| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Francis, Jean Zhao, Qing Meyer, Rosanna Harrold, Itrat Kiang, Chrystelle Edelman, Elazer R. Feng, Hui Chitalia, Vipul C. Rahimi, Nader Shivanna, Sowmya Shashar, Moshe |
| Description |
Author Affiliation: Shivanna S ( From the Renal Section, Department of Medicine.); Harrold I ( Section of Hematology and Medical Oncology, Departments of Pharmacology and Medicine, and.); Shashar M ( From the Renal Section, Department of Medicine.); Meyer R ( the Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.); Kiang C ( 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.); Francis J ( From the Renal Section, Department of Medicine.); Zhao Q ( the Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.); Feng H ( Section of Hematology and Medical Oncology, Departments of Pharmacology and Medicine, and.); Edelman ER ( 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.); Rahimi N ( the Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.); Chitalia VC ( From the Renal Section, Department of Medicine, vichital@bu.edu.) |
| Abstract |
Wnt signaling plays important roles in both the tumor-induced angiogenesis and tumorigenesis through the transcriptionally active nuclear ß-catenin. Recently, c-Cbl was identified as a unique E3 ubiquitin ligase targeting the active nuclear ß-catenin. However, little is known about the molecular mechanisms by which c-Cbl regulates ubiquitination and degradation of active ß-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 ß-catenin. Tyr-731 phosphorylation and dimerization mediate c-Cbl nuclear translocation and lead to the degradation of nuclearly active ß-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 ß-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. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
20 |
| Volume Number |
290 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2015-05-15 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Human Umbilical Vein Endothelial Cells Metabolism Neovascularization, Physiologic Physiology Proto-Oncogene Proteins C-cbl Wnt Signaling Pathway Zebrafish Proteins Zebrafish Beta Catenin Amino Acid Substitution Animals Cell Nucleus Genetics Cytology Mutation, Missense Phosphorylation Protein Multimerization Proteolysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
