Program in Molecular Medicine
Active Transport, Cell Nucleus; Animals; Bone Morphogenetic Proteins; Cell Nucleus; DNA-Binding Proteins; Drosophila; Drosophila Proteins; Genome, Insect; Humans; Karyopherins; RNA Interference; Receptors, Cytoplasmic and Nuclear; Smad Proteins; Transcription Factors; Transforming Growth Factor beta
Life Sciences | Medicine and Health Sciences
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.
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Citation: J Cell Biol. 2007 Sep 10;178(6):981-94. Epub 2007 Sep 4. Link to article on publisher's site