期刊
MOLECULAR PHARMACOLOGY
卷 73, 期 5, 页码 1356-1361出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.108.044990
关键词
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资金
- NHLBI NIH HHS [HL07605, HL071755, T32 HL007605, R01 HL071755] Funding Source: Medline
- NICHD NIH HHS [T32 HD007009] Funding Source: Medline
- NIGMS NIH HHS [R01 GM085058-01A1, R01 GM085058] Funding Source: Medline
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 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'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.
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