Received for publication January 4, 2008.
Revised February 19, 2008.
Accepted for publication February 19, 2008.

Regulation of Smad-mediated gene transcription by RGS3

Abstract

Regulator of G protein signaling (RGS) proteins are united into a family by the presence of the homologous RGS domain that binds the alpha 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 G-alpha 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-beta (TGF-beta) receptor signaling. This interaction is mediated by the region of RGS3 outside of the RGS domain, and by Smad' Mad homology 2 (MH2) domain. Overexpression of RGS3 results in inhibition of Smad-mediated gene transcription. RGS3 does not affect TGF-beta - induced Smad phosphorylation, but it prevents heteromerization of Smad3 with Smad4 which is required for transcriptional activity of Smads. Fuctionally, this translates to inhibition of TGF-beta - induced myofibroblast differentiation by RGS3. In conclusion, this study identifies a novel, non-canonical role of RGS3 in regulation of TGF-beta signaling through its interaction with Smads and interfering with Smad heteromerization.

Key words: Gi family, Gq/11 family, G protein regulation, RGS proteins