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

Smads proteins play a key role in the intracellular signaling of the transforming growth factor (TGF)-beta family of growth factors, which exhibits a diverse set of cellular responses, including cell proliferation and differentiation. In particular, Smad7 acts as an antagonist of TGF-beta signaling, which could determine the intensity or duration ...
of its signaling cascade. In this study we identified a protein inhibitor of activated STAT (signal transducers and activators of transcription), PIASy, as a novel interaction partner of Smad7 by yeast two-hybrid screening using the MH2 domain of Smad7 as bait. The association of Smad7 and PIASy was confirmed using co-expressed tagged proteins in 293T cells. Moreover, we found that other Smads including Smad3 also associated with PIASy through its MH2 domain, and PIASy suppressed TGF-beta-mediated activation of Smad3. PIASy also stimulated the sumoylation of Smad3 in vivo. Furthermore, endogenous PIASy expression was induced by TGF-beta in Hep3B cells. These findings provide the first evidence that a PIAS family protein, PIASy, associates with Smads and involves the regulation of TGF-beta signaling using the negative feedback loop.
Mesh Terms:
Animals, Blotting, Northern, COS Cells, Carrier Proteins, Cell Differentiation, Cell Division, Cell Line, DNA-Binding Proteins, Fluorescent Antibody Technique, Indirect, Gene Expression Regulation, Humans, Immunoblotting, Intracellular Signaling Peptides and Proteins, Protein Binding, Protein Inhibitors of Activated STAT, Protein Structure, Tertiary, Recombinant Fusion Proteins, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, SUMO-1 Protein, Saccharomyces cerevisiae, Signal Transduction, Smad3 Protein, Smad6 Protein, Smad7 Protein, Time Factors, Trans-Activators, Transcription, Genetic, Transfection, Transforming Growth Factor beta, Tumor Cells, Cultured, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Sep. 05, 2003
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