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REVIEWS TGFβ signalling in context Joan Massagué Abstract | The basic elements of the transforming growth factor‑β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers. Myoblasts Transforming growth factor‑β (TGFβ) signalling Writing on this subject at the time, the phrase Mesenchymal progenitor provides animal cells with a versatile means of driv‑ “How cells read TGFβ signals” was picked as a title for cells that are committed to ing developmental programmes and controlling cell two reasons2. It was an affirmation that a molecular differentiate into muscle cells. behaviour, a role that is evident in the many effects framework for the exploration of TGFβ biology was Epithelial–mesenchymal of TGFβ-related cytokines on cell proliferation, dif‑ firmly in hand. Fleshing out the newly defined path‑ transition ferentiation, morphogenesis, tissue homeostasis and way became the next task, and the field keenly obliged (EMT). A phenotypic change regener­ation, and the severe diseases that result from by identifying additional components, regulators, that is characteristic of some their malfunctions. ancillary pathways and biological effects of the TGFβ developing tissues and certain Pioneers in this field in the 1980s welcomed the family. However, that phrase also implied a challeng‑ forms of cancer. During EMT, cells lose intercellular junctions multifunctional­ nature of TGFβ with mixed feelings. Up ing question: how does the cellular context determine and apical–basal polarity, to that point, endocrinology was forged on the princi‑ the response to TGFβ? It was not clear how TGFβ can become migratory and, in ple that, by and large, a hormone has one main role and inhibit cell proliferation but also promote cell growth, the case of cancer, become this role only. With TGFβ it was clear from the begin‑ enhance stem cell pluripotency but also differentiation, invasive. ning that this paradigm did not quite fit. The effects of regulate muscle genes in myoblasts and neural genes TGFβ were different, even opposite, depending on the in neuroblasts, or suppress pre-malignant cells but cell type and the conditions. The cellular context more encourage metastatic ones. These paradoxes suggested than the cytokine dictated the nature of the response. that cells read TGFβ signals in ways that could not be To those intent on elucidating the TGFβ pathway, this explained. Non-canonical TGFβ pathways and malig‑ contextual functionality was sobering news, as it raised nant switches were explored as alternatives but yielded the specter of an impossibly complicated signal trans‑ no answers either. Fifty thousand TGFβ papers later, duction process. Yet, the work uncovered a pathway that the old enigma carries on. is relatively simple (in hindsight) and with the power Interest in solving this puzzle is growing, and it is Cancer Biology and to mediate most effects of any TGFβ family member in driven by the importance of TGFβ signalling in medi‑ Genetics Program, any cell type. The TGFβ receptor system, its activation cally relevant processes of immunity, inflammation, Memorial Sloan-Kettering mechanism and SMAD proteins, which function both cancer and fibrosis, as well as bone, muscle, adipose, Cancer Center, New York, New York 10065, USA. as substrates for TGFβ receptors and signal transduc‑ vascular and haematopoietic homeostasis. At last, Howard Hughes Medical ers, came to light in quick succession. Disease-causing recent progress is pointing to a resolution. To cover this Institute, Chevy Chase, mutations in these components stressed the medical progress, the present article provides an overview of the Maryland 20815, USA. relevance of the new findings. Regulators and comple‑ contextual determinants of TGFβ action followed by an Box 116, Memorial Sloan-Kettering Cancer mentary pathways were also found. TGFβ target genes update on the signalling, transcriptional and genomic Center, 1275 York Avenue, that trigger differentiation in stem cells, cell cycle elements of the pathway. Building on this, the final New York, New York 10065, arrest in epithelial cells or homeostatic constraint in section covers, in broad strokes, the mode of action of USA. immune and vascular cells were identified. Crystal TGFβ in various contexts, including embryonic stem Correspondence to J. M. structures of the pathway components were emerging (ES) cells, lineage-committed progenitors, cells under‑ e‑mail: [email protected] epithelial–mesenchymal transition doi:10.1038/nrm3434 in the blink of an eye as the century was drawing to a going (EMT), induced 1 Published online close . The TGFβ pathway had been solved, to a first pluripotent stem (iPS) cells, differentiated cells and cells 20 September 2012 approximation at least. at various stages of malignancy. 616 | OCTOBER 2012 | VOLUME 13 www.nature.com/reviews/molcellbio © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS a 1 Three types of contextual determinants shape the TGFβ transcriptional response in a cell (FIG. 1). Within a given epigenetic and transcriptional context the response Pathway regulators of a cell is determined by the extracellular and intracellu‑ lar composition of the TGFβ signal transduction system. Ligand– 2 The abundance and activity of different TGFβ ligands, receptor SMAD proteins and signalling cofactors complex receptors and regulators determine the nature and inten‑ sity of the TGFβ signal in the nucleus, and coexisting Partner transcription factors 3 3 cues further shape the response by regulating SMAD function or activating non-canonical pathways13–15. Inputs that affect the intensity of the TGFβ signal may DNA qualitatively influence the cellular response. A dramatic example is the different cell fates that emerge from finely 4 Epigenetic status tuned gradients of bone morphogenetic protein (BMP) b Determinants acting alongside WNT and Hedgehog signals during Signal transduction Transcription Epigenetic status development16–18. Ligand isoforms Pluripotency factors Heterochromatin A second set of determinants is the factors that Ligand traps Lineage regulators Pluripotency marks co­operate with SMAD proteins to regulate transcrip‑ Co-receptors DNA-binding cofactors Lineage marks Receptor subtypes HATs and HDACs EMT marks tion (FIG. 1). The role of such factors was originally Inhibitory SMAD proteins SWI/SNF iPS cell marks highlighted with the identification of forkhead box H1 Crosstalk inputs Chromatin readers Oncogenic marks (FOXH1; also known as FAST1) as a factor that allows Figure 1 | Contextual determinants of TGF action. a Three types of contextual SMAD proteins to recognize ‘activin response elements’ β Nature |Reviews | Molecular Cell Biology determinants shape the transforming growth factor-β (TGFβ)-mediated transcriptional (AREs) in promoters of genes involved in mesoderm response in a cell. First, a large number of signal transduction regulatory factors differentiation19. This principle was extended to the determine the access of TGFβ ligands to signalling receptors (1), and of receptors to TGFβ subfamily of BMPs with the identification of zinc- SMAD proteins and other signal delivery factors (2). Second, transcription factors, finger protein 423 (ZFP423; also known as OAZ), which histone readers and modifiers and chromatin remodellers that bind to activated SMAD is a SMAD cofactor for the activation of ventral meso‑ proteins determine what genes will be targeted by the signal transduction complexes derm homeobox genes20. Lineage-specific transcrip‑ and whether expression of the target genes will be positively or negatively regulated (3). tion factors direct TGFβ- and BMP-activated SMAD The third type of contextual determinants is presented by the epigenetic status of the proteins to specific loci genome-wide in myoblasts, cell. The epigenetic state dictates whether genes are in an active ‘open’ chromatin pro‑B cells, myeloid precursors and erythroid precur‑ conformation (and are therefore accessible for SMAD complexes), in a repressive 4,8 chromatin conformation (and therefore in a silenced ‘closed’ state that is not accessible sors . In differentiated cells, diverse transcription fac‑ for transcriptional regulation), or whether these genes are in a poised chromatin state tors guide SMAD proteins to distinct subsets of target 21 that is silenced yet responsive to TGFβ signalling and the appropriate chromatin readers genes . The resulting SMAD complexes then recruit (4). Composite enhancer elements are represented as bi‑coloured segments on the DNA, chromatin readers, modifiers and remodellers to regu‑ inside a shaded box if the genes are in repressive chromatin, and unoccupied if the cell late transcription. The availability of all these SMAD does not express the required DNA-binding SMAD cofactor. b | A list of the contextual partners determines what genes will be targeted and determinants that affect the signal transduction and transcription steps and the whether they will be activated or repressed. regulators of the epigenetic status. EMT, epithelial–mesenchymal transition; HATs, Last, but not least, the epigenetic landscape of the

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