Importin beta mediates nuclear translocation of Smad 3.

Smad proteins are intracellular mediators of transforming growth factor-beta (TGF-beta) and related cytokines. Although ligand-induced nuclear translocation of Smad proteins is clearly established, the pathway mediating this import is yet to be determined. We previously identified a nuclear localization signal (NLS) in the N-terminal region of Smad 3, the major ...
Smad protein involved in TGF-beta signal transduction. This basic motif (Lys(40-)Lys-Leu-Lys-Lys(44)), conserved among all the pathway-specific Smad proteins, is required for Smad 3 nuclear import in response to ligand. Here we studied the nuclear import pathway of Smad 3 mediated by this NLS. We demonstrate that the isolated Smad 3 MH1 domain displays significant specific binding to importin beta, which is diminished or eliminated by mutations in the NLS. Full-size Smad 3 exhibits weak but specific binding to importin beta, which is enhanced after phosphorylation by the type I TGF-beta receptor. In contrast, no interaction was observed between importin alpha and Smad 3 or its MH1 domain, indicating that nuclear translocation of Smad proteins may occur through direct binding to importin beta. We propose that activation of all of the pathway-specific Smad proteins (Smads 1, 2, 3, 5, 8, and 9) exposes the conserved NLS motif, which then binds directly to importin beta and triggers nuclear translocation.
Mesh Terms:
Activin Receptors, Type I, Amino Acid Motifs, Biological Transport, Cell Compartmentation, Cell Nucleus, DNA-Binding Proteins, Green Fluorescent Proteins, Karyopherins, Luminescent Proteins, Microscopy, Fluorescence, Models, Biological, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Recombinant Fusion Proteins, Smad3 Protein, Trans-Activators
J. Biol. Chem.
Date: Aug. 04, 2000
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