Laboratory of Biological Chemistry, Medical School, University of Ioannina, 45110 Ioannina, Greece.
J Cell Sci. 2011 Oct 1;124(Pt 19):3209-22. doi: 10.1242/jcs.062307. Epub 2011 Aug 30.
SARA, an early endosomal protein, plays a key role in TGFβ signalling, as it presents SMAD2 and SMAD3 for phosphorylation by the activated TGFβ receptors. Here, we show that ERBIN is a new SARA-interacting protein that can be recruited by SARA to early endosomes. ERBIN was recently shown to bind and segregate phosphorylated SMAD2 and SMAD3 (SMAD2/3) in the cytoplasm, thereby inhibiting SMAD2/3-dependent transcription. SARA binds to ERBIN using a new domain, which we have called the ERBID (ERBIN-binding domain), whereas ERBIN binds to SARA using a domain (amino acids 1208-1265) that also interacts with SMAD2 and SMAD3, which we have called the SSID (SARA- and SMAD-interacting domain). We additionally show that SARA competes with SMAD2/3 for binding to ERBIN. In agreement, overexpression of SARA or the ERBID peptide reverses the inhibitory effect of ERBIN on SMAD2/3-dependent transcription. Taken together, these data suggest that the response of cells to TGFβ and activin A can be influenced by the relative concentrations of SARA, ERBIN and SMAD2/3.
SARA 是一种早期内体蛋白，在 TGFβ 信号转导中发挥关键作用，因为它将 SMAD2 和 SMAD3 呈现给激活的 TGFβ 受体进行磷酸化。在这里，我们表明 ERBIN 是一种新的 SARA 相互作用蛋白，可以被 SARA 招募到早期内体。最近的研究表明，ERBIN 可以结合和分隔细胞质中磷酸化的 SMAD2 和 SMAD3（SMAD2/3），从而抑制 SMAD2/3 依赖性转录。SARA 使用我们称为 ERBID（ERBIN 结合结构域）的新结构域与 ERBIN 结合，而 ERBIN 使用与 SMAD2 和 SMAD3 相互作用的结构域（氨基酸 1208-1265）与 SARA 结合，我们称之为 SSID（SARA 和 SMAD 相互作用结构域）。我们还表明，SARA 与 ERBIN 竞争与 SMAD2/3 的结合。一致地，SARA 的过表达或 ERBID 肽的过表达逆转了 ERBIN 对 SMAD2/3 依赖性转录的抑制作用。总之，这些数据表明，细胞对 TGFβ 和激活素 A 的反应可以受到 SARA、ERBIN 和 SMAD2/3 的相对浓度的影响。
