c-Cbl, a ubiquitin E3 ligase that targets active β-catenin: a novel layer of Wnt signaling regulation

• Published in: The Journal of biological chemistry Vol. 288; no. 32; pp. 23505 - 23517
• Main Authors: Chitalia, Vipul, Shivanna, Sowmya, Martorell, Jordi, Meyer, Rosana, Edelman, Elazer, Rahimi, Nader
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 09.08.2013
• Subjects: Active Transport, Cell Nucleus - physiology; beta Catenin - genetics; beta Catenin - metabolism; Cell Biology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Proto-Oncogene Proteins c-cbl - genetics; Proto-Oncogene Proteins c-cbl - metabolism; Ubiquitination - physiology; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; Wnt Signaling Pathway - physiology; Gene Transcription; Wnt Signaling; Angiogenesis; Cancer Biology; Ubiquitin Ligase; Cbl; Dimerization
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.473801

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.