Mechanism and Regulation of Nucleocytoplasmic Trafficking of Smad

Smad proteins are the intracellular mediators of transforming growth factor β (TGF-β) signaling. Smads function as transcription factors and their activities require carboxyl-terminal phosphorylation by TGF-β receptor kinases which are embedded in the cell membrane. Therefore, the translocation of activated Smads from the cytoplasm into the nucleus is a rate-limiting step in TGF-β signal transduction into the nucleus. On the other hand, the export of Smads out of the nucleus turns off TGF-β effect. Such spatial control of Smad ensures a tight regulation of TGF-β target genes. Several cross-talk pathways have been shown to affect TGF-β signaling by impairing nuclear translocation of Smad, exemplifying the biological importance of the nuclear transport process. Many laboratories have investigated the underlying molecular mechanism of Smad nucleocytoplasmic translocation, combining genetics, biochemistry and sophisticated live cell imaging approaches. The last few years have witnessed the elucidation of several key players in Smad nuclear transport, most importantly the karyopherins that carry Smads across the nuclear envelope and nuclear pore proteins that facilitate the trans-nuclear envelope movement. The foundation is now set to further elucidate how the nuclear transport process is regulated and exploit such knowledge to manipulate TGF-β signaling. In this review we will discuss the current understanding of the molecular machinery responsible for nuclear import and export of Smads.