Smads are a class of proteins that function as intracellular signaling effectors for the TGF-β superfamily of secreted polypeptides. TGF-β-related factors regulate cell proliferation and differentiation in organisms ranging from insects and worms to mammals. Although only the receptors for TGF-βs, activins, and BMPs have been characterized, all TGF-β-related factors, with the exception of the distantly related GDNF, are thought to act through a cell surface complex of two types of transmembrane serine/threonine kinase receptors. Most receptor complexes bind several ligands, and several type I receptors form combinatorial interactions with type II receptors, thus creating signaling diversity. Following ligand binding, the type II receptor kinases phosphorylate and thereby activate the type I receptor cytoplasmic domains. The Smads then act as type I receptor–activated signaling effectors, which regulate transcription of select genes in response to ligand (