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.
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 the functional role of signal strength and duration. How are these quantitative aspects of the extracellular signal regulated? How are they then sensed and interpreted, and how do they affect responses?
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We would like to thank M. Howell, L. Raftery, E. Sahai, S. Leevers and members of the Hill laboratory for comments on the manuscript. Work in the Hill laboratory is funded by Cancer Research UK and the European Union (EU). B.S. was supported by an Erwin-Schrödinger Fellowship of the Austrian Science Foundation and an EU Marie Curie Fellowship.
- Hereditary haemorrhagic telangiectasia
An autosomal dominant disorder that is characterized by multisystemic vascular dysplasia and recurrent haemorrhage, caused by mutations in the endothelium-specific type I receptor ALK1 or the co-receptor endoglin.
A ligand that is secreted by cells and, by spreading to other cells, determines distinct cell fates in a dose-dependent manner.
One of a class of actively signalling homo- or heterodimers that consist of two of several β-chains (βA, βB, βC or βE in mammals).
- Subtilisin-like proprotein convertase (SPC) family
A major family of endoproteolytic processing enzymes of the secretory pathway.
- MH1 and MH2 domains
Conserved N-terminal and C-terminal domains, respectively, that are found in SMADs. MH stands for MAD homology in reference to the founder member of the SMAD family, Drosophila mothers against decapentaplegic (MAD).
- FYVE domain
Named after the four first proteins that were found to contain this domain (Fab1, YOTB, Vac1 and EEA1). FYVE domains bind phosphatidylinositol-3-phosphate and target proteins to endosomal membranes.
A zinc-finger transcription factor that mediates DPP-induced repression together with MAD–Medea in D. melanogaster, but acts as an activator in response to BMPs in mammals.
- EEA1-positive endosome
A vesicular body that is highly enriched in phosphatidylinositol-3-phosphate, which binds the FYVE-domain protein EEA1 (early endosomal antigen-1).
One of a group of structurally unrelated proteins that are divided into two functional subgroups: importins bind a cargo in the cytoplasm, transport it through the nuclear pore and release it in the nucleus on binding of the small GTPase Ran in its GTP-bound form. Exportins bind a cargo in the nucleus together with Ran-GTP, transport it into the cytoplasm and release it upon GTP hydrolysis.
- Nuclear localization signal
(NLS). A short basic stretch of amino acids, rich in Arg or Lys, that is recognized by importin-α–importin-β complexes.
The prototypic nuclear export receptor, transporting a plethora of substrates. Specifically inhibited by the drug leptomycin B.
- Nuclear export signal
(NES). A short, Leu- or Ile-rich motif recognized by exportin-1.
- BMP1 family
A small group of extracellular metalloproteases that process precursors to form mature functional proteins, which are necessary for extracellular matrix formation, such as procollagens. Members of this family are crucially involved in signalling because they cleave the BMP2–BMP4 inhibitor chordin and the latent precursors of TGFβ, GDF8 and GDF11.
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Schmierer, B., Hill, C. TGFβ–SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8, 970–982 (2007). https://doi.org/10.1038/nrm2297
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