Transcriptional Activators of TGF-β Responses: Smads

Programs in Cell Biology and Developmental Biology ence with Smad signaling inhibits the ligand-induced response, Smads are considered as effectors for the ligand-induced transcriptional responses. Recent progress provides insight into the mechanisms through which Smads regulate transcription and explains the sequence heterogeneity of the TGF-␤/activin-respon-Smads are a class of proteins that function as intracellu-sive promoter sites. Thus, Smads have been shown to lar signaling effectors for the TGF-␤ superfamily of se-act as transcription factors through their ability to di-creted polypeptides. TGF-␤-related factors regulate cell rectly bind DNA, and to induce transcriptional responses proliferation and differentiation in organisms ranging through cooperativity with other transcription factors. from insects and worms to mammals. Although only the Smads Bind Directly to Promoter DNA Sequences receptors for TGF-␤s, activins, and BMPs have been Following nuclear translocation, Smads regulate tran-characterized, all TGF-␤-related factors, with the excep-scription through physical interaction of the heteromeric tion of the distantly related GDNF, are thought to act Smad complex with a ligand-responsive promoter se-through a cell surface complex of two types of trans-quence. For example, the Smad2/4 complex interacts in membrane serine/threonine kinase receptors. Most re-response to activin with the Mix.2 promoter of Xenopus ceptor complexes bind several ligands, and several type through FAST-1, a winged-helix transcription factor that I receptors form combinatorial interactions with type II binds to an activin-response element (Chen et al., 1996, receptors, thus creating signaling diversity. Following 1997). Whereas Smad2 interacts directly with FAST-1, ligand binding, the type II receptor kinases phosphory-Smad4 participates in the Smad2/FAST-1 complex pri-late and thereby activate the type I receptor cytoplasmic marily through its association with Smad2 (Chen et al., domains. The Smads then act as type I receptor–acti-1997; Liu et al., 1997). At the goosecoid promoter, the vated signaling effectors, which regulate transcription Smad2/4 complex interacts similarly with an activin-of select genes in response to ligand (Derynck and Feng, response sequence, but this interaction occurs through FAST-2, which is structurally related to FAST-1 and 1998). binds to a sequence similar to the FAST-1 binding se-The Smads received their name as a contraction of quence (Labbé et al., 1998). In an analogous way, the the names of the C. elegans Sma and Drosophila Mad, the first identified members of this class of signaling effectors. Their sequence alignments show two large conserved domains, the MH1 or N domain, and the MH2 or C domain, separated by a less conserved linker (L) segment …