TGFβ–SMAD signal transduction: molecular specificity and functional flexibility

Key Points More than 30 mammalian genes comprise the TGFβ superfamily of growth factors. They have important roles in the regulation of cellular functions both in the adult organism and during embryogenesis. Signal duration and signal magnitude are crucial determinants of the outcome of TGFβ superfamily signalling, in particular in early embryonic patterning, in which TGFβ superfamily ligands act as morphogens that elicit distinct responses in a dose-dependent fashion. The canonical TGFβ signalling pathway involves ligand-dependent assembly of a heteromeric receptor complex, receptor-kinase activation and subsequent phosphorylation and activation of SMAD proteins, which are transcriptional regulators that consequently accumulate in the nucleus. Thus, SMADs both transmit the signal into the nucleus and execute the downstream effects by directly regulating target-gene transcription. Signal duration and signal magnitude are relayed faithfully into the nucleus in a quantitative manner. Such continuous sensing of signal intensity might involve cycling of receptors through the endocytic pathway. In addition, nuclear accumulation of active nuclear SMAD complexes is dynamically maintained in strict accordance with the degree of receptor activation at any time of signalling. SMAD phosphorylation by active receptors, and constitutive SMAD dephosphorylation by nuclear phosphatases, are coupled through nucleocytoplasmic shuttling of SMADs. An in-depth understanding of the pleiotropic cellular functions that can be evoked by TGFβ superfamily signalling will depend on a more quantitative knowledge of temporal and spatial characteristics of the pathway. Transforming growth factor-β (TGFβ)-induced signalling converges on a limited number of SMAD complexes. These complexes effect a plethora of specific and functional responses in both embryos and adult organisms. How are these complex cellular responses elicited? Ligands of the transforming growth factor-β (TGFβ) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand–receptor interactions. Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. Current research is focused on the mechanisms that regulate SMAD activity to evoke cell-type-specific and context-dependent transcriptional programmes. An equally important challenge is understanding th