Erbin inhibits transforming growth factor β signaling through a novel Smad-interacting domain
Erbin inhibits transforming growth factor β signaling through a novel Smad-interacting domain
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DOI：
10.1128/mcb.00132-07
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发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Feng, Xin-Hua
中科院分区：
文献类型：
--
作者：
Dai, Fangyan;Chang, Chenbei;Feng, Xin-Hua
Smad蛋白是转化生长因子β超家族的重要细胞内信号调节因子。在这里，我们报告了Erbin(即“ErbB2/Her2相互作用蛋白”)，它包含一个富含亮氨酸重复序列和一个PDZ(PSD-95/DLG/ZO-1)结构域，它与Smad3特异地相互作用，在较小程度上，通过与其PDZ结构域相邻的一个新的Smad相互作用结构域(SID)与Smad2相互作用。Erbin的表达增加并不影响转化生长因子β诱导的Smad2/Smad3的磷酸化水平，但它物理上隔离了Smad2/Smad3与Smad4的关联，从而负面调节了转化生长因子β依赖的转录反应和细胞生长抑制。在人体组织中，由选择性剪接转录本编码的Erbin的一种异构体缺乏这种SID，并且无法抑制转化生长因子β反应。一以贯之，用短发夹状RNA敲除内源性Erbin基因可以增强转化生长因子β诱导的抗增殖和转录反应。此外，Erbin抑制激活素/Smad2依赖的内源基因表达，但不抑制BMP/Smad1介导的内源基因表达。因此，这些结果将Erbin定义为一种新的Smad2/Smad3功能的负调控因子，并扩展了Erbin在调节转化生长因子β信号中的生理作用。
Smad proteins are critical intracellular signaling mediators for the transforming growth factor beta (TGF beta) superfamily. Here, we report that Erbin (for "ErbB2/Her2-interacting protein"), which contains leucine-rich repeats and a PDZ (PSD-95/DLG/ZO-1) domain, interacts specifically with Smad3 and, to a lesser extent, with Smad2 through a novel Smad-interacting domain (SID) adjacent to its PDZ domain. Increased expression of Erbin does not affect the level of TGF beta-induced phosphorylation of Smad2/Smad3, but it physically sequesters Smad2/Smad3 from their association with Smad4 and hence negatively modulates TGF beta-dependent transcriptional responses and cell growth inhibition. An isoform of Erbin encoded by an alternatively spliced transcript in human tissues lacks this SID and fails to inhibit TGF beta responses. Consistently, knockdown of the endogenous Erbin gene with short hairpin RNA enhances TGF beta-induced antiproliferative and transcriptional responses. In addition, Erbin suppresses activin/Smad2-dependent, but not BMP/Smad1-mediated, induction of endogenous gene expression in Xenopus embryos. Therefore, these results define Erbin as a novel negative modulator of Smad2/Smad3 functions and expand the physiological role of Erbin to the regulation of TGF beta signaling.