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

Mei Wan, Yi Tang, Ewan M. Tytler, Chongyuan Lu, Bingwen Jin, Selwyn M. Vickers, Lei Yang, Xing Ming Shi, Xu Cao

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14484-14487
Number of pages4
JournalJournal of Biological Chemistry
Volume279
Issue number15
DOIs
StatePublished - Apr 9 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wan, M., Tang, Y., Tytler, E. M., Lu, C., Jin, B., Vickers, S. M., Yang, L., Shi, X. M., & Cao, X. (2004). Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1. Journal of Biological Chemistry, 279(15), 14484-14487. https://doi.org/10.1074/jbc.C400005200