Regulation of Smad Activity

binding by the ternary Smad–FAST complex. Smad3 can bers are a group of secreted polypeptides that regulate replace Smad2 in this complex and at the Mix.2 element a diverse array of developmental and biological pro-can activate transcription (Yeo et al., 1999), whereas at the cesses. Disruption of the ligands or of components of goosecoid promoter Smad3 blocks activation (Labbé et their signaling pathways are associated with human dis-al., 1998). This suggests that Smad-dependent activa-eases including cancer and hereditary conditions (Mas-tion of FAST target genes may be promoter dependent. sagué , 1998). Superfamily members include TGF␤s, ac-There are now many examples in which Smads coop-tivins/inhibins and the bone morphogenetic proteins erate with DNA binding partners to regulate transcription (BMPs). These factors signal through heteromeric com-of TGF␤/activin target genes. For example, Smad2 and/ plexes of transmembrane type I and type II Ser/Thr ki-or Smad3 can associate with c-Jun/c-Fos, ATF2, TFE3, nase receptors. Within this complex the type II receptor PEBP2/CBF, and the vitamin D receptor (Figure 1). As kinase activates the type I receptor kinase, which subse-for Smad/FAST-dependent activation of transcription, quently propagates signals to the Smad pathway (De-the R-Smad/Smad4 complex is recruited to specific pro-rynck et al., 1998; Massagué , 1998). Smad proteins play moters through the direct interaction of the R-Smad with a critical role in transmitting TGF␤ superfamily signals these specific DNA binding partners (Derynck et al., from the cell-surface to the nucleus (Derynck et al., 1998; 1998). Furthermore, regulation of these elements often Massagué , 1998). Smads have two conserved domains requires direct binding of the Smad MH1 domain to in their amino-and carboxy-terminal regions, termed adjacent DNA elements. Once recruited to specific ele-the MH1 and MH2 domains, respectively, as well as ments, both R-Smads and Smad4 can activate tran-a central proline-rich linker region. Smads are subdi-scription by recruiting the coactivators CBP/p300 and Smads can both positively or negatively regulate tran-R-Smad-receptor interactions are mediated by loop 3 scription of specific genes in response to TGF␤ family in the MH2 domain of Smads and loop 45 in the type I signaling. receptor kinase (Massagué , 1998). A basic pocket that The BMP Pathway is present in the R-Smads may facilitate this interaction Much of the work on Smad nuclear function has concen-by providing a docking site for the phosphorylated GS trated on analysis of the TGF␤ and activin signaling domain of the activated type I receptor (Wu et al., …