Importin β Mediates Nuclear Translocation of Smad 3*

By Zhang Xiao, Xuedong Liu, H. Lodish. Journal of Biological Chemistry, 2000

166 citations recorded by the source corpus.

Smad proteins are intracellular mediators of transforming growth factor-β (TGF-β) 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-β signal transduction. This basic motif (Lys40-Lys-Leu-Lys-Lys44), 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 β, which is diminished or eliminated by mutations in the NLS. Full-size Smad 3 exhibits weak but specific binding to importin β, which is enhanced after phosphorylation by the type I TGF-β receptor. In contrast, no interaction was observed between importin α and Smad 3 or its MH1 domain, indicating that nuclear translocation of Smad proteins may occur through direct binding to importin β. 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 β and triggers nuclear translocation.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/266d17e14d678282176a21a18f545dae718451ce

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In Molecular Biology

1. J. Massagué
2. J. Seoane
3. D. Wotton
4. A. Moustakas
5. C. Heldin
6. E. Batlle
7. R. Weinberg
8. R. Derynck

In Pathology and Forensic Medicine

1. J. Seoane
2. J. Massagué
3. D. Wotton

Citations in the corpus

• How cells read TGF-β signals (2000, background): “This possibility is raised by the presence of a conserved lysine-rich sequence in SMADs that, when mutated in SMAD2, prevents its nuclear impor”
• Smad transcription factors. (2005, background): “A conserved lysine-rich sequence in the MH1 domain of Smads that resembles classical NLS motifs was hypothesized, and shown, to interact with importins (Xiao et al. 2000; Kurisaki et al. 2001).”