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 Citations (Scopus)

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

Fingerprint

Smad4 Protein
SKP Cullin F-Box Protein Ligases
Protein Stability
Transforming Growth Factors
Ubiquitin-Protein Ligases
Receptor-Regulated Smad Proteins
Degradation
Cells
F-Box Proteins
Ubiquitination
Gene Silencing
Ubiquitin
Cell Cycle Checkpoints
Yeast
Small Interfering RNA
Proteolysis
Tumors
Intercellular Signaling Peptides and Proteins
Genes
Yeasts

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., ... 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

Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1 . / Wan, Mei; Tang, Yi; Tytler, Ewan M.; Lu, Chongyuan; Jin, Bingwen; Vickers, Selwyn M.; Yang, Lei; Shi, Xing Ming; Cao, Xu.

In: Journal of Biological Chemistry, Vol. 279, No. 15, 09.04.2004, p. 14484-14487.

Research output: Contribution to journalArticle

Wan, M, Tang, Y, Tytler, EM, Lu, C, Jin, B, Vickers, SM, Yang, L, Shi, XM & Cao, X 2004, 'Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1 ', Journal of Biological Chemistry, vol. 279, no. 15, pp. 14484-14487. https://doi.org/10.1074/jbc.C400005200
Wan, Mei ; Tang, Yi ; Tytler, Ewan M. ; Lu, Chongyuan ; Jin, Bingwen ; Vickers, Selwyn M. ; Yang, Lei ; Shi, Xing Ming ; Cao, Xu. / Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1 In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 15. pp. 14484-14487.
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