title: The c-Cbl ubiquitin ligase regulates nuclear β-catenin and angiogenesis by its tyrosine phosphorylation mediated through the Wnt signaling pathway.
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.
authors.affiliation: From the Renal Section, Department of Medicine.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Shivanna
authors.affiliation: Section of Hematology and Medical Oncology, Departments of Pharmacology and Medicine, and.
authors.forename: Itrat
authors.initials: I
authors.lastname: Harrold
authors.affiliation: From the Renal Section, Department of Medicine.
authors.forename: Moshe
authors.initials: M
authors.lastname: Shashar
authors.affiliation: the Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Meyer
authors.affiliation: the Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Kiang
authors.affiliation: From the Renal Section, Department of Medicine.
authors.forename: Jean
authors.initials: J
authors.lastname: Francis
authors.affiliation: the Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Section of Hematology and Medical Oncology, Departments of Pharmacology and Medicine, and.
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.affiliation: the Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
authors.affiliation: the Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
authors.affiliation: From the Renal Section, Department of Medicine, vichital@bu.edu.
authors.forename: Vipul C
authors.initials: VC
authors.lastname: Chitalia
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; D051176:beta Catenin; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
keywords: Angiogenesis; Cbl; E3 Ubiquitin Ligase; Tumor Cell Biology; Tumorigenesis; Tumors; Wnt Signaling; Zebrafish; β-Catenin