Inoue H, Imamura T, Ishidou Y, Takase M, Udagawa Y, Oka Y, Tsuneizumi K, Tabata T, Miyazono K, Kawabata M
Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research, and Research for the Future Program, Japan Society for the Promotion of Science, Tokyo 170-8455, Japan.
Mol Biol Cell. 1998 Aug;9(8):2145-56. doi: 10.1091/mbc.9.8.2145.
Decapentaplegic (Dpp) plays an essential role in Drosophila development, and analyses of the Dpp signaling pathway have contributed greatly to understanding of the actions of the TGF-beta superfamily. Intracellular signaling of the TGF-beta superfamily is mediated by Smad proteins, which are now grouped into three classes. Two Smads have been identified in Drosophila. Mothers against dpp (Mad) is a pathway-specific Smad, whereas Daughters against dpp (Dad) is an inhibitory Smad genetically shown to antagonize Dpp signaling. Here we report the identification of a common mediator Smad in Drosophila, which is closely related to human Smad4. Mad forms a heteromeric complex with Drosophila Smad4 (Medea) upon phosphorylation by Thick veins (Tkv), a type I receptor for Dpp. Dad stably associates with Tkv and thereby inhibits Tkv-induced Mad phosphorylation. Dad also blocks hetero-oligomerization and nuclear translocation of Mad. We also show that Mad exists as a monomer in the absence of Tkv stimulation. Tkv induces homo-oligomerization of Mad, and Dad inhibits this step. Finally, we propose a model for Dpp signaling by Drosophila Smad proteins.
果蝇的“截瘫蛋白”（Dpp）在果蝇发育过程中起着至关重要的作用，对Dpp信号通路的分析极大地促进了对转化生长因子-β（TGF-β）超家族作用的理解。TGF-β超家族的细胞内信号传导由Smad蛋白介导，Smad蛋白现分为三类。在果蝇中已鉴定出两种Smad蛋白。“母亲抗Dpp蛋白”（Mad）是一种特定于该信号通路的Smad蛋白，而“女儿抗Dpp蛋白”（Dad）是一种抑制性Smad蛋白，遗传学研究表明它能拮抗Dpp信号传导。在此，我们报告在果蝇中鉴定出一种常见的介导型Smad蛋白，它与人类Smad4密切相关。Mad在被Dpp的I型受体“粗脉”（Tkv）磷酸化后，与果蝇Smad4（Medea）形成异源复合物。Dad与Tkv稳定结合，从而抑制Tkv诱导的Mad磷酸化。Dad还会阻断Mad的异源寡聚化和核转位。我们还表明，在没有Tkv刺激的情况下，Mad以单体形式存在。Tkv诱导Mad的同源寡聚化，而Dad会抑制这一步骤。最后，我们提出了一个由果蝇Smad蛋白介导的Dpp信号传导模型。
