Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases.
Smad4 mediates signaling by the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Smad signaling is negatively regulated by inhibitory (I) Smads and ubiquitin-mediated processes. Known mechanisms of proteasomal degradation of Smads depend on the direct interaction of specific E3 ligases with Smads. Alternatively, I-Smads elicit degradation of the TGF-beta receptor ... by recruiting the WW and HECT domain E3 ligases, Smurfs, WWP1, or NEDD4-2. We describe an equivalent mechanism of degradation of Smad4 by the above E3 ligases, via formation of ternary complexes between Smad4 and Smurfs, mediated by R-Smads (Smad2) or I-Smads (Smad6/7), acting as adaptors. Smurfs, which otherwise cannot directly bind to Smad4, mediated poly-ubiquitination of Smad4 in the presence of Smad6 or Smad7. Smad4 co-localized with Smad7 and Smurf1 primarily in the cytoplasm and in peripheral cell protrusions. Smad2 or Smad7 mutants defective in Smad4 interaction failed to induce Smurf1-mediated down-regulation of Smad4. A Smad4 mutant defective in Smad2 or Smad7 interaction could not be effectively down-regulated by Smurf1. We propose that Smad4 is targeted for degradation by multiple ubiquitin ligases that can simultaneously act on R-Smads and signaling receptors. Such mechanisms of down-regulation of TGF-beta signaling may be critical for proper physiological response to this pathway.
Mesh Terms:
Adenoviridae, Cell Line, Cytoplasm, DNA-Binding Proteins, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Genetic Vectors, Glutathione Transferase, Green Fluorescent Proteins, Humans, Microscopy, Fluorescence, Mutation, Plasmids, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Tertiary, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad2 Protein, Smad4 Protein, Smad7 Protein, Trans-Activators, Transfection, Transforming Growth Factor beta, Ubiquitin, Ubiquitin-Protein Ligases
Adenoviridae, Cell Line, Cytoplasm, DNA-Binding Proteins, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Genetic Vectors, Glutathione Transferase, Green Fluorescent Proteins, Humans, Microscopy, Fluorescence, Mutation, Plasmids, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Tertiary, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad2 Protein, Smad4 Protein, Smad7 Protein, Trans-Activators, Transfection, Transforming Growth Factor beta, Ubiquitin, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Jun. 10, 2005
PubMed ID: 15817471
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