TGF-beta signaling by Smad proteins.

Members of the transforming growth factor-beta (TGF-beta) family bind to type II and type I serine/threonine kinase receptors, which initiate intracellular signals through activation of Smad proteins. Receptor-regulated Smads (R-Smads) are anchored to the cell membrane by interaction with membrane-bound proteins, including Smad anchor for receptor activation (SARA). Upon ligand stimulation, R-Smads are phosphorylated by the receptors and form oligomeric complexes with common-partner Smads (Co-Smads). The oligomeric Smad complexes then translocate into the nucleus, where they regulate the transcription of target genes by direct binding to DNA, interaction with various DNA-binding proteins, and recruitment of transcriptional coactivators or corepressors. A third class of Smads, inhibitory Smads (I-Smads), inhibits the signals from the serine/threonine kinase receptors. Since the expression of I-Smads is induced by the TGF-beta superfamily proteins, Smads constitute an autoinhibitory signaling pathway. The functions of Smads are regulated by other signaling pathways, such as the MAP kinase pathway. Moreover, Smads interact with and modulate the functions of various transcription factors which are downstream targets of other signaling pathways. Loss of function of certain Smads is involved in tumorigenesis, e.g., pancreatic and colorectal cancers. Analyses by gene targeting revealed pivotal roles of Smads in early embryogenesis, angiogenesis, and immune functions in vivo.