Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus
Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus
复制标题
DOI：
10.1006/dbio.1998.9168
复制
发表时间：
1999-03-15
影响因子：
2.7
通讯作者：
Thomsen, GH
中科院分区：
文献类型：
--
作者：
Hoodless, PA;Tsukazaki, T;Thomsen, GH
Smads是TGF β超家族信号转导的中心介质。然而，Smad介导的信号通路在早期发育中的确切功能尚不清楚。在这里，我们证明了在爪蟾发育过程中的背前轴形成的Smad 2信号的要求。使用两个点突变的Smad 2以前确定在结直肠癌中，我们表明，Smad 2迎来Smad 4到细胞核形成一个转录激活复合物与核DNA结合蛋白FAST-1和突变蛋白相互作用正常FAST-1，但未能招募Smad 4到细胞核中。这种抑制机制特异性地将这些突变体的显性负性活性限制于激活素/Vg 1信号通路而不抑制BMP。此外，这些突变体的表达在非洲爪蟾动物帽抑制，但不取消激活素和Vg 1诱导中胚层和胚胎中的结果在一个截短的背前轴。这些研究定义了一种机制，通过这种机制，Smad 2突变可能会阻断TGF β依赖性信号传导，并表明在非洲爪蟾组织者功能中由Smad 2途径介导的诱导信号传导的关键作用。(C)北京：科学出版社.
Smads are central mediators of signal transduction for the TGF beta superfamily. However, the precise functions of Smad-mediated signaling pathways in early development are unclear. Here we demonstrate a requirement for Smad2 signaling in dorsoanterior axis formation during Xenopus development. Using two point mutations of Smad2 previously identified in colorectal carcinomas, we show that Smad2 ushers Smad4 to the nucleus to form a transcriptional activation complex with the nuclear DNA-binding protein FAST-1 and that the mutant proteins interact normally with FAST-1 but fail to recruit Smad4 into the nucleus. This mechanism of inhibition specifically restricts the dominant-negative activity of these mutants to the activin/Vg1 signaling pathway without inhibiting BMPs. Furthermore, expression of these mutants in Xenopus animal caps inhibits but does not abolish activin and Vg1 induction of mesoderm and in the embryo results in a truncated dorsoanterior axis. These studies define a mechanism through which mutations in Smad2 may block TGF beta-dependent signaling and suggest a critical role for inductive signaling mediated by the Smad2 pathway in Xenopus organizer function. (C) 1999 Academic Press.