Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype

Constance E. Runyan*, Tomoko Hayashida, Susan Hubchak, Jessica F. Curley, H. William Schnaper

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

By inducing epithelial-to-mesenchymal transition (EMT), transforming growth factor-β (TGF-β) promotes cancer progression and fibrosis. Here we show that expression of the TGF-β receptor-associated protein, SARA (Smad anchor for receptor activation), decreases within 72 h of exposure to TGF-β and that this decline is both required and sufficient for the induction of several markers of EMT. It has been suggested recently that expression of the TGF-β signaling mediators, Smad2 and Smad3, may have different functional effects, with Smad2 loss being more permissive for EMT progression. We find that the loss of SARA expression leads to a concomitant decrease in Smad2 expression and a disruption of Smad2-specific transcriptional activity, with no effect on Smad3 signaling or expression. Further, the effects of inducing the loss of Smad2 mimic those of the loss of SARA, enhancing expression of the EMT marker, smooth muscle α-actin. Smad2 mRNA levels are not affected by the loss of SARA. However, the ubiquitination of Smad2 is increased in SARA-deficient cells. We therefore examined the E3 ubiquitin ligase Smurf2 and found that although Smurf2 expression was unaltered in SARA-deficient cells, the interaction of Smad2 and Smurf2 was enhanced. These results describe a significant role for SARA in regulating cell phenotype and suggest that its effects are mediated through modification of the balance between Smad2 and Smad3 signaling. In part, this is achieved by enhancing the association of Smad2 with Smurf2, leading to Smad2 degradation.

Original languageEnglish (US)
Pages (from-to)25181-25189
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number37
DOIs
StatePublished - Sep 11 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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