Nuclear targeting of transforming growth factor-beta-activated Smad complexes
Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology
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.
Rights and Permissions
Citation: J Biol Chem. 2005 Jun 3;280(22):21329-36. Epub 2005 Mar 30. Link to article on publisher's site
The Journal of biological chemistry
Chen, Hong B.; Rud, Jonathan G.; Lin, Kai; and Xu, Lan, "Nuclear targeting of transforming growth factor-beta-activated Smad complexes" (2005). Open Access Articles. 691.