Abstract
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Cell Compartmentation / drug effects
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Embryo, Mammalian / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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HEK293 Cells
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Humans
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Leukemia / metabolism
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Leukemia / pathology
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Mice
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Molecular Sequence Data
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Mutation / genetics
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NEDD8 Protein
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NIH 3T3 Cells
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / metabolism*
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Proteolysis* / drug effects
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-cbl / chemistry
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction / drug effects
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Smad Proteins / metabolism
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Transforming Growth Factor beta / pharmacology
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Ubiquitination* / drug effects
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Ubiquitins / metabolism*
Substances
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MAS1 protein, human
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NEDD8 Protein
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NEDD8 protein, human
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Nedd8 protein, mouse
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Proto-Oncogene Mas
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta
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Ubiquitins
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Proto-Oncogene Proteins c-cbl
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II