Xu Lan, Yao Xiaohao, Chen Xiaochu, Lu Peiyuan, Zhang Biliang, Ip Y Tony
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
J Cell Biol. 2007 Sep 10;178(6):981-94. doi: 10.1083/jcb.200703106. Epub 2007 Sep 4.
Nuclear translocation of Smad proteins is a critical step in signal transduction of transforming growth factor beta (TGF-beta) and bone morphogenetic proteins (BMPs). Using nuclear accumulation of the Drosophila Smad Mothers against Decapentaplegic (Mad) as the readout, we carried out a whole-genome RNAi screening in Drosophila cells. The screen identified moleskin (msk) as important for the nuclear import of phosphorylated Mad. Genetic evidence in the developing eye imaginal discs also demonstrates the critical functions of msk in regulating phospho-Mad. Moreover, knockdown of importin 7 and 8 (Imp7 and 8), the mammalian orthologues of Msk, markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-beta. Biochemical studies further suggest that Smads are novel nuclear import substrates of Imp7 and 8. We have thus identified new evolutionarily conserved proteins that are important in the signal transduction of TGF-beta and BMP into the nucleus.
Smad蛋白的核转位是转化生长因子β（TGF-β）和骨形态发生蛋白（BMP）信号转导中的关键步骤。我们以果蝇Smad蛋白“抗五体不全”母亲（Mad）的核积累作为读数，在果蝇细胞中进行了全基因组RNA干扰筛选。该筛选确定了“鼹鼠皮”（msk）对磷酸化Mad的核输入很重要。在发育中的眼成虫盘的遗传证据也证明了msk在调节磷酸化Mad中的关键功能。此外，敲低Msk的哺乳动物同源物输入蛋白7和8（Imp7和8），会显著损害响应BMP2时Smad1的核积累以及响应TGF-β时Smad2/3的核积累。生化研究进一步表明，Smads是Imp7和8新的核输入底物。因此，我们鉴定出了在TGF-β和BMP信号转导入核过程中起重要作用的新的进化保守蛋白。
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