New insights into TGF-β–Smad signalling

Abstract Transforming growth factor β (TGF-β) initiates its diverse cellular responses by binding to and activating specific cell surface receptors that have intrinsic serine/threonine kinase activity. These activated TGF-β receptors stimulate the phosphorylation of receptor-regulated Smad proteins, which in turn form complexes with Smad4 that accumulate in the nucleus and regulate the transcription of target genes. TGF-β responses can be cell-type specific and are dependent on both the concentration of TGF-β signalling components and the activity of other signal transduction pathways, which can either synergize with or antagonize the TGF-β pathway. Recent research has provided insights into the specificity determinants of TGF-β–Smad signalling, including combinatorial ligand–receptor associations, selective interactions between the Smads and other pathway components that are mediated through defined binding motifs, and the differential regulation of duration and intensity of signalling.

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