Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Contextual determinants of TGFβ action in development, immunity and cancer

A Publisher Correction to this article was published on 08 May 2018

This article has been updated

Abstract

Few cell signals match the impact of the transforming growth factor-β (TGFβ) family in metazoan biology. TGFβ cytokines regulate cell fate decisions during development, tissue homeostasis and regeneration, and are major players in tumorigenesis, fibrotic disorders, immune malfunctions and various congenital diseases. The effects of the TGFβ family are mediated by a combinatorial set of ligands and receptors and by a common set of receptor-activated mothers against decapentaplegic homologue (SMAD) transcription factors, yet the effects can differ dramatically depending on the cell type and the conditions. Recent progress has illuminated a model of TGFβ action in which SMADs bind genome-wide in partnership with lineage-determining transcription factors and additionally integrate inputs from other pathways and the chromatin to trigger specific cellular responses. These new insights clarify the operating logic of the TGFβ pathway in physiology and disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The TGFβ–SMAD pathway in the basal and activated states.
Fig. 2: LDTFs and SDTFs as contextual determinants of TGFβ–SMAD action.
Fig. 3: SMAD cooperation with different DNA binding partners.
Fig. 4: Transcriptional determinants of TGFβ regulation of immune cell fate.
Fig. 5: Determinants of TGFβ tumour suppression and its subversion in cancer.

Similar content being viewed by others

Change history

  • 08 May 2018

    In the section 'Combinatorial ligand perception' of the original article, DMP1 was incorrectly used in place of BMP. This has now been corrected in the HTML and PDF versions of the article.

References

  1. Massagué, J. How cells read TGF-beta signals. Nat. Rev. Mol. Cell Biol. 1, 169–178 (2000).

    Article  PubMed  Google Scholar 

  2. Josso, N., Belville, C., di Clemente, N. & Picard, J. Y. AMH and AMH receptor defects in persistent Mullerian duct syndrome. Hum. Reprod. Update 11, 351–356 (2005).

    Article  PubMed  CAS  Google Scholar 

  3. Lindsay, M. E. & Dietz, H. C. The genetic basis of aortic aneurysm. Cold Spring Harb. Perspect. Med. 4, a015909 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Matzuk, M. M. & Burns, K. H. Genetics of mammalian reproduction: modeling the end of the germline. Annu. Rev. Physiol. 74, 503–528 (2012).

    Article  PubMed  CAS  Google Scholar 

  5. Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. TGF-beta: the master regulator of fibrosis. Nat. Rev. Nephrol. 12, 325–338 (2016).

    Article  PubMed  CAS  Google Scholar 

  6. Salazar, V. S., Gamer, L. W. & Rosen, V. BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12, 203–221 (2016).

    Article  PubMed  CAS  Google Scholar 

  7. van der Kraan, P. M. The changing role of TGFbeta in healthy, ageing and osteoarthritic joints. Nat. Rev. Rheumatol 13, 155–163 (2017).

    Article  PubMed  CAS  Google Scholar 

  8. Cai, J., Pardali, E., Sanchez-Duffhues, G. & ten Dijke, P. BMP signaling in vascular diseases. FEBS Lett. 586, 1993–2002 (2012).

    Article  PubMed  CAS  Google Scholar 

  9. Massagué, J. TGFbeta in cancer. Cell 134, 215–230 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Pickup, M., Novitskiy, S. & Moses, H. L. The roles of TGFbeta in the tumour microenvironment. Nat. Rev. Cancer 13, 788–799 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Tauriello, D. V. F. & Batlle, E. Targeting the microenvironment in advanced colorectal cancer. Trends Cancer 2, 495–504 (2016).

    Article  PubMed  Google Scholar 

  12. Wakefield, L. M. & Hill, C. S. Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat. Rev. Cancer 13, 328–341 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Massagué, J. TGFbeta signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Mullen, A. C. & Wrana, J. L. TGF-beta family signaling in embryonic and somatic stem-cell renewal and differentiation. Cold Spring Harb. Perspect. Biol. 9, a022186 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Oshimori, N. & Fuchs, E. The harmonies played by TGF-beta in stem cell biology. Cell Stem Cell 11, 751–764 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Pauklin, S. & Vallier, L. Activin/Nodal signalling in stem cells. Development 142, 607–619 (2015).

    Article  PubMed  CAS  Google Scholar 

  17. Chen, W. & Ten Dijke, P. Immunoregulation by members of the TGFbeta superfamily. Nat. Rev. Immunol. 16, 723–740 (2016).

    Article  PubMed  CAS  Google Scholar 

  18. Sanjabi, S., Oh, S. A. & Li, M. O. Regulation of the immune response by TGF-beta: from conception to autoimmunity and infection. Cold Spring Harb. Perspect. Biol. 9, a022236 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shi, Y. & Massagué, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    Article  PubMed  CAS  Google Scholar 

  20. Wrana, J. L. et al. TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003–1014 (1992).

    Article  PubMed  CAS  Google Scholar 

  21. Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. & Massagué, J. Mechanism of activation of the TGF-beta receptor. Nature 370, 341–347 (1994).

    Article  PubMed  CAS  Google Scholar 

  22. Inman, G. J., Nicolas, F. J. & Hill, C. S. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol. Cell 10, 283–294 (2002).

    Article  PubMed  CAS  Google Scholar 

  23. Xu, L., Kang, Y., Col, S. & Massague, J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus. Mol. Cell 10, 271–282 (2002).

    Article  PubMed  CAS  Google Scholar 

  24. Martin-Malpartida, P. et al. Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors. Nat. Commun. 8, 2070 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Hinck, A. P., Mueller, T. D. & Springer, T. A. Structural biology and evolution of the TGF-beta family. Cold Spring Harb. Perspect. Biol. 8, a022103 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Macias, M. J., Martin-Malpartida, P. & Massagué, J. Structural determinants of Smad function in TGF-beta signaling. Trends Biochem. Sci. 40, 296–308 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Nolan, K. & Thompson, T. B. The DAN family: modulators of TGF-beta signaling and beyond. Protein Sci. 23, 999–1012 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hata, A. & Chen, Y. G. TGF-beta signaling from receptors to Smads. Cold Spring Harb. Perspect. Biol. 8, a022061 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lamouille, S. & Derynck, R. Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-beta-induced epithelial-mesenchymal transition. Cells Tissues Organs 193, 8–22 (2011).

    Article  PubMed  CAS  Google Scholar 

  30. Heldin, C. H. & Moustakas, A. Signaling receptors for TGF-beta family members. Cold Spring Harb. Perspect. Biol. 8, a022053 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565–576 (2011). This paper highlights the tendency of SMADs to bind to the genome in close association with LDTFs.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Sun, L. T. et al. Nanog co-regulated by Nodal/Smad2 and Oct4 is required for pluripotency in developing mouse epiblast. Dev. Biol. 392, 182–192 (2014).

    Article  PubMed  CAS  Google Scholar 

  33. Wang, W. et al. Smad2 and Smad3 regulate chondrocyte proliferation and differentiation in the growth plate. PLoS Genet. 12, e1006352 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massagué, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).

    Article  PubMed  CAS  Google Scholar 

  35. Chen, C. R., Kang, Y., Siegel, P. M. & Massague, J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110, 19–32 (2002).

    Article  PubMed  CAS  Google Scholar 

  36. Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Guasch, G. et al. Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 12, 313–327 (2007). In this paper, the authors carefully dissect the in vivo effects of Tgfbr2 in normal and neoplastic skin, demonstrating the key role of TGFβ-induced apoptosis in tumour suppression.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. David, C. J. et al. TGF-beta tumor suppression through a lethal EMT. Cell 164, 1015–1030 (2016). This paper is a demonstration that in PDA cells, a TGFβ-induced EMT can result in disruption of an essential lineage-specific transcriptional network, leading to apoptosis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kang, Y. et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl Acad. Sci. USA 102, 13909–13914 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Bisgrove, B. W., Su, Y. C. & Yost, H. J. Maternal Gdf3 is an obligatory cofactor in Nodal signaling for embryonic axis formation in zebrafish. eLife 6, e28534 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Montague, T. G. & Schier, A. F. Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm. eLife 6, e28183 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Pelliccia, J. L., Jindal, G. A. & Burdine, R. D. Gdf3 is required for robust Nodal signaling during germ layer formation and left-right patterning. eLife 6, e28635 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Brazil, D. P., Church, R. H., Surae, S., Godson, C. & Martin, F. BMP signalling: agony and antagony in the family. Trends Cell Biol. 25, 249–264 (2015).

    Article  PubMed  CAS  Google Scholar 

  45. Wang, R. N. et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis. 1, 87–105 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cheifetz, S. et al. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell 48, 409–415 (1987).

    Article  PubMed  CAS  Google Scholar 

  47. Ling, N. et al. Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature 321, 779–782 (1986).

    Article  PubMed  CAS  Google Scholar 

  48. Little, S. C. & Mullins, M. C. Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat. Cell Biol. 11, 637–643 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Shimmi, O., Umulis, D., Othmer, H. & O’Connor, M. B. Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo. Cell 120, 873–886 (2005).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005).

    Article  PubMed  CAS  Google Scholar 

  51. Kashima, R. et al. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci. Signal 9, ra58 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Lee-Hoeflich, S. T. et al. Activation of LIMK1 by binding to the BMP receptor, BMPRII, regulates BMP-dependent dendritogenesis. EMBO J. 23, 4792–4801 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hsiung, F., Ramirez-Weber, F. A., Iwaki, D. D. & Kornberg, T. B. Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 437, 560–563 (2005).

    Article  PubMed  CAS  Google Scholar 

  54. Kicheva, A. et al. Kinetics of morphogen gradient formation. Science 315, 521–525 (2007).

    Article  PubMed  CAS  Google Scholar 

  55. Keller, B. et al. Interaction of TGFbeta and BMP signaling pathways during chondrogenesis. PLoS ONE 6, e16421 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Klammert, U. et al. GDF-5 can act as a context-dependent BMP-2 antagonist. BMC Biol. 13, 77 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Piscione, T. D. et al. BMP-2 and OP-1 exert direct and opposite effects on renal branching morphogenesis. Am. J. Physiol. 273, F961–975 (1997).

    PubMed  CAS  Google Scholar 

  58. Ying, Y., Qi, X. & Zhao, G. Q. Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc. Natl Acad. Sci. USA 98, 7858–7862 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Antebi, Y. E. et al. Combinatorial signal perception in the BMP pathway. Cell 170, 1184–1196.e24 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Xi, Q. et al. A poised chromatin platform for TGF-beta access to master regulators. Cell 147, 1511–1524 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Feng, X. H., Zhang, Y., Wu, R. Y. & Derynck, R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev. 12, 2153–2163 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Janknecht, R., Wells, N. J. & Hunter, T. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 12, 2114–2119 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Pouponnot, C., Jayaraman, L. & Massague, J. Physical and functional interaction of SMADs and p300/CBP. J. Biol. Chem. 273, 22865–22868 (1998).

    Article  PubMed  CAS  Google Scholar 

  64. Wotton, D., Lo, R. S., Lee, S. & Massagué, J. A. Smad transcriptional corepressor. Cell 97, 29–39 (1999).

    Article  PubMed  CAS  Google Scholar 

  65. Kretzschmar, M., Doody, J. & Massague, J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389, 618–622 (1997).

    Article  PubMed  CAS  Google Scholar 

  66. Pera, E. M., Ikeda, A., Eivers, E. & De Robertis, E. M. Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev. 17, 3023–3028 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Sapkota, G., Alarcon, C., Spagnoli, F. M., Brivanlou, A. H. & Massague, J. Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol. Cell 25, 441–454 (2007).

    Article  PubMed  CAS  Google Scholar 

  68. Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139, 757–769 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Aragon, E. et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 25, 1275–1288 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Gao, S. et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol. Cell 36, 457–468 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Matsuura, I. et al. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430, 226–231 (2004).

    Article  PubMed  CAS  Google Scholar 

  72. Fuentealba, L. C. et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131, 980–993 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Tsukamoto, S. et al. Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling. Sci. Rep. 4, 7596 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Wiater, E. & Vale, W. Roles of activin family in pancreatic development and homeostasis. Mol. Cell Endocrinol. 359, 23–29 (2012).

    Article  PubMed  CAS  Google Scholar 

  75. Bruce, D. L. & Sapkota, G. P. Phosphatases in SMAD regulation. FEBS Lett. 586, 1897–1905 (2012).

    Article  PubMed  CAS  Google Scholar 

  76. Dong, X. et al. Force interacts with macromolecular structure in activation of TGF-beta. Nature 542, 55–59 (2017). This remarkable paper provides evidence for a force-dependent mechanism of activation for latent extracellular TGFβ.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Dupont, S., Inui, M. & Newfeld, S. J. Regulation of TGF-beta signal transduction by mono- and deubiquitylation of Smads. FEBS Lett. 586, 1913–1920 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Herhaus, L. & Sapkota, G. P. The emerging roles of deubiquitylating enzymes (DUBs) in the TGFbeta and BMP pathways. Cell Signal 26, 2186–2192 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Luo, K. Ski and SnoN: negative regulators of TGF-beta signaling. Curr. Opin. Genet. Dev. 14, 65–70 (2004).

    Article  PubMed  CAS  Google Scholar 

  80. Miyazawa, K. & Miyazono, K. Regulation of TGF-beta family signaling by inhibitory Smads. Cold Spring Harb. Perspect. Biol. 9, a022095 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. Parrow, N. L. & Fleming, R. E. Bone morphogenetic proteins as regulators of iron metabolism. Annu. Rev. Nutr. 34, 77–94 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Saito, T. et al. Structural basis of the human endoglin-BMP9 interaction: insights into BMP signaling and HHT1. Cell Rep. 19, 1917–1928 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Siebold, C., Yamashita, T., Monnier, P. P., Mueller, B. K. & Pasterkamp, R. J. RGMs: structural insights, molecular regulation, and downstream signaling. Trends Cell Biol 27, 365–378 (2017).

    Article  PubMed  CAS  Google Scholar 

  84. Pirruccello-Straub, M. et al. Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. Sci. Rep. 8, 2292 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Roberts, A. B. et al. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc. Natl Acad. Sci. USA 82, 119–123 (1985).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Tucker, R. F., Shipley, G. D., Moses, H. L. & Holley, R. W. Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226, 705–707 (1984).

    Article  PubMed  CAS  Google Scholar 

  87. Ohta, M., Greenberger, J. S., Anklesaria, P., Bassols, A. & Massagué, J. Two forms of transforming growth factor-beta distinguished by multipotential haematopoietic progenitor cells. Nature 329, 539–541 (1987).

    Article  PubMed  CAS  Google Scholar 

  88. Sporn, M. B. et al. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science 219, 1329–1331 (1983).

    Article  PubMed  CAS  Google Scholar 

  89. Zawel, L. et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1, 611–617 (1998).

    Article  PubMed  CAS  Google Scholar 

  90. Shi, Y. et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94, 585–594 (1998).

    Article  PubMed  CAS  Google Scholar 

  91. BabuRajendran, N. et al. Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-beta effectors. Nucleic Acids Res. 38, 3477–3488 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Kusanagi, K. et al. Characterization of a bone morphogenetic protein-responsive Smad-binding element. Mol. Biol. Cell 11, 555–565 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Labbe, E., Silvestri, C., Hoodless, P. A., Wrana, J. L. & Attisano, L. Smad2 and Smad3 positively and negatively regulate TGF beta-dependent transcription through the forkhead DNA-binding protein FAST2. Mol. Cell 2, 109–120 (1998).

    Article  PubMed  CAS  Google Scholar 

  94. Morikawa, M. et al. ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res. 39, 8712–8727 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Wang, Q. et al. The p53 family coordinates Wnt and nodal Inputs in mesendodermal differentiation of embryonic stem cells. Cell Stem Cell 20, 70–86 (2017). This work highlights the role of p53 in promoting mesenchymal differentiation by coordinating crosstalk between the WNT and the Nodal and activin pathways.

    Article  PubMed  CAS  Google Scholar 

  96. Yoon, S. J., Foley, J. W. & Baker, J. C. HEB associates with PRC2 and SMAD2/3 to regulate developmental fates. Nat. Commun. 6, 6546 (2015).

    Article  PubMed  CAS  Google Scholar 

  97. Zhang, D. X. & Glass, C. K. Towards an understanding of cell-specific functions of signal-dependent transcription factors. J. Mol. Endocrinol. 51, T37–50 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Chen, X., Rubock, M. J. & Whitman, M. A transcriptional partner for MAD proteins in TGF-beta signalling. Nature 383, 691–696 (1996).

    Article  PubMed  CAS  Google Scholar 

  99. Chen, X. et al. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85–89 (1997).

    Article  PubMed  CAS  Google Scholar 

  100. Hata, A. et al. OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100, 229–240 (2000).

    Article  PubMed  CAS  Google Scholar 

  101. Trompouki, E. et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147, 577–589 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Attisano, L. & Wrana, J. L. Signal integration in TGF-beta, WNT, and Hippo pathways. F1000Prime Rep. 5, 17 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Guo, X. & Wang, X. F. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 19, 71–88 (2009).

    Article  PubMed  CAS  Google Scholar 

  104. Qing, J., Zhang, Y. & Derynck, R. Structural and functional characterization of the transforming growth factor-beta -induced Smad3/c-Jun transcriptional cooperativity. J. Biol. Chem. 275, 38802–38812 (2000).

    Article  PubMed  CAS  Google Scholar 

  105. Park, S. R., Seo, G. Y., Choi, A. J., Stavnezer, J. & Kim, P. H. Analysis of transforming growth factor-beta1-induced Ig germ-line gamma2b transcription and its implication for IgA isotype switching. Eur. J. Immunol. 35, 946–956 (2005).

    Article  PubMed  CAS  Google Scholar 

  106. Kang, Y., Chen, C. R. & Massagué, J. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915–926 (2003).

    Article  PubMed  CAS  Google Scholar 

  107. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013). This work shows that lineage-defining super-enhancers are constructed through the cooperative actions of LDTFs and SDTFs.

    Article  PubMed  CAS  Google Scholar 

  108. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Hnisz, D. et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol. Cell 58, 362–370 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Loose, M. & Patient, R. A genetic regulatory network for Xenopus mesendoderm formation. Dev. Biol. 271, 467–478 (2004).

    Article  PubMed  CAS  Google Scholar 

  111. Gaarenstroom, T. & Hill, C. S. TGF-beta signaling to chromatin: how Smads regulate transcription during self-renewal and differentiation. Semin. Cell Dev. Biol. 32, 107–118 (2014).

    Article  PubMed  CAS  Google Scholar 

  112. Charney, R. M. et al. Foxh1 Occupies cis-Regulatory Modules Prior to Dynamic Transcription Factor Interactions Controlling the Mesendoderm Gene Program. Dev. Cell 40, 595–607.e4 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Kim, S. W. et al. Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. Dev. Biol. 357, 492–504 (2011).

    Article  PubMed  CAS  Google Scholar 

  114. Nelson, A. C. et al. In vivo regulation of the zebrafish endoderm progenitor niche by T-box transcription factors. Cell Rep. 19, 2782–2795 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Coda, D. M. et al. Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling. eLife 6, e22474 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Dupont, S. et al. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell 121, 87–99 (2005).

    Article  PubMed  CAS  Google Scholar 

  117. Genander, M. et al. BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. Cell Stem Cell 15, 619–633 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Hwang, J., Mehrani, T., Millar, S. E. & Morasso, M. I. Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Development 135, 3149–3159 (2008).

    Article  PubMed  CAS  Google Scholar 

  119. Faial, T. et al. Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells. Development 142, 2121–2135 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Izzi, L. et al. Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development. EMBO J. 26, 3132–3143 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Teo, A. K. et al. Pluripotency factors regulate definitive endoderm specification through eomesodermin. Genes Dev. 25, 238–250 (2011). This paper demonstrates that the early master regulator of mesenchymal fate EOMES dictates binding of SMAD genome-wide during ESC differentiation, an early demonstration of the concept further elucidated by Mullen et al.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Germain, S., Howell, M., Esslemont, G. M. & Hill, C. S. Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev. 14, 435–451 (2000).

    PubMed  PubMed Central  CAS  Google Scholar 

  123. Sancho, E., Batlle, E. & Clevers, H. Signaling pathways in intestinal development and cancer. Annu. Rev. Cell Dev. Biol. 20, 695–723 (2004).

    Article  PubMed  CAS  Google Scholar 

  124. Watabe, T. et al. Molecular mechanisms of Spemann’s organizer formation: conserved growth factor synergy between Xenopus and mouse. Genes Dev. 9, 3038–3050 (1995).

    Article  PubMed  CAS  Google Scholar 

  125. Reid, C. D., Zhang, Y., Sheets, M. D. & Kessler, D. S. Transcriptional integration of Wnt and Nodal pathways in establishment of the Spemann organizer. Dev. Biol. 368, 231–241 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Stevens, M. L. et al. Genomic integration of Wnt/beta-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs. Development 144, 1283–1295 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Shigeta, M. et al. Maintenance of pluripotency in mouse ES cells without Trp53. Sci. Rep. 3, 2944 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Cordenonsi, M. et al. Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell 113, 301–314 (2003).

    Article  PubMed  CAS  Google Scholar 

  129. Wallingford, J. B., Seufert, D. W., Virta, V. C. & Vize, P. D. p53 activity is essential for normal development in Xenopus. Curr. Biol. 7, 747–757 (1997).

    Article  PubMed  CAS  Google Scholar 

  130. Beyer, T. A. et al. Switch enhancers interpret TGF-beta and Hippo signaling to control cell fate in human embryonic stem cells. Cell Rep. 5, 1611–1624 (2013). This paper demonstrates important crosstalk between Hippo and TGFβ–SMAD signalling in determining the transition from self-renewal into mesenchymal differentiation of human ESCs.

    Article  PubMed  CAS  Google Scholar 

  131. Estaras, C., Benner, C. & Jones, K. A. SMADs and YAP compete to control elongation of beta-catenin:LEF-1-recruited RNAPII during hESC differentiation. Mol. Cell 58, 780–793 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev. Cell 19, 831–844 (2010).

    Article  PubMed  CAS  Google Scholar 

  133. Singh, A. M. et al. Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10, 312–326 (2012). This work highlights key cross-pathway interactions that determine the outcome of TGFβ–SMAD signalling during early development.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Omata, Y. et al. Genomewide comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced osteoclastogenesis. J. Bone Miner. Res. 30, 869–877 (2015).

    Article  PubMed  CAS  Google Scholar 

  135. Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. Emt: 2016. Cell 166, 21–45 (2016).

    Article  PubMed  CAS  Google Scholar 

  136. Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127, 2021–2036 (1994).

    Article  PubMed  CAS  Google Scholar 

  137. Oft, M. et al. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 10, 2462–2477 (1996).

    Article  PubMed  CAS  Google Scholar 

  138. Moustakas, A. & Heldin, C. H. Mechanisms of TGFbeta-induced epithelial-mesenchymal transition. J. Clin. Med. 5, 63 (2016).

    Article  PubMed Central  CAS  Google Scholar 

  139. Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    Article  PubMed  CAS  Google Scholar 

  140. Boyer, A. S. et al. TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev. Biol. 208, 530–545 (1999).

    Article  PubMed  CAS  Google Scholar 

  141. Romano, L. A. & Runyan, R. B. Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. Dev. Biol. 223, 91–102 (2000).

    Article  PubMed  CAS  Google Scholar 

  142. Oshimori, N., Oristian, D. & Fuchs, E. TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell 160, 963–976 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  144. Ye, X. & Weinberg, R. A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Gotzmann, J. et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. J. Cell Sci. 115, 1189–1202 (2002).

    PubMed  CAS  Google Scholar 

  146. Oft, M., Akhurst, R. J. & Balmain, A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat. Cell Biol. 4, 487–494 (2002).

    Article  PubMed  CAS  Google Scholar 

  147. Horiguchi, K. et al. Role of Ras signaling in the induction of snail by transforming growth factor-beta. J. Biol. Chem. 284, 245–253 (2009).

    Article  PubMed  CAS  Google Scholar 

  148. Peinado, H., Quintanilla, M. & Cano, A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J. Biol. Chem. 278, 21113–21123 (2003).

    Article  PubMed  CAS  Google Scholar 

  149. Stritesky, G. L., Jameson, S. C. & Hogquist, K. A. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30, 95–114 (2012).

    Article  PubMed  CAS  Google Scholar 

  150. Brabletz, T. et al. Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol. Cell. Biol. 13, 1155–1162 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Thomas, D. A. & Massagué, J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).

    Article  PubMed  CAS  Google Scholar 

  152. Budhu, S. et al. Blockade of surface-bound TGF-beta on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci. Signal. 10, eaak9702 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  154. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  PubMed  CAS  Google Scholar 

  155. Chen, W. et al. Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202 (2008).

    Article  PubMed  CAS  Google Scholar 

  157. Wu, C. et al. The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat. Immunol. 18, 344–353 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Ouyang, W., Beckett, O., Ma, Q. & Li, M. O. Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32, 642–653 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Zhou, L. et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453, 236–240 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 + T helper cells. Cell 126, 1121–1133 (2006).

    Article  PubMed  CAS  Google Scholar 

  161. Takimoto, T. et al. Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J. Immunol. 185, 842–855 (2010).

    Article  PubMed  CAS  Google Scholar 

  162. Martinez, G. J. et al. Smad2 positively regulates the generation of Th17 cells. J. Biol. Chem. 285, 29039–29043 (2010). This work shows that SMAD2 physically interacts with the TH17 master regulator RORγ2 and promotes its lineage-defining function.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Gorelik, L., Constant, S. & Flavell, R. A. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195, 1499–1505 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Kuwahara, M. et al. The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-beta and suppresses T(H)2 differentiation. Nat. Immunol. 13, 778–786 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Markowitz, S. et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    Article  PubMed  CAS  Google Scholar 

  166. Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    Article  PubMed  CAS  Google Scholar 

  167. Shi, Y., Hata, A., Lo, R. S., Massagué, J. & Pavletich, N. P. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature 388, 87–93 (1997).

    Article  PubMed  CAS  Google Scholar 

  168. Zorn, A. M. & Wells, J. M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 25, 221–251 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371, 257–261 (1994).

    Article  PubMed  CAS  Google Scholar 

  171. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 (1994).

    Article  PubMed  CAS  Google Scholar 

  172. Reynisdóttir, I., Polyak, K., Iavarone, A. & Massagué, J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 9, 1831–1845 (1995).

    Article  PubMed  Google Scholar 

  173. Scandura, J. M., Boccuni, P., Massagué, J. & Nimer, S. D. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc. Natl Acad. Sci. USA 101, 15231–15236 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Ding, Z. et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Bjerke, G. A., Yang, C. S., Frierson, H. F., Paschal, B. M. & Wotton, D. Activation of Akt signaling in prostate induces a TGFbeta-mediated restraint on cancer progression and metastasis. Oncogene 33, 3660–3667 (2014).

    Article  PubMed  CAS  Google Scholar 

  176. Nandan, M. O., Ghaleb, A. M., Bialkowska, A. B. & Yang, V. W. Kruppel-like factor 5 is essential for proliferation and survival of mouse intestinal epithelial stem cells. Stem Cell Res. 14, 10–19 (2015).

    Article  PubMed  CAS  Google Scholar 

  177. Diaferia, G. R. et al. Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer. EMBO J. 35, 595–617 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Zhang, B. et al. KLF5 activates microRNA 200 transcription to maintain epithelial characteristics and prevent induced epithelial-mesenchymal transition in epithelial cells. Mol. Cell. Biol. 33, 4919–4935 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Chia, N. Y. et al. Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut 64, 707–719 (2015).

    Article  PubMed  CAS  Google Scholar 

  180. Tan, T. Z. et al. Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol. Med. 6, 1279–1293 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Gal, A. et al. Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene 27, 1218–1230 (2008). This paper demonstrates that the acute response of mammary epithelial cells induced to undergo EMT by TGFβ is widespread cell death, but a proliferative EMT-competent subpopulation can be selected after chronic exposure to the cytokine.

    Article  PubMed  CAS  Google Scholar 

  182. Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014).

    Article  PubMed  CAS  Google Scholar 

  183. Friess, H. et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105, 1846–1856 (1993).

    Article  PubMed  CAS  Google Scholar 

  184. Wagner, M., Kleeff, J., Friess, H., Buchler, M. W. & Korc, M. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 19, 370–376 (1999).

    Article  PubMed  CAS  Google Scholar 

  185. Diepenbruck, M. & Christofori, G. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr. Opin. Cell Biol. 43, 7–13 (2016).

    Article  PubMed  CAS  Google Scholar 

  186. Tiwari, N. et al. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 23, 768–783 (2013).

    Article  PubMed  CAS  Google Scholar 

  187. Penuelas, S. et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315–327 (2009).

    Article  PubMed  CAS  Google Scholar 

  188. Padua, D. et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Kakonen, S. M. et al. Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J. Biol. Chem. 277, 24571–24578 (2002).

    Article  PubMed  CAS  Google Scholar 

  190. Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Malladi, S. et al. Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165, 45–60 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Calon, A. et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 47, 320–329 (2015).

    Article  PubMed  CAS  Google Scholar 

  193. Calon, A. et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    Article  PubMed  CAS  Google Scholar 

  195. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554,544–548 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed equally to all aspects of the article preparation, including researching data for the article, discussion of content, and writing and editing of the manuscript before submission.

Corresponding author

Correspondence to Joan Massagué.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reviewer information

Nature Reviews Molecular Cell Biology thanks L. Wakefield, R. Akhurst and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Glossary

Signal-driven transcription factors

(SDTFs). Transcription factors that are often ubiquitously expressed but are only switched on in response to activation of a given signalling pathway.

Lineage-determining transcription factors

(LDTFs). Tissue-restricted or cell type-restricted transcription factors that play a dominant role in establishing cellular gene expression patterns, thereby helping to specify cellular identity and function.

Anti-Muellerian hormone

A developmentally restricted TGFβ superfamily member expressed at high levels in male Sertoli cells to guide testicular development and to a lesser extent in female granulosa cells where it regulates follicle development.

Chromatin readers

Proteins containing one or more domains that interact specifically with modified histones, providing a readout of and often enforcing the transcriptional status (active versus silent) of nearby genes.

RAS

A family of small GTPases involved in signal transduction that are activated in response to a number of extracellular signals, often functioning as oncogenes upon constitutive activation by point mutations.

Neddylation

A process analogous to ubiquitylation in which the ubiquitin-like protein NEDD8 is conjugated to target proteins.

Immunoglobulin class switching

Immunoglobulin class switching, also known as class-switch recombination, is a process that switches theproduction of one immunoglobulin isotype to another (e.g. IgM to IgG) in B cells.

PHD domain

A 50–80 amino acid, Cys4-His-Cys3-containing domain found in some chromatin readers, usually displaying a binding preference for lysine-methylated histone tails.

Bromodomain

An approximately 100-amino-acid domain frequently found in chromatin readers, displaying a preference for acetylated lysine residues.

PTEN

A tumour suppressor that restrains activity of the PI3K–AKT pathway through dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate.

Cancer-associated fibroblasts

(CAFs). Fibroblasts present in the tumour stroma that have an important role in promoting tumour growth, invasion and metastasis.

Tumour mutational burden

(TMB). The total number of mutations per coding area of a tumour genome, which is a quantitative index that is used as a biomarker for cancer immunotherapy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

David, C.J., Massagué, J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol 19, 419–435 (2018). https://doi.org/10.1038/s41580-018-0007-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-018-0007-0

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer