Regulation of transforming growth factor-beta signaling by protein inhibitor of activated STAT, PIASy through Smad3

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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Published on: October 27, 2020

Seiyu Imoto1, Kenji Sugiyama, Ryuta Muromoto

  • 1Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.

The Journal of Biological Chemistry
|June 20, 2003
PubMed

Insights

Protein inhibitor of activated STAT, PIASy, interacts with Smad7 and Smad3, revealing a novel negative feedback loop in transforming growth factor-beta signaling. This interaction regulates TGF-beta pathway activity and Smad protein sumoylation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Smad proteins are crucial intracellular mediators of transforming growth factor-beta (TGF-beta) signaling.
  • Smad7 functions as a key antagonist in the TGF-beta signaling pathway, modulating its intensity and duration.
  • Understanding the regulation of TGF-beta signaling is vital due to its role in cellular processes like proliferation and differentiation.

Purpose of the Study:

  • To identify novel interaction partners of Smad7.
  • To investigate the role of PIASy in TGF-beta signaling regulation.
  • To elucidate the mechanism by which PIASy influences Smad protein activity.

Main Methods:

  • Yeast two-hybrid screening using the Smad7 MH2 domain to identify interacting proteins.
  • Co-immunoprecipitation assays with co-expressed tagged proteins in 293T cells to confirm interactions.
  • In vivo sumoylation assays and Western blotting to assess protein modification and expression levels.

Main Results:

  • PIASy was identified as a novel interaction partner of Smad7.
  • PIASy was shown to associate with Smad3 via its MH2 domain.
  • PIASy suppressed TGF-beta-mediated activation of Smad3 and stimulated Smad3 sumoylation in vivo.
  • TGF-beta treatment induced endogenous PIASy expression in Hep3B cells.

Conclusions:

  • PIASy interacts with Smad proteins, including Smad7 and Smad3.
  • PIASy plays a regulatory role in TGF-beta signaling through a negative feedback mechanism.
  • The findings highlight PIASy as a significant component in the intricate network of TGF-beta signal transduction.

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