c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor

Mol Cell. 2013 Feb 7;49(3):499-510. doi: 10.1016/j.molcel.2012.12.002. Epub 2013 Jan 1.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Compartmentation / drug effects
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Embryo, Mammalian / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Leukemia / metabolism
  • Leukemia / pathology
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics
  • NEDD8 Protein
  • NIH 3T3 Cells
  • 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*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Ubiquitination* / drug effects
  • Ubiquitins / metabolism*

Substances

  • NEDD8 Protein
  • NEDD8 protein, human
  • Nedd8 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta
  • Ubiquitins
  • Proto-Oncogene Proteins c-cbl
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II