Figure 7.

 Determinants of specificity in TGF-β signal transduction. In the TGF-β or BMP receptor complexes, the type I receptor recognizes and phosphorylates a specific R-Smad, such as Smad2 in the TGF-β pathway or Smad1 in the BMP pathway (Heldin et al. 1997; Massagué 1998). The R-Smad then associates with Smad4 (not shown) and moves into the nucleus. Specific association with the DNA-binding factor Fast1 in the nucleus takes the Smad2–Smad4 complex to specific target genes such as Mix.2, activating their transcription (X. Chen et al. 1996, 1997; Liu et al. 1997). Selection of a R-Smad by a receptor is specified by the type I receptor L45 loop and the R-Smad L3 loop, whereas selection of a DNA-binding factor (such as Fast1 in the case of Smad2) is specified by the α-helix 2 of the R-Smad. Exchanging any of these three elements between the TGF-β and BMP receptors or between Smad1 and Smad2 causes a switch in the signaling specificity of these two pathways. Specific activation of other target genes by Smad1 or Smad2 complexes is presumed to involve different DNA-binding partners.