TGF-β signaling from receptors to the nucleus

Abstract In the past three years, a novel signal transduction pathway downstream of the transforming growth factor-beta (TGF-β) superfamily receptor serine-threonine kinases has been shown to be mediated by a family of latent transcription factors called `Smads'. These proteins mediate a short-circuited pathway in which a set of receptor-activated Smads are phosphorylated directly by the receptor kinase and then translocate to the nucleus complexed to the common mediator, Smad4, to participate in transcriptional complexes. Smads 2 and 3 mediate signals predominantly from the TGF-β receptors. Of these, specific roles have been ascribed to Smad3 in control of chemotaxis of neutrophils and macrophages and the inhibition of Smad3 activity by the oncogene Evi-1 suggests that it may play a role in leukemogenesis. Other data, such as the induction by the inflammatory cytokine interferon-γ of an inhibitory Smad, Smad7, which blocks the actions of Smad3, suggest that identification of the specific gene targets of Smad proteins in immune cells will provide new insight into the mechanisms of TGF-β action on these cells.