ZFIN ID: ZDB-PUB-150319-4
c-Cbl regulates nuclear β-catenin and angiogenesis through its Wnt-mediated phosphorylation
Shivanna, S., Harrold, I., Shashar, M., Meyer, R., Kiang, C., Francis, J., Zhao, Q., Feng, H., Edelman, E.R., Rahimi, N., Chitalia, V.C.
Date: 2015
Source: The Journal of biological chemistry   290(20): 12537-46 (Journal)
Registered Authors: Feng, Hui, Harrold, Itrat
Keywords: E3 ubiquitin ligase, Wnt signaling, angiogenesis, beta catenin, cbl, tumor cell biology, tumorigenesis, tumors, zebrafish
MeSH Terms:
  • Amino Acid Substitution
  • Animals
  • Cell Nucleus/genetics
  • Cell Nucleus/metabolism
  • Human Umbilical Vein Endothelial Cells/cytology
  • Human Umbilical Vein Endothelial Cells/metabolism*
  • Humans
  • Mutation, Missense
  • Neovascularization, Physiologic/physiology*
  • Phosphorylation/physiology
  • Protein Multimerization/physiology
  • Proteolysis
  • Proto-Oncogene Proteins c-cbl/genetics
  • Proto-Oncogene Proteins c-cbl/metabolism*
  • Wnt Signaling Pathway/physiology*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • beta Catenin/genetics
  • beta Catenin/metabolism*
PubMed: 25784557 Full text @ J. Biol. Chem.
Wnt signaling plays important roles in both the tumor-induced angiogenesis and tumorigenesis through the transcriptionally active nuclear beta catenin. Recently, c-Cbl was identified as a unique E3 ubiquitin ligase targeting the active nuclear beta catenin. However, little is known about the molecular mechanisms by which c-Cbl regulates ubiquitination and degradation of active beta catenin. Here we demonstrate that Wnt activation promotes the phosphorylation of c-Cbl at tyrosine 731(Y731), which increases c-Cbl dimerization and binding to beta catenin. Y731 phosphorylation and dimerization mediates c-Cbl nuclear translocation and leads to the degradation of nuclear active beta catenin in Wnt-on phase. c-Cbl activation also inhibits expression of the pro-angiogenic Wnt targets, IL-8 and VEGF. Phospho-Y731-inactive mutant c-Cbl (Y731F) enhances, whereas phosphomimetic mutant c-Cbl, (Y731E) suppresses angiogenesis in zebrafish. Taken together, we have identified a novel mechanism for the regulation of active nuclear beta 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.