c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Base Sequence, Cell Compartmentation, Cell Membrane, Embryo, Mammalian, Fibroblasts, HEK293 Cells, Humans, Leukemia, Mice, Molecular Sequence Data, Mutation, NIH 3T3 Cells, Protein Binding, Protein-Serine-Threonine Kinases, Proteolysis, Proto-Oncogene Proteins c-cbl, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Ubiquitination, Ubiquitins
Amino Acid Sequence, Animals, Base Sequence, Cell Compartmentation, Cell Membrane, Embryo, Mammalian, Fibroblasts, HEK293 Cells, Humans, Leukemia, Mice, Molecular Sequence Data, Mutation, NIH 3T3 Cells, Protein Binding, Protein-Serine-Threonine Kinases, Proteolysis, Proto-Oncogene Proteins c-cbl, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Ubiquitination, Ubiquitins
Mol. Cell
Date: Feb. 07, 2013
PubMed ID: 23290524
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