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

• Published in: Molecular cell 2013-02, Vol.49 (3), p.499-510
• Main Authors: Zuo, Wei, Huang, Fei, Chiang, Y. Jeffrey, Li, Meng, Du, Jun, Ding, Yi, Zhang, Ting, Lee, Hyuk Woo, Jeong, Lak Shin, Chen, Yuling, Deng, Haiteng, Feng, Xin-Hua, Luo, Shiwen, Gao, Chunji, Chen, Ye-Guang
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Cell Compartmentation - drug effects; Cell Membrane - drug effects; Cell Membrane - metabolism; Embryo, Mammalian - cytology; endocytosis; endosomes; Fibroblasts - drug effects; Fibroblasts - metabolism; HEK293 Cells; Humans; leukemia; Leukemia - metabolism; Leukemia - pathology; lymphoma; Mice; Molecular Sequence Data; mutation; Mutation - genetics; NEDD8 Protein; neoplasm cells; NIH 3T3 Cells; patients; Protein Binding - drug effects; Protein-Serine-Threonine Kinases - metabolism; Proteolysis - drug effects; Proto-Oncogene Proteins c-cbl - chemistry; Proto-Oncogene Proteins c-cbl - genetics; Proto-Oncogene Proteins c-cbl - metabolism; proto-oncogenes; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction - drug effects; Smad Proteins - metabolism; stem cells; transforming growth factor beta; Transforming Growth Factor beta - pharmacology; ubiquitin-protein ligase; ubiquitination; Ubiquitination - drug effects; Ubiquitins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.12.002

Transforming growth factor β (TGF-β) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-β 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-β signaling by neddylating and stabilizing the type II receptor (TβRII). Knockout of c-Cbl decreases the TβRII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-β stimulation, while c-Cbl overexpression stabilizes TβRII and sensitizes leukemia cells to TGF-β. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to TβRII at Lys556 and Lys567. Neddylation of TβRII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting TβRII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant TβRII neddylation and leukemia development. [Display omitted] ► c-Cbl is a NEDD8 E3 ligase of TβRII ► c-Cbl neddylates TβRII at Lys556 and Lys567 ► Neddylation stabilizes TβRII by regulating receptor endocytic routes ► Aberrant neddylation of TβRII is associated with leukemia