Regulator of G protein signaling (RGS) proteins are united into a family by the presence of the homologous RGS domain that binds the a subunits of heterotrimeric G proteins and accelerates their GTPase activity. A member of this family, RGS3 regulates the signaling mediated by Gq and Gi proteins by binding the corresponding Ga subunits. Here we show that RGS3 interacts with the novel partners Smad2, Smad3, and Smad4—the transcription factors that are activated through a transforming growth factor-ß (TGF-ß) receptor signaling. This interaction is mediated by the region of RGS3 outside of the RGS domain and by Smad's Mad homology 2 domain. Overexpression of RGS3 results in inhibition of Smad-mediated gene transcription. RGS3 does not affect TGF-ß-induced Smad phosphorylation, but it prevents heteromerization of Smad3 with Smad4, which is required for transcriptional activity of Smads. This translates to functional inhibition of TGF-ß-induced myofibroblast differentiation by RGS3. In conclusion, this study identifies a novel, noncanonical role of RGS3 in regulation of TGF-ß signaling through its interaction with Smads and interfering with Smad heteromerization.

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