Signaling of transforming growth factor-beta family members through Smad proteins

Smads are pivotal intracellular nuclear effecters of transforming growth fa ctor-beta (TGF-beta) family members. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity trigger ph osphorylation of receptor-regulated Smads (R-Smads), whereas Smad2 and Smad 3 are phosphorylated by TGF-beta, and activin type I receptors, Smad1, Smad 5 and Smad8, act downstream of BMP type I receptors. Activated R-Smads form heteromeric complexes with common-partner Smads (Co-Smads), e.g. Smad4, wh ich translocate efficiently to the nucleus, where they regulate, in co-oper ation with other transcription factors, coactivators and corepressors, the transcription of target genes. Inhibitory Smads act in most cases in an opp osite manner from R- and Co-Smads. Like other components in the TGF-beta fa mily signaling cascade, Smad activity is intricately regulated. The multifu nctional and context dependency of TGF-beta family responses are reflected in the function of Smads as signal integrators. Certain Smads are somatical ly mutated at high frequency in particular types of human cancers. Gene abl ation of Smads in the mouse has revealed their critical roles during embryo nic development. Here we review the latest advances in our understanding of the Smad mechanism of action and their in vivo functions.