of transcriptionally active nuclear β-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 β-catenin during the Wnt-off phase, but little is known about the fate of active nuclear β-catenin in the Wnt-on phase. We now describe ubiquitination of active β-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 β-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 β-catenin. Deletion of the c-Cbl UBA domain abrogates its dimerization, binding to β-catenin, Wnt-induced c-Cbl nuclear translocation, and ubiquitination of nuclear β-catenin. c-Cbl activity inhibits pro-angiogenic Wnt targets IL-8 and VEGF levels and angiogenesis in a β-catenin-dependent manner. This study defines for the first time c-Cbl as a ubiquitin E3 ligase that targets nuclearly active β-catenin in the Wnt-on phase and uncovers a novel layer of regulation of Wnt signaling.
authors.affiliation: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA. vichital@bu.edu
authors.forename: Vipul
authors.initials: V
authors.lastname: Chitalia
authors.forename: Sowmya
authors.initials: S
authors.lastname: Shivanna
authors.forename: Jordi
authors.initials: J
authors.lastname: Martorell
authors.forename: Rosana
authors.initials: R
authors.lastname: Meyer
authors.forename: Elazer
authors.initials: E
authors.lastname: Edelman
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
keywords: Angiogenesis; Cancer Biology; Cbl; Dimerization; Gene Transcription; Ubiquitin Ligase; Wnt Signaling