Nuclear targeting of transforming growth factor-beta-activated Smad complexes

UMMS Affiliation

Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Active Transport, Cell Nucleus; Animals; COS Cells; Cell Nucleolus; Cell Nucleus; Cytosol; DNA-Binding Proteins; Dimerization; Glutathione Transferase; Hela Cells; Humans; Immunohistochemistry; Immunoprecipitation; Karyopherins; Microscopy, Fluorescence; Mutation; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Protein Transport; Recombinant Proteins; Signal Transduction; Smad Proteins; Smad3 Protein; Smad4 Protein; Trans-Activators; Transfection; Transforming Growth Factor beta


Life Sciences | Medicine and Health Sciences


Upon stimulation by the transforming growth factor beta (TGF-beta), Smad2 and Smad3 are phosphorylated at their C termini and assemble into stable heteromeric complexes with Smad4. These complexes are the functional entities that translocate into the nucleus and regulate the expression of TGF-beta target genes. Here we report that the TGF-beta-activated phospho-Smad3/Smad4 complex utilizes an importin-independent mechanism for nuclear import and engages different nucleoporins for nuclear import compared with the monomeric Smad4. Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. We also demonstrate that the binding of phospho-Smad3 to Smad4 prevents Smad4 from interacting with the nuclear export receptor chromosome region maintenance 1. In this way, TGF-beta signaling suppresses nuclear export of Smad4 by chromosome region maintenance 1 and thereby targets Smad4 into the nucleus. Indeed tumorigenic mutations in Smad4 that affect its interaction with Smad2 or Smad3 impair nuclear accumulation of Smad4 in response to TGF-beta.

DOI of Published Version



J Biol Chem. 2005 Jun 3;280(22):21329-36. Epub 2005 Mar 30. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID