Department of Molecular & Cellular Biology, Texas A&M Health Sciences Center, Houston, Texas 77030, USA.
EMBO Rep. 2011 Oct 28;12(11):1175-81. doi: 10.1038/embor.2011.174.
Smad2 and Smad3 (Smad2/3) are essential signal transducers and transcription factors in the canonical transforming growth factor-β (TGF-β) signalling pathway. Active Smad2/3 signalling in the nucleus is terminated by dephosphorylation and subsequent nuclear export of Smad2/3. Here we report that protein phosphatase PPM1A regulates the nuclear export of Smad2/3 through targeting nuclear exporter RanBP3. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser 58 in vitro and in vivo. Consistently, RanBP3 phosphorylation was elevated in PPM1A-null mouse embryonic fibroblasts. Dephosphorylation of RanBP3 at Ser 58 promoted its ability to export Smad2/3 and terminate TGF-β responses. Our findings indicate the critical role of PPM1A in maximizing exporter activity of RanBP3 for efficient termination of canonical TGF-β signalling.
Smad2 和 Smad3（Smad2/3）是经典转化生长因子-β（TGF-β）信号通路中的必需信号转导蛋白和转录因子。Smad2/3 的活性信号在细胞核中通过磷酸化和随后的 Smad2/3 核输出而终止。在这里，我们报告蛋白磷酸酶 PPM1A 通过靶向核输出 RanBP3 来调节 Smad2/3 的核输出。PPM1A 在体外和体内均直接与核输出 RanBP3 相互作用，并使其第 58 位丝氨酸磷酸化。一致地，PPM1A 缺失的小鼠胚胎成纤维细胞中的 RanBP3 磷酸化水平升高。RanBP3 第 58 位丝氨酸的去磷酸化促进了其将 Smad2/3 输出并终止 TGF-β 反应的能力。我们的研究结果表明 PPM1A 在最大限度地提高 RanBP3 的输出活性以有效终止经典 TGF-β 信号转导方面起着关键作用。
