TGF-beta Signalling Through the Smad Pathway

Trans forming growth factor beta(TGF-beta) and related cytokines regulate cell fate by signalling through two receptor serine kinases that act in sequence. Signalling by these receptors is mediated by the recently identified Smad protein family. Upon phosphorylation by activated receptors, Smads form complexes, move into the nucleus, associate with DNA-bindingproteins and activate gene transcription. Responses mediated by Smads include crucial morphogenic events during fly and frog development as well as cell-cycle arrest in mammalian cells. Furthermore, Smads that mediate growth-inhibitory responses are tumour suppressors mutated in cancer. This review describes how the discovery of the Smad family lets us, for the first time, trace a signalling pathway from TGF-beta receptors to target genes.