Pin1 down-regulates transforming growth factor-β (TGF-β) signaling by inducing degradation of Smad proteins

Ayako Nakano, Daizo Koinuma, Keiji Miyazawa, Takafumi Uchida, Masao Saitoh, Masahiro Kawabata, Jun Ichi Hanai, Hirotada Akiyama, Masahiro Abe, Kohel Miyazono, Toshio Matsumoto, Takeshi Imamura

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

Transforming growth factor-β (TGF-β) is crucial in numerous cellular processes, such as proliferation, differentiation, migration, and apoptosis. TGF-β signaling is transduced by intracellular Smad proteins that are regulated by the ubiquitin-proteasome system. Smad ubiquitin regulatory factor 2 (Smurf2) prevents TGF-β and bone morphogenetic protein signaling by interacting with Smads and inducing their ubiquitin-mediated degradation. Here we identified Pin1, a peptidylprolyl cis-trans isomerase, as a novel protein binding Smads. Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. Pin1 reduced Smad2/3 protein levels in a manner dependent on its peptidyl-prolyl cis-trans isomerase activity. Knockdown of Pin1 increased the protein levels of endogenous Smad2/3. In addition, Pin1 both enhanced the interaction of Smurf2 with Smads and enhanced Smad ubiquitination. Pin1 inhibited TGF-β-induced transcription and gene expression, suggesting that Pin1 negatively regulates TGF-β signaling by down-regulating Smad2/3 protein levels via induction of Smurf2-mediated ubiquitin-proteasomal degradation.

Original languageEnglish
Pages (from-to)6109-6115
Number of pages7
JournalJournal of Biological Chemistry
Volume284
Issue number10
DOIs
Publication statusPublished - 2009 Mar 6

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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