c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor

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 (T beta RII). Knockout of c-Cbl decreases the T beta RII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-beta stimulation, while c-Cbl overexpression stabilizes T beta RII and sensitizes leukemia cells to TGF-beta. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to T beta RII at Lys556 and Lys567. Neddylation of T beta RII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting T beta RII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant T beta RII neddylation and leukemia development.