Regulation of Smad-mediated gene transcription by RGS3.
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 G(q) and G(i) proteins by binding the corresponding Galpha 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's Mad homology 2 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. This translates to functional inhibition of TGF-beta-induced myofibroblast differentiation by RGS3. In conclusion, this study identifies a novel, noncanonical role of RGS3 in regulation of TGF-beta signaling through its interaction with Smads and interfering with Smad heteromerization.
Yau
Douglas M
DM
Section of Pulmonary and Critical Care Medicine, the University of Chicago Department of Medicine, 5841 S. Maryland Ave, MC 6076, Chicago, IL 60637, USA.
Sethakorn
Nan
N
Taurin
Sebastien
S
Kregel
Steven
S
Sandbo
Nathan
N
Camoretti-Mercado
Blanca
B
Sperling
Anne I
AI
Dulin
Nickolai O
NO
D000199:Actins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018076:DNA, Complementary; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D020710:RGS Proteins; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000199:Actins; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D020710:RGS Proteins; C485898:RGS3 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D019204:GTP-Binding Proteins