TGFβ signalling in context

Nature Reviews Molecular Cell Biology

Volumn 13, Issue 10, 2012, Pages 616-630

  Massagué, Joan ^a,b  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MICRORNA; MITOGEN ACTIVATED PROTEIN KINASE; NUCLEOPORIN; PHOSPHATIDYLINOSITOL 3 KINASE; RNA POLYMERASE II; SMAD PROTEIN; TRANSCRIPTION FACTOR; TRANSFORMING GROWTH FACTOR BETA;

CANCER INHIBITION; CELL DIFFERENTIATION; CELL LINEAGE; CELL MEMBRANE; CELL NUCLEUS; CELL RENEWAL; CHROMATIN; DNA MODIFICATION; DROSOPHILA; EMBRYONIC STEM CELL; EPIGENETICS; EPITHELIAL MESENCHYMAL TRANSITION; GENETIC TRANSCRIPTION; HOMEOSTASIS; HUMAN; NONHUMAN; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN DOMAIN; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH;

ANIMALS; CELL MEMBRANE; CELL NUCLEUS; CHROMATIN; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; NEOPLASMS; PHOSPHORYLATION; RECEPTORS, TRANSFORMING GROWTH FACTOR BETA; SIGNAL TRANSDUCTION; SMAD PROTEINS; TRANSFORMING GROWTH FACTOR BETA;

EID: 84866742560     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3434     Document Type: Review

References (149)

1. Shi, Y. & Massagué, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685-700 (2003).
2. Massagu, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169-178 (2000).
3. Huminiecki, L. et al. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol. Biol. 9, 28 (2009 ).
4. Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 147, 565-576 (2011).
5. Xi, Q. et al. A poised chromatin platform for TGF-β access to master regulators. Cell 147, 1511-1524 (2011).
6. Feng, X. H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659-693 (2005).
7. Massagu, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783-2810 (2005).
8. Trompouki, E. et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147, 577-589 (2011).
9. Kang, Y., Chen, C. R. & Massagu, J. A self-enabling TGFβ response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915-926 (2003).
10. Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66-77 (2008).
11. Kavsak, P. et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol. Cell 6, 1365-1375 (2000).
12. Wu, J. W. et al. Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-β signaling. Cell 111, 357-367 (2002).
13. Heldin, C. H., Landstrom, M. & Moustakas, A. Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr. Opin. Cell Biol. 21, 166-176 (2009).
14. Massagu, J. TGFβ in cancer. Cell 134, 215-230 (2008).
15. Wu, M. Y. & Hill, C. S. Tgf-β superfamily signaling in embryonic development and homeostasis. Dev. Cell 16, 329-343 (2009).
16. Affolter, M. & Basler, K. The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nature Rev. Genet. 8, 663-674 (2007).
17. Kicheva, A. & Gonzalez-Gaitan, M. The Decapentaplegic morphogen gradient: a precise definition. Curr. Opin. Cell Biol. 20, 137-143 (2008).
18. Plouhinec, J. L., Zakin, L. & De Robertis, E. M. Systems control of BMP morphogen flow in vertebrate embryos. Curr. Opin. Genet. Dev. 21, 696-703 (2011).
19. Chen, X. et al. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85-89 (1997).
20. 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).
21. Gomis, R. R. et al. A FoxO-Smad synexpression group in human keratinocytes. Proc. Natl Acad. Sci. USA 103, 12747-12752 (2006).
22. Orkin, S. H. & Hochedlinger, K. Chromatin connections to pluripotency and cellular reprogramming. Cell 145, 835-850 (2011).
23. Young, R. A. Control of the embryonic stem cell state. Cell 144, 940-954 (2011).
24. Nieto, M. A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu. Rev. Cell Dev. Biol. 27, 347-376 (2011).
25. Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926-940 (2011).
26. Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. & Massagu, J. Mechanism of activation of the TGF-β receptor. Nature 370, 341-347 (1994).
27. Huse, M. et al. The TGFβ receptor activation process: an inhibitor-to substrate-binding switch. Mol. Cell 8, 671-682 (2001).
28. Greenwald, J. et al. The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol. Cell 11, 605-617 (2003).
29. Groppe, J. et al. Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol. Cell 29, 157-168 (2008).
30. Moustakas, A. & Heldin, C. H. The regulation of TGFβ signal transduction. Development 136, 3699-3714 (2009).
31. Pardali, E., Goumans, M. J. & ten Dijke, P. Signaling by members of the TGF-β family in vascular morphogenesis and disease. Trends Cell Biol. 20, 556-567 (2010).
32. Cheifetz, S. et al. The transforming growth factor-β system, a complex pattern of cross-reactive ligands and receptors. Cell 48, 409-415 (1987).
33. Zakin, L. & De Robertis, E. M. Extracellular regulation of BMP signaling. Curr. Biol. 20, R89-R92 (2010).
34. Zilberberg, L. et al. Specificity of latent TGF-β binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. J. Cell Physiol. 227, 3828-3836 (2012).
35. Groppe, J. et al. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420, 636-642 (2002).
36. Potti, T. A., Petty, E. M. & Lesperance, M. M. A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD). Hum. Mutat. 32, 877-886 (2011).
37. Sneddon, J. B. et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc. Natl Acad. Sci. USA 103, 14842-14847 (2006).
38. Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343-349 (2011).
39. Lindsay, M. E. & Dietz, H. C. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 473, 308-316 (2011).
40. Muller, P. et al. Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system. Science 336, 721-724 (2012).
41. Schier, A. F. Nodal morphogens. Cold Spring Harb. Perspect. Biol. 1, a003459 (2009).
42. Lewis, K. A. et al. β-glycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 404, 411-414 (2000).
43. Wiater, E., Harrison, C. A., Lewis, K. A., Gray, P. C. & Vale, W. W. Identification of distinct inhibin and transforming growth factor β-binding sites on β-glycan: functional separation of β-glycan co-receptor actions. J. Biol. Chem. 281, 17011-17022 (2006).
44. Lopez-Casillas, F., Wrana, J. L. & Massagu, J. β-glycan presents ligand to the TGFβ signaling receptor. Cell 73, 1435-1444 (1993).
45. Gritsman, K. et al. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97, 121-132 (1999).
46. Gallione, C. et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am. J. Med. Genet. A 152A, 333-339 (2010).
47. Marchuk, D. A. Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr. Opin. Hematol. 5, 332-338 (1998).
48. Xu, L., Kang, Y., Col, S. & Massagu, J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus. Mol. Cell 10, 271-282 (2002).
49. Chen, X. & Xu, L. Specific nucleoporin requirement for Smad nuclear translocation. Mol. Cell. Biol. 30, 4022-4034 (2010).
50. Hill, C. S. Nucleocytoplasmic shuttling of Smad proteins. Cell Res. 19, 36-46 (2009).
51. Dai, F., Lin, X., Chang, C. & Feng, X. H. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-β signaling. Dev. Cell 16, 345-357 (2009).
52. BabuRajendran, N. et al. Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors. Nucleic Acids Res. 38, 3477-3488 (2010).
53. Shi, Y. et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-β signaling. Cell 94, 585-594 (1998).
54. Korchynskyi, O. & ten Dijke, P. Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J. Biol. Chem. 277, 4883-4891 (2002).
55. Yoon, S. J., Wills, A. E., Chuong, E., Gupta, R. & Baker, J. C. HEB and E2A function as SMAD/FOXH1 cofactors. Genes Dev. 25, 1654-1661 (2011).
56. Koinuma, D. et al. Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 100, 2133-2142 (2009).
57. Fei, T. et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res. 20, 36-44 (2010).
58. 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).
59. Alarcn, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139, 757-769 (2009).
60. Gao, S. et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling. Mol. Cell 36, 457-468 (2009).
61. Fuentealba, L. C. et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131, 980-993 (2007).
62. Sapkota, G., Alarcn, C., Spagnoli, F. M., Brivanlou, A. H. & Massagu, J. Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol. Cell 25, 441-454 (2007).
63. Aragn, E. et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 25, 1275-1288 (2011).
64. Conaway, R. C., Sato, S., Tomomori-Sato, C., Yao, T. & Conaway, J. W. The mammalian Mediator complex and its role in transcriptional regulation. Trends Briochem. Sci. 30, 250-255 (2005).
65. Bruce, D. L. & Sapkota, G. P. Phosphatases in SMAD regulation. FEBS Lett. 586, 1897-1905 (2012).
66. Sapkota, G. et al. 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-β pathways. J. Biol. Chem. 281, 40412-40419 (2006).
67. Ghosh, A., Shuman, S. & Lima, C. D. The structure of Fcp1, an essential RNA polymerase II CTD phosphatase. Mol. Cell 32, 478-490 (2008).
68. Lin, X. et al. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling. Cell 125, 915-928 (2006).
69. Simonsson, M., Kanduri, M., Gronroos, E., Heldin, C. H. & Ericsson, J. The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation. J. Biol. Chem. 281, 39870-39880 (2006).
70. Lonn, P. et al. PARP-1 attenuates Smad-mediated transcription. Mol. Cell 40, 521-532 (2010).
71. Ebisawa, T. et al. Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J. Biol. Chem. 276, 12477-12480 (2001).
72. Al-Salihi, M. A., Herhaus, L., Maccartney, T. & Sapkota, G. USP11 augments TGFb signalling by deubiquitylating ALK5. Open Biol. 2, 120063 (2010).
73. Eichhorn, P. J. et al. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nature Med. 18, 429-435 (2012).
74. Zhang, L. et al. USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor. Nature Cell Biol. 14, 717-726 (2012).
75. Inui, M. et al. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nature Cell Biol. 13, 1368-1375 (2011).
76. Paulsen, M., Legewie, S., Eils, R., Karaulanov, E. & Niehrs, C. Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development. Proc. Natl Acad. Sci. USA 108, 10202-10207 (2011).
77. Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q. & Luo, K. Negative feedback regulation of TGF-β signaling by the SnoN oncoprotein. Science 286, 771-774 (1999).
78. Koinuma, D. et al. Arkadia amplifies TGF-β superfamily signalling through degradation of Smad7. EMBO J. 22, 6458-6470 (2003).
79. Levy, L. et al. Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Mol. Cell. Biol. 27, 6068-6083 (2007).
80. Kretzschmar, M., Doody, J. & Massagu, J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618-622 (1997).
81. Matsuura, I. et al. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430, 226-231 (2004).
82. Labb, E., Letamendia, A. & Attisano, L. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-β and wnt pathways. Proc. Natl Acad. Sci. USA 97, 8358-8363 (2000).
83. Labb, E. et al. Transcriptional cooperation between the transforming growth factor-β and Wnt pathways in mammary and intestinal tumorigenesis. Cancer Res. 67, 75-84 (2007).
84. Nakano, N. et al. Requirement of TCF7L2 for TGF-β-dependent transcriptional activation of the TMEPAI gene. J. Biol. Chem. 285, 38023-38033 (2010).
85. Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massagu J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211-223 (2004).
86. Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676-680 (2010).
87. Vincent, T. et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nature Cell Biol. 11, 943-950 (2009).
88. Varelas, X. & Wrana, J. L. Coordinating developmental signaling: novel roles for the Hippo pathway. Trends Cell Biol. 22, 88-96 (2012).
89. Agricola, E., Randall, R. A., Gaarenstroom, T., Dupont, S. & Hill, C. S. Recruitment of TIF1γ to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol. Cell 43, 85-96 (2011).
90. Ross, S. et al. Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. EMBO J. 25, 4490-4502 (2006).
91. Zerlanko, B. J., Bartholin, L., Melhuish, T. A. & Wotton, D. Premature senescence and increased TGFβ signaling in the absence of Tgif1. PLoS ONE 7, e35460 (2012).
92. Taniguchi, K., Anderson, A. E., Sutherland, A. E. & Wotton, D. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS Genet. 8, e1002524 (2012).
93. Thillainadesan, G. et al. TGF-β-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex. Mol. Cell 46, 636-649 (2012).
94. Gomis, R. R., Alarcn, C., Nadal, C., Van Poznak, C. & Massagu, J. C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203-214 (2006).
95. Seoane, J. et al. TGFβ influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nature Cell Biol. 3, 400-408 (2001).
96. Xi, Q., He, W., Zhang, X. H., Le, H. V. & Massagu, J. Genome-wide impact of the BRG1 SWI/SNF chromatin remodeler on the transforming growth factor-β transcriptional program. J. Biol. Chem. 283, 1146-1155 (2008).
97. Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nature Rev. Cancer 11, 481-492 (2011).
98. Hatakeyama, S. TRIM proteins and cancer. Nature Rev. Cancer 11, 792-804 (2011).
99. He, W. et al. Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell 125, 929-941 (2006).
100. Dupont, S. et al. FAM/USP9x, a deubiquitinating enzyme essential for TGFβ signaling, controls Smad4 monoubiquitination. Cell 136, 123-135 (2009).
101. Morsut, L. et al. Negative control of Smad activity by ectodermin/Tif1γ patterns the mammalian embryo. Development 137, 2571-2578 (2010).
102. Vincent, D. F. et al. Inactivation of TIF1γ cooperates with Kras to induce cystic tumors of the pancreas. PLoS Genet. 5, e1000575 (2009).
103. 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).
104. Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603-1609 (2005).
105. Viloria-Petit, A. M. et al. A role for the TGFβ-Par6 polarity pathway in breast cancer progression. Proc. Natl Acad. Sci. USA 106, 14028-14033 (2009).
106. Yi, J. J., Barnes, A. P., Hand, R., Polleux, F. & Ehlers, M. D. TGF-β signaling specifies axons during brain development. Cell 142, 144-157 (2010).
107. Morrell, N. W. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc. Am. Thorac. Soc. 3, 680-686 (2006).
108. Foletta, V. C. et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J. Cell Biol. 162, 1089-1098 (2003).
109. 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).
110. Park, K. S. & Gumbiner, B. M. Cadherin-6B stimulates an epithelial mesenchymal transition and the delamination of cells from the neural ectoderm via LIMK/cofilin mediated non-canonical BMP receptor signaling. Dev. Biol. 366, 232-243 (2012).
111. Holm, T. M. et al. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332, 358-361 (2011).
112. Mu, Y., Gudey, S. K. & Landstrom, M. Non-Smad signaling pathways. Cell Tissue Res. 347, 11-20 (2012).
113. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890 (2009).
114. Bruna, A. et al. High TGFβ-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11, 147-160 (2007).
115. Ikushima, H. et al. Autocrine TGF-β signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5, 504-514 (2009).
116. Peρuelas, S. et al. TGF-β increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315-327 (2009).
117. Kang, Y. et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl Acad. Sci. USA 102, 13909-13914 (2005).
118. Davis, B. N., Hilyard, A. C., Nguyen, P. H., Lagna, G. & Hata, A. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol. Cell 39, 373-384 (2010).
119. Davis, B. N., Hilyard, A. C., Lagna, G. & Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56-61 (2008).
120. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106-1117 (2008).
121. Ying, Q. L., Nichols, J., Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115, 281-292 (2003).
122. Liu, F., Pouponnot, C. & Massagu, J. Dual role of the Smad4/DPC4 tumor suppressor in TGFβ-inducible transcriptional complexes. Genes Dev. 11, 3157-3167 (1997).
123. Brabletz, S. & Brabletz, T. The ZEB/miR-200 feedback loop-a motor of cellular plasticity in development and cancer? EMBO Rep. 11, 670-677 (2010).
124. Derynck, R. & Akhurst, R. J. Differentiation plasticity regulated by TGF-β family proteins in development and disease. Nature Cell Biol. 9, 1000-1004 (2007).
125. Tan, E. J. et al. Regulation of transcription factor Twist expression by the DNA architectural protein high mobility group A2 during epithelial-to- mesenchymal transition. J. Biol. Chem. 287, 7134-7145 (2012).
126. Thuault, S. et al. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J. Biol. Chem. 283, 33437-33446 (2008).
127. Nawshad, A., Medici, D., Liu, C. C. & Hay, E. D. TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex. J. Cell Sci. 120, 1646-1653 (2007).
128. Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64-77 (2010).
129. McDonald, O. G., Wu, H., Timp, W., Doi, A. & Feinberg, A. P. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nature Struct. Mol. Biol. 18, 867-874 (2011).
130. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 (2006).
131. Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51-63 (2010).
132. Ichida, J. K. et al. A small-molecule inhibitor of tgf-β signaling replaces Sox2 in reprogramming by inducing Nanog. Cell Stem Cell 5, 491-503 (2009).
133. Maherali, N. & Hochedlinger, K. Tgfβ signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr. Biol. 19, 1718-1723 (2009).
134. Roberts, A. B. et al. Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev. 17, 19-27 (2006).
135. Yang, L., Pang, Y. & Moses, H. L. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31, 220-227 (2010).
136. Li, M. O. & Flavell, R. A. TGF-β: a master of all T cell trades. Cell 134, 392-404 (2008).
137. Littman, D. R. & Rudensky, A. Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845-858 (2010).
138. Yang, L. et al. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 454, 350-352 (2008).
139. Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236-240 (2008).
140. Koinuma, D. et al. Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor β signaling. Mol. Cell. Biol. 29, 172-186 (2009).
141. Chen, C. R., Kang, Y., Siegel, P. M. & Massagu, J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 110, 19-32 (2002).
142. Arany, P. R. et al. Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure. Proc. Natl Acad. Sci. USA 103, 9250-9255 (2006).
143. Guasch, G. et al. Loss of TGFβ signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 12, 313-327 (2007).
144. Levy, L. & Hill, C. S. Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 17, 41-58 (2006).
145. Arnal-Estap, A. et al. HER2 silences tumor suppression in breast cancer cells by switching expression of C/EBPβ isoforms. Cancer Res. 70, 9927-9936 (2010).
146. Labelle, M., Begum, S. & Hynes, R. O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576-590 (2011).
147. 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).
148. Mohammad, K. S. et al. TGF-β-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. 71, 175-184 (2011).
149. Anido, J. et al. TGF-β receptor inhibitors target the CD44high/Id1high glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655-668 (2010).