Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1

Academic Article


  • Smad4 is a key intracellular mediator for the transforming growth factor-β (TGF-β) superfamily of growth factors and is also an important tumor suppressor. The receptor-regulated Smad (R-Smad) proteins are regulated by ubiquitin-mediated degradation, yet the precise control of Smad4 protein stability is unclear. We have identified SCFβ-TrCP1, a ubiquitin (E3) ligase, as a critical determinant for the protein degradation of Smad4 protein. F-box protein β-TrCP1 in this E3 ligase interacts with Smad4 both in yeast and in mammalian cells, but has no interaction with Smad2 and has weak interaction with Smad3. The β-TrCP1/Smad3 interaction was abolished by Smad4 gene silencing, indicating the interaction is indirect and is through Smad4. Ectopic expression of SCF complex containing β-TrCP1 is sufficient to induce the ubiquitination and degradation of Smad4. Furthermore, small interfering RNA-triggered endogenous β-TrCP1 suppression increases the expression of Smad4 protein. Consistent with these results, cells that overexpress the SCF complex display an inhibited TGF-β-dependent transcriptional activity and an impaired cell cycle arrest function. Thus, SCFβ-TrCP1 abrogates TGF-β function in vivo by decreasing Smad4 stability.
  • Published In

    Digital Object Identifier (doi)

    Pubmed Id

  • 18931552
  • Author List

  • Wan M; Tang Y; Tytler EM; Lu C; Jin B; Vickers SM; Yang L; Shi X; Cao X
  • Start Page

  • 14484
  • End Page

  • 14487
  • Volume

  • 279
  • Issue

  • 15