Smad regulation in TGF-β signal transduction

Members of the transforming growth factor-β (TGF-β) family control growth, differentiation and apoptosis of cells, and have important functions during embryonic development (Derynck et al., 2001; Massagué et al., 2000; Whitman, 1998). The human genome encodes 28 genes that encode members of this family (Venter et al., 2001), including TGF-β isoforms, activins and bone morphogenetic proteins (BMPs). These proteins signal by stimulating formation of specific heteromeric complexes of type I and type II serine/threonine kinase receptors. The type II receptors are encoded by five known mammalian genes, bind to ligands, and phosphorylate and activate the type I receptors, of which there are seven mammalian members (Fig. 1). The available data support the notion that the type I receptors are responsible for the specificity of downstream signalling. The ligands, receptors and their intracellular effectors, the Smads, are conserved in eukaryotes from Caenorhabditis elegans and Drosophila to Here, we review the mechanisms by which Smad signalling is regulated, that is, how Smad molecules are activated, translocated to the nucleus, interact with other nuclear partners and how they are degraded.