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Cited by 851TGF-β signaling in diseasesDevelopmental Biology and Gene RegulationSignaling Pathways in Disease

Contextual determinants of TGFβ action in development, immunity and cancer

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David, Charles J., Massagué, Joan·2018·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-018-0007-0PMC PMC7457231
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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.

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  • NicheNet predicted that broadly expressed TGFB1 and CAF-specific TGFB3 regulate TSKs.

    “Further supporting TSKs as an EMT-like population, NicheNet predicted that broadly expressed TGFB1 and CAF-specific TGFB3 regulate TSKs (David and Massagué, 2018).”

    From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as David and Massagué, 2018

    The section on determinants of TGF-β-induced EMT discusses TGF-β as an EMT inducer, but does not report a NicheNet prediction about TSKs. Searches for NicheNet, TSKs, CAFs, TGFB1, and TGFB3 found no passage addressing the claimed expression patterns or predicted regulation. (LLM, conf=0.77)

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  1. [1]Massagué J How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1, 169– 178 (2000). 11252892
  2. [2]Josso N, Belville C, di Clemente N & Picard JY AMH and AMH receptor defects in persistent Mullerian duct syndrome. Hum Reprod Update 11, 351– 356 (2005). 15878900
  3. [3]Lindsay ME & Dietz HC The genetic basis of aortic aneurysm. Cold Spring Harb Perspect Med 4, a015909 (2014). 25183854 PMC4143103
  4. [4]Matzuk MM & Burns KH Genetics of mammalian reproduction: modeling the end of the germline. Annu Rev Physiol 74, 503– 528 (2012). 22335799
  5. [5]Meng XM, Nikolic-Paterson DJ & Lan HY TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol 12, 325– 338 (2016). 27108839
  6. [6]Salazar VS, Gamer LW & Rosen V BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol 12, 203– 221 (2016). 26893264
  7. [7]van der Kraan PM The changing role of TGFbeta in healthy, ageing and osteoarthritic joints. Nat Rev Rheumatol 13, 155– 163 (2017). 28148919
  8. [8]Cai J, Pardali E, Sanchez-Duffhues G & ten Dijke P BMP signaling in vascular diseases. FEBS Lett 586, 1993– 2002 (2012). 22710160
  9. [9]Massagué J TGFbeta in cancer. Cell 134, 215– 230 (2008). 18662538 PMC3512574
  10. [10]Pickup M, Novitskiy S & Moses HL The roles of TGFbeta in the tumour microenvironment. Nat Rev Cancer 13, 788– 799 (2013). 24132110 PMC4025940
  11. [11]Tauriello DVF & Batlle E Targeting the Microenvironment in Advanced Colorectal Cancer. Trends Cancer 2, 495– 504 (2016). 28741478
  12. [12]Wakefield LM & Hill CS Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat Rev Cancer 13, 328– 341 (2013). 23612460 PMC7608560
  13. [13]Massagué J TGFbeta signalling in context. Nat Rev Mol Cell Biol 13, 616– 630 (2012). 22992590 PMC4027049
  14. [14]Mullen AC & Wrana JL TGF-beta family signaling in embryonic and somatic stem-cell renewal and differentiation. Cold Spring Harb Perspect Biol 9 (2017). PMC5495062 28108485 This paper highlighted the tendency of Smads to bind the genome in close association with lineage-specific master transcription factor.
  15. [15]Oshimori N & Fuchs E The harmonies played by TGF-beta in stem cell biology. Cell Stem Cell 11, 751– 764 (2012). 23217421 PMC3612991
  16. [16]Pauklin S & Vallier L Activin/Nodal signalling in stem cells. Development 142, 607– 619 (2015). 25670788
  17. [17]Chen W & Ten Dijke P Immunoregulation by members of the TGFbeta superfamily. Nat Rev Immunol 16, 723– 740 (2016). 27885276
  18. [18]Sanjabi S, Oh SA & Li MO Regulation of the Immune Response by TGF-beta: From Conception to Autoimmunity and Infection. Cold Spring Harb Perspect Biol (2017). PMC5453394 28108486
  19. [19]Shi Y & Massagué J Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685– 700 (2003). 12809600
  20. [20]Wrana JL TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003– 1014 (1992). 1333888
  21. [21]Wrana JL, Attisano L, Wieser R, Ventura F & Massagué J Mechanism of activation of the TGF-beta receptor. Nature 370, 341– 347 (1994). 8047140
  22. [22]Inman GJ, Nicolas FJ & Hill CS Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell 10, 283– 294 (2002). 12191474
  23. [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). 12191473
  24. [24]Martin-Malpartida P Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors. Nature Communications (in press). PMC5727232 29234012
  25. [25]Hinck AP, Mueller TD & Springer TA Structural Biology and Evolution of the TGF-beta Family. Cold Spring Harb Perspect Biol 8 (2016). PMC5131774 27638177
  26. [26]Macias MJ, Martin-Malpartida P & Massagué J Structural determinants of Smad function in TGF-beta signaling. Trends Biochem Sci 40, 296– 308 (2015). 25935112 PMC4485443
  27. [27]Nolan K & Thompson TB The DAN family: modulators of TGF-beta signaling and beyond. Protein Sci 23, 999– 1012 (2014). 24810382 PMC4116650
  28. [28]Hata A & Chen YG TGF-beta Signaling from Receptors to Smads. Cold Spring Harb Perspect Biol 8 (2016). PMC5008074 27449815
  29. [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). 21041997 PMC3030503
  30. [31]Mullen AC Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565– 576 (2011). 22036565 PMC3212730 This paper highlighted the tendency of Smads to bind the genome in close association with lineage-specific master transcription factor.
  31. [32]Sun LT Nanog co-regulated by Nodal/Smad2 and Oct4 is required for pluripotency in developing mouse epiblast. Dev Biol 392, 182– 192 (2014). 24929238
  32. [33]Wang W Smad2 and Smad3 Regulate Chondrocyte Proliferation and Differentiation in the Growth Plate. PLoS Genet 12, e1006352 (2016). 27741240 PMC5065210 This work highlights the role of p53 in promoting ME differentiation by coordinating crosstalk between the Wnt and Nodal/activin pathways.
  33. [34]Seoane J, Le HV, Shen L, Anderson SA & Massagué J Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211– 223 (2004). 15084259
  34. [35]Chen CR, Kang Y, Siegel PM & Massague J E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110, 19– 32 (2002). 12150994
  35. [36]Bardeesy N Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 20, 3130– 3146 (2006). 17114584 PMC1635148
  36. [37]Guasch G Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 12, 313– 327 (2007). 17936557 PMC2424201 The authors carefully dissected the in vivo effects of Tgfbr2 in normal and neoplastic skin, demonstrating the key role of TGF-β-induced apoptosis in tumor suppression.
  37. [38]David CJ TGF-beta tumor suppression through a lethal EMT. Cell 164, 1015– 1030 (2016). 26898331 PMC4801341 Demonstration that in PDA cells, a TGF-β-induced EMT can result in disruption of an essential lineage-specific transcriptional network, leading to apoptosis.
  38. [39]Kang Y Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A 102, 13909– 13914(2005). 16172383 PMC1236573
  39. [40]Sethi N, Dai X, Winter CG & 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). 21295524 PMC3040415
  40. [41]Bisgrove BW, Su YC & Yost HJ Maternal Gdf3 is an obligatory cofactor in Nodal signaling for embryonic axis formation in zebrafish. Elife 6 (2017). PMC5745076 29140249
  41. [42]Montague TG & Schier AF Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm. Elife 6 (2017). PMC5745085 29140251
  42. [43]Pelliccia JL, Jindal GA & Burdine RD Gdf3 is required for robust Nodal signaling during germ layer formation and left-right patterning. Elife 6 (2017). PMC5745080 29140250
  43. [44]Brazil DP, Church RH, Surae S, Godson C & Martin F BMP signalling: agony and antagony in the family. Trends Cell Biol 25, 249– 264 (2015). 25592806
  44. [45]Wang RN Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis 1, 87– 105 (2014). 25401122 PMC4232216 This work highlights the role of p53 in promoting ME differentiation by coordinating crosstalk between the Wnt and Nodal/activin pathways.
  45. [46]Cheifetz S The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell 48, 409– 415 (1987). 2879635
  46. [47]Ling N Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature 321, 779– 782 (1986). 3086749
  47. [48]Little SC & Mullins MC Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat Cell Biol 11, 637– 643 (2009). 19377468 PMC2757091
  48. [49]Shimmi O, Umulis D, Othmer H & O'Connor MB Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo. Cell 120, 873– 886 (2005). 15797386 PMC6460932
  49. [50]Ozdamar B Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307, 1603– 1609 (2005). 15761148
  50. [51]Kashima R Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci Signal 9, ra58 (2016). 27273096 PMC5274719
  51. [52]Lee-Hoeflich ST Activation of LIMK1 by binding to the BMP receptor, BMPRII, regulates BMP-dependent dendritogenesis. EMBO J 23, 4792– 4801 (2004). 15538389 PMC535083
  52. [53]Hsiung F, Ramirez-Weber FA, Iwaki DD & Kornberg TB Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 437, 560– 563 (2005). 16177792
  53. [54]Kicheva A Kinetics of morphogen gradient formation. Science 315, 521– 525 (2007). 17255514
  54. [55]Keller B Interaction of TGFbeta and BMP signaling pathways during chondrogenesis. PLoS One 6, e16421 (2011). 21297990 PMC3030581
  55. [56]Klammert U GDF-5 can act as a context-dependent BMP-2 antagonist. BMC Biol 13, 77 (2015). 26385096 PMC4575486
  56. [57]Piscione TD BMP-2 and OP-1 exert direct and opposite effects on renal branching morphogenesis. Am J Physiol 273, F961– 975 (1997). 9435686
  57. [58]Ying Y, Qi X & Zhao GQ Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc Natl Acad Sci U S A 98, 7858– 7862 (2001). 11427739 PMC35432
  58. [59]Antebi YE Combinatorial Signal Perception in the BMP Pathway. Cell 170, 1184– 1196 e1124 (2017). 28886385 PMC5612783
  59. [60]Xi Q A poised chromatin platform for TGF-beta access to master regulators. Cell 147, 1511– 1524 (2011). 22196728 PMC3582033 The authors demonstrate that early developmental master regulator genes are accessed by Smads with the assistance of a Trim33, a chromatin reader that recognizes silencing-associated histone marks.
  60. [61]Feng XH, Zhang Y, Wu RY & 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). 9679060 PMC317015
  61. [62]Janknecht R, Wells NJ & Hunter T TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev 12, 2114– 2119 (1998). 9679056 PMC317012
  62. [63]Pouponnot C, Jayaraman L & Massague J Physical and functional interaction of SMADs and p300/CBP. J Biol Chem 273, 22865– 22868 (1998). 9722503
  63. [64]Wotton D, Lo RS, Lee S & Massagué J A Smad transcriptional corepressor. Cell 97, 29– 39 (1999). 10199400
  64. [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). 9335504
  65. [66]Pera EM, Ikeda A, Eivers E & De Robertis EM Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev 17, 3023– 3028 (2003). 14701872 PMC305254
  66. [67]Sapkota G, Alarcon C, Spagnoli FM, Brivanlou AH & Massague J Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell 25, 441– 454 (2007). 17289590
  67. [68]Alarcon C Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139, 757– 769 (2009). 19914168 PMC2818353
  68. [69]Matsuura I Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430, 226– 231 (2004). 15241418
  69. [71]Wiater E & Vale W Roles of activin family in pancreatic development and homeostasis. Mol Cell Endocrinol 359, 23– 29 (2012). 22406274
  70. [72]Gao S Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol Cell 36, 457– 468 (2009). 19917253 PMC2796330
  71. [73]Aragon E A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 25, 1275– 1288 (2011). 21685363 PMC3127429
  72. [74]Sapkota G Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways. J Biol Chem 281, 40412– 40419 (2006). 17085434
  73. [75]Lonn P PARP-1 attenuates Smad-mediated transcription. Mol Cell 40, 521– 532 (2010). 21095583
  74. [76]Roberts AB Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A 82, 119– 123 (1985). 3871521 PMC396983
  75. [77]Tucker RF, Shipley GD, Moses HL & Holley RW Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226, 705– 707 (1984). 6093254
  76. [78]Ohta M, Greenberger JS, Anklesaria P, Bassols A & Massagué J Two forms of transforming growth factor-beta distinguished by multipotential haematopoietic progenitor cells. Nature 329, 539– 541 (1987). 2889143
  77. [79]Sporn MB Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science 219, 1329– 1331 (1983). 6572416
  78. [80]Zawel L Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1, 611– 617 (1998). 9660945
  79. [81]Shi Y Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94, 585– 594 (1998). 9741623
  80. [82]BabuRajendran N Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-beta effectors. Nucleic Acids Res 38, 3477– 3488 (2010). 20147459 PMC2879523
  81. [83]Kusanagi K Characterization of a bone morphogenetic protein-responsive Smad-binding element. Mol Biol Cell 11, 555– 565 (2000). 10679014 PMC14793
  82. [84]Labbe E, Silvestri C, Hoodless PA, Wrana JL & 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). 9702197
  83. [85]Morikawa M ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res 39, 8712– 8727 (2011). 21764776 PMC3203580
  84. [86]Wang Q The p53 family coordinates Wnt and nodal Inputs in mesendodermal differentiation of embryonic stem cells. Cell Stem Cell 20, 70– 86 (2017). 27889317 PMC5218926 This work highlights the role of p53 in promoting ME differentiation by coordinating crosstalk between the Wnt and Nodal/activin pathways.
  85. [87]Yoon SJ, Foley JW & Baker JC HEB associates with PRC2 and SMAD2/3 to regulate developmental fates. Nat Commun 6, 6546 (2015). 25775035
  86. [88]Zhang DX & Glass CK Towards an understanding of cell-specific functions of signal-dependent transcription factors. J Mol Endocrinol 51, T37– 50 (2013). 24130129 PMC4128342
  87. [89]Chen X, Rubock MJ & Whitman M A transcriptional partner for MAD proteins in TGF-beta signalling. Nature 383, 691– 696 (1996). 8878477
  88. [90]Chen X Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85– 89 (1997). 9288972
  89. [91]Hata A OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100, 229– 240 (2000). 10660046
  90. [92]Trompouki E Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147, 577– 589 (2011). 22036566 PMC3219441
  91. [93]Attisano L & Wrana JL Signal integration in TGF-beta, WNT, and Hippo pathways. F1000Prime Rep 5, 17 (2013). 23755364 PMC3672943
  92. [94]Guo X & Wang XF Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 19, 71– 88 (2009). 19002158 PMC3606489
  93. [95]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). 10995748
  94. [96]Park SR, Seo GY, Choi AJ, Stavnezer J & Kim PH 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). 15688346
  95. [97]Kang Y, Chen CR & 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). 12718878
  96. [99]Whyte WA Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307– 319 (2013). 23582322 PMC3653129
  97. [100]Hnisz D Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell 58, 362– 370 (2015). 25801169 PMC4402134 This work showed that lineage-defining super-enhancers are constructed through the cooperative actions of LDTFs and SDTFs.
  98. [101]Loose M & Patient R A genetic regulatory network for Xenopus mesendoderm formation. Dev Biol 271, 467– 478 (2004). 15223347
  99. [102]Gaarenstroom T & Hill CS TGF-beta signaling to chromatin: how Smads regulate transcription during self-renewal and differentiation. Semin Cell Dev Biol 32, 107– 118 (2014). 24503509
  100. [103]Charney RM Foxh1 Occupies cis-Regulatory Modules Prior to Dynamic Transcription Factor Interactions Controlling the Mesendoderm Gene Program. Dev Cell 40, 595– 607 e594 (2017). 28325473 PMC5434453
  101. [104]Kim SW Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. Dev Biol 357, 492– 504 (2011). 21741376
  102. [105]Nelson AC In Vivo Regulation of the Zebrafish Endoderm Progenitor Niche by T-Box Transcription Factors. Cell Rep 19, 2782– 2795 (2017). 28658625 PMC5494305
  103. [106]Coda DM Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling. Elife 6 (2017). PMC5305219 28191871
  104. [107]Dupont S Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell 121, 87– 99 (2005). 15820681
  105. [108]Genander M BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. Cell Stem Cell 15, 619– 633 (2014). 25312496 PMC4276600
  106. [109]Hwang M, Mehrani T, Millar SE & Morasso MI Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Development 135, 3149– 3159 (2008). 18684741 PMC2707782
  107. [110]Faial T Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells. Development 142, 2121– 2135 (2015). 26015544 PMC4483767
  108. [111]Izzi L Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development. EMBO J 26, 3132– 3143 (2007). 17568773 PMC1914101
  109. [112]Teo AK Pluripotency factors regulate definitive endoderm specification through eomesodermin. Genes Dev 25, 238– 250 (2011). 21245162 PMC3034899 Demonstration that the early ME master regulator Eomes dictates Smad genome-wide binding during ES cell differentiation, an early demonstration of the concept further elucidated by Mullen et al.
  110. [113]Germain S, Howell M, Esslemont GM & Hill CS 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). 10691736 PMC316385
  111. [114]Sancho E, Batlle E & Clevers H Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 20, 695– 723 (2004). 15473857
  112. [115]Watabe T Molecular mechanisms of Spemann's organizer formation: conserved growth factor synergy between Xenopus and mouse. Genes Dev 9, 3038– 3050 (1995). 8543150
  113. [116]Reid CD, Zhang Y, Sheets MD & Kessler DS Transcriptional integration of Wnt and Nodal pathways in establishment of the Spemann organizer. Dev Biol 368, 231– 241 (2012). 22627292 PMC3572767
  114. [117]Stevens ML Genomic integration of Wnt/beta-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs. Development 144, 1283– 1295 (2017). 28219948 PMC5399627
  115. [118]Shigeta M Maintenance of pluripotency in mouse ES cells without Trp53. Sci Rep 3, 2944 (2013). 24126347 PMC3796736
  116. [119]Cordenonsi M Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell 113, 301– 314 (2003). 12732139
  117. [120]Wallingford JB, Seufert DW, Virta VC & Vize PD p53 activity is essential for normal development in Xenopus. Curr Biol 7, 747– 757 (1997). 9368757
  118. [121]Beyer TA Switch enhancers interpret TGF-beta and Hippo signaling to control cell fate in human embryonic stem cells. Cell Rep 5, 1611– 1624 (2013). 24332857 These authors demonstrate important crosstalk between Hippo and TGF-β–Smad signaling in determining the transition from self-renewal into ME differentiation of human embryonic stem cells.
  119. [122]Estaras C, Benner C & Jones KA SMADs and YAP compete to control elongation of beta-catenin:LEF-1-recruited RNAPII during hESC differentiation. Mol Cell 58, 780– 793 (2015). 25936800 PMC5315497
  120. [123]Varelas X The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19, 831– 844 (2010). 21145499
  121. [124]Singh AM 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). 22385658 PMC3294294 This work highlights key cross-pathway interactions that determine the outcome of TGFβ/Smad signaling during early development..
  122. [125]Omata Y Genomewide comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced osteoclastogenesis. J Bone Miner Res 30, 869– 877 (2015). 25431176
  123. [126]Nieto MA, Huang RY, Jackson RA & Thiery JP Emt: 2016. Cell 166, 21– 45 (2016). 27368099
  124. [127]Miettinen PJ, Ebner R, Lopez AR & Deiynck R TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127, 2021– 2036 (1994). 7806579 PMC2120317
  125. [128]Oft M TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10, 2462– 2477 (1996). 8843198
  126. [129]Moustakas A & Heldin CH Mechanisms of TGFbeta-induced epithelial-mesenchymal transition. J Clin Med 5 (2016). PMC4961994 27367735
  127. [130]Yang J & Weinberg RA Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14, 818– 829 (2008). 18539112
  128. [131]Boyer AS TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol 208, 530– 545 (1999). 10191064
  129. [132]Romano LA & Runyan RB Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. Dev Biol 223, 91– 102 (2000). 10864463
  130. [134]Puram SV Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell 171, 1611– 1624 e1624 (2017). 29198524 PMC5878932
  131. [135]Ye X & Weinberg RA Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression. Trends Cell Biol 25, 675– 686 (2015). 26437589 PMC4628843
  132. [136]Gotzmann J Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. JCell Sci 115, 1189– 1202 (2002). 11884518
  133. [137]Oft M, Akhurst RJ & Balmain A Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4, 487– 494 (2002). 12105419
  134. [138]Horiguchi K Role of Ras signaling in the induction of snail by transforming growth factor-beta. J Biol Chem 284, 245– 253 (2009). 19010789
  135. [139]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). 12665527
  136. [140]Sanjabi S, Oh SA & Li MO Regulation of the Immune Response by TGF-beta: From Conception to Autoimmunity and Infection. Cold Spring Harb Perspect Biol 9 (2017). PMC5453394 28108486
  137. [141]Stritesky GL, Jameson SC & Hogquist KA Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30, 95– 114 (2012). 22149933 PMC3518413
  138. [142]Brabletz T 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). 8423782 PMC359000
  139. [143]Thomas DA & Massagué J TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369– 380 (2005). 16286245
  140. [144]Budhu S Blockade of surface-bound TGF-beta on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal 10 (2017). PMC5851440 28851824
  141. [145]Josefowicz SZ, Lu LF & Rudensky AY Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30, 531– 564 (2012). 22224781 PMC6066374
  142. [147]Chen W 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). 14676299 PMC2194145
  143. [149]Wu C The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat Immunol 18, 344– 353 (2017). 28114290 PMC5591438
  144. [150]Ouyang W, Beckett O, Ma Q & Li MO Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32, 642– 653 (2010). 20471291 PMC2880228
  145. [151]Zhou L TGF-beta-induced Foxp3 inhibits T(H) 17 cell differentiation by antagonizing RORgammat function. Nature 453, 236– 240 (2008). 18368049 PMC2597437
  146. [153]Takimoto T 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). 20548029
  147. [154]Martinez GJ Smad2 positively regulates the generation of Th17 cells. Biol Chem 285, 29039– 29043 (2010). PMC2937933 20667820 This work showed that Smad2 phyiscally interacts with the Th17 master regulator Rorγt and promotes its lineage-defining function.
  148. [155]Gorelik L, Constant S & Flavell RA Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195, 1499– 1505 (2002). 12045248 PMC2193549
  149. [156]Kuwahara M 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). 22751141 PMC3477402
  150. [157]Markowitz S Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336– 1338 (1995). 7761852
  151. [159]Shi Y, Hata A, Lo RS, Massagué J & Pavletich NP A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature 388, 87– 93 (1997). 9214508
  152. [161]Ijichi H 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). 17114585 PMC1635149
  153. [163]Polyak K Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59– 66 (1994). 8033212
  154. [164]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). 7649471
  155. [165]Scandura JM, Boccuni P, Massagué J & Nimer SD Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 upregulation. Proc Natl Acad Sci U S A 101, 15231– 15236 (2004). 15477587 PMC524079
  156. [166]Ding Z SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269– 273 (2011). 21289624 PMC3753179
  157. [167]Bjerke GA, Yang CS, Frierson HF, Paschal BM & Wotton D Activation of Akt signaling in prostate induces a TGFbeta-mediated restraint on cancer progression and metastasis. Oncogene 33, 3660– 3667 (2014). 23995785 PMC3939071
  158. [168]Nandan MO, Ghaleb AM, Bialkowska AB & Yang VW Kruppel-like factor 5 is essential for proliferation and survival of mouse intestinal epithelial stem cells. Stem Cell Res 14, 10– 19 (2015). 25460247 PMC4310780
  159. [169]Diaferia GR Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer. EMBO J 35, 595– 617 (2016). 26769127 PMC4801945
  160. [170]Zhang B 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). 24126055 PMC3889554
  161. [171]Chia NY Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut 64, 707– 719 (2015). 25053715
  162. [173]Gal A 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). 17724470 Demonstration that the acute response of mammary epithelial cells induced to undergo an EMT by TGF-β is widespread cell death, while a proliferative EMT-competent subpopulation can be selected after chronic exposure to the cytokine.
  163. [174]Diepenbruck M & Christofori G Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol 43, 7– 13 (2016). 27371787
  164. [175]Tiwari N Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 23, 768– 783 (2013). 23764001
  165. [176]Penuelas S TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315– 327 (2009). 19345330
  166. [177]Padua D TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66– 77 (2008). 18394990 PMC2390892
  167. [178]Kakonen SM 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). 11964407
  168. [179]Massague J & Obenauf AC Metastatic colonization by circulating tumour cells. Nature 529, 298– 306 (2016). 26791720 PMC5029466
  169. [182]Calon A Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571– 584 (2012). 23153532 PMC3512565
  170. [183]Terabe M Blockade of only TGF-beta 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. Oncoimmunology 6, e1308616 (2017). 28638730 PMC5467996
  171. [184]Bruce DL & Sapkota GP Phosphatases in SMAD regulation. FEBS Lett 586, 1897– 1905 (2012). 22576046
  172. [186]Dupont S, Inui M & Newfeld SJ Regulation of TGF-beta signal transduction by mono- and deubiquitylation of Smads. FEBS Lett 586, 1913– 1920 (2012). 22710170 PMC3383349
  173. [187]Herhaus L & Sapkota GP The emerging roles of deubiquitylating enzymes (DUBs) in the TGFbeta and BMP pathways. Cell Signal 26, 2186– 2192 (2014). 25007997 PMC4443431
  174. [188]Luo K Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev 14, 65– 70 (2004). 15108807
  175. [189]Miyazawa K & Miyazono K Regulation of TGF-beta Family Signaling by Inhibitory Smads. Cold Spring Harb Perspect Biol 9 (2017). PMC5334261 27920040
  176. [190]Parrow NL & Fleming RE Bone morphogenetic proteins as regulators of iron metabolism. Anna Rev Nutr 34, 77– 94 (2014). 24995692 PMC7713507
  177. [191]Saito T Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell Rep 19, 1917– 1928 (2017). 28564608 PMC5464963
  178. [192]Siebold C, Yamashita T, Monnier PP, Mueller BK & Pasterkamp RJ RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling. Trends Cell Biol 27, 365– 378(2017). 28007423 PMC5404723
  179. [193]Ryan DP, Hong TS & Bardeesy N Pancreatic adenocarcinoma. N Engl J Med 371, 1039– 1049 (2014). 25207767
  180. [194]Friess H Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105, 1846– 1856(1993). 8253361
  181. [195]Wagner M, Kleeff J, Friess H, Buchler MW & 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). 10547197
  182. [196]Gao J Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6, pl1 (2013). 23550210 PMC4160307

Cited by

Sorted by citations

Authors
David, C. J., & Massagué, J.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Massagué, Joan
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2018-04-11
Volume
19
Issue
7
Pages
419-435
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-018-0007-0
PMC
PMC7457231
OpenAlex
W2798233554
Cited by
851
References
15
Citations by year
2026: 62 · 2025: 96 · 2024: 116 · 2023: 101 · 2022: 139 · 2021: 144 · 2020: 96 · 2019: 77 · 2018: 19
FWCI
8.35
Type
journal article
Language
en
Update notices
correction (2018-05-08)
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (T32CA160001, R01CA034610, P30CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
TGF-beta signaling, Smad transcription factors, TGF-beta receptor, context-dependent signaling, cell fate determination, developmental biology, tissue regeneration, tissue homeostasis, carcinogenesis, fibrosis, immune regulation, chromatin regulation, gene expression regulation

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