| First Author | Zuo W | Year | 2013 |
| Journal | Mol Cell | Volume | 49 |
| Issue | 3 | Pages | 499-510 |
| PubMed ID | 23290524 | Mgi Jnum | J:195089 |
| Mgi Id | MGI:5476409 | Doi | 10.1016/j.molcel.2012.12.002 |
| Citation | Zuo W, et al. (2013) c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-beta type II receptor. Mol Cell 49(3):499-510 |
| abstractText | Transforming growth factor beta (TGF-beta) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-beta signaling is associated with the development of many cancers, including leukemia, though the molecular mechanisms are largely unclear. Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-beta signaling by neddylating and stabilizing the type II receptor (TbetaRII). Knockout of c-Cbl decreases the TbetaRII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-beta stimulation, while c-Cbl overexpression stabilizes TbetaRII and sensitizes leukemia cells to TGF-beta. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to TbetaRII at Lys556 and Lys567. Neddylation of TbetaRII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting TbetaRII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant TbetaRII neddylation and leukemia development. |
