THE MAD-RELATED PROTEIN SMAD7 ASSOCIATES WITH THE TGF-BETA RECEPTOR AND FUNCTIONS AS AN ANTAGONIST OF TGF-BETA SIGNALING

TGF beta signaling is initiated when the type I receptor phosphorylate s the MAD-related protein, Smad2, on C-terminal serine residues. This leads to Smad2 association with Smad4, translocation to the nucleus, a nd regulation of transcriptional responses. Here we demonstrate that S mad7 is an inhibitor of TGF beta signaling. Smad7 prevents TGF beta-de pendent formation of Smad2/Smad4 complexes and inhibits the nuclear ac cumulation of Smad2. Smad7 interacts stably with the activated TGF bet a type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2. Furthermore, mutations in Smad7 that interfer e with receptor binding disrupt its inhibitory activity. These studies thus define a novel function for MAD-related proteins as intracellula r antagonists of the type I kinase domain of TGF beta family receptors .