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.
- The Journal of biological chemistry 290(20): 12537-46 (Journal)
- Registered Authors
- Feng, Hui, Harrold, Itrat
- E3 ubiquitin ligase, Wnt signaling, angiogenesis, beta catenin, cbl, tumor cell biology, tumorigenesis, tumors, zebrafish
- MeSH Terms
- Amino Acid Substitution
- Cell Nucleus/genetics
- Cell Nucleus/metabolism
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/metabolism*
- Mutation, Missense
- Neovascularization, Physiologic/physiology*
- Protein Multimerization/physiology
- Proto-Oncogene Proteins c-cbl/genetics
- Proto-Oncogene Proteins c-cbl/metabolism*
- Wnt Signaling Pathway/physiology*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- beta Catenin/genetics
- beta Catenin/metabolism*
- 25784557 Full text @ J. Biol. Chem.
Shivanna, S., Harrold, I., Shashar, M., Meyer, R., Kiang, C., Francis, J., Zhao, Q., Feng, H., Edelman, E.R., Rahimi, N., Chitalia, V.C. (2015) c-Cbl regulates nuclear β-catenin and angiogenesis through its Wnt-mediated phosphorylation. The Journal of biological chemistry. 290(20):12537-46.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes