The tale of transforming growth factor-beta (TGFβ) signaling: A soigné enigma

IUBMB Life

Volumn 61, Issue 10, 2009, Pages 929-939

  Chaudhury, Arindam ^a,b   Howe, Philip H ^a,b  

^a LERNER RESEARCH INSTITUTE   (United States)

^b CLEVELAND STATE UNIVERSITY   (United States)

Author keywords

Canonical signaling; Carcinogenesis; Cytostatic effects; Epithelial to mesenchymal transition (EMT); Non canonical signaling; Smads; TGF receptors; Transforming growth factor beta (TGF )

Indexed keywords

TRANSFORMING GROWTH FACTOR BETA; SMAD PROTEIN; TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TUMOR SUPPRESSOR PROTEIN;

APOPTOSIS; AUTOCRINE EFFECT; CANCER GROWTH; CANCER INHIBITION; CARCINOGENESIS; HUMAN; METASTASIS; REVIEW; SIGNAL TRANSDUCTION; TUMOR PROMOTION; ANIMAL; CELL TRANSFORMATION; EPITHELIUM CELL; FORECASTING; GENETICS; MESODERM; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; EPITHELIAL CELLS; FORECASTING; HUMANS; MESODERM; RECEPTORS, TRANSFORMING GROWTH FACTOR BETA; SIGNAL TRANSDUCTION; SMAD PROTEINS; TRANSFORMING GROWTH FACTOR BETA; TUMOR SUPPRESSOR PROTEINS;

EID: 73349111306     PISSN: 15216543     EISSN: 15216551     Source Type: Journal    
DOI: 10.1002/iub.239     Document Type: Review

References (155)

1. Sporn, M. B. (1999) TGF-beta: 20 years and counting. Microbes Infect. 1, 1251-1253.
2. de Larco, J. E. and Todaro, G. J. (1978) Growth factors from murine sarcoma virus-transformed cells. Proc. Natl. Acad. Sci. USA 75, 4001-4005.
3. Roberts, A. B., Anzano, M. A., Lamb, L. C., Smith, J. M., and Sporn, M. B. (1981) New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc. Natl. Acad. Sci. USA 78, 5339-5343.
4. Childs, C. B., Proper, J. A., Tucker, R. F., and Moses, H. L. (1982) Serum contains a platelet-derived transforming growth factor. Proc. Natl. Acad. Sci. USA 79, 5312-5316.
5. Roberts, A. B., Frolik, C. A., Anzano, M. A., and Sporn, M. B. (1983) Transforming growth factors from neoplastic and nonneoplastic tissues. Fed. Proc. 42, 2621-2626.
6. Assoian, R. K., Komoriya, A., Meyers, C. A., Miller, D. M., and Sporn, M. B. (1983) Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J. Biol. Chem. 258, 7155-7160.
7. Frolik, C. A., Dart, L. L., Meyers, C. A., Smith, D. M., and Sporn, M. B. (1983) Purification and initial characterization of a type beta transforming growth factor from human placenta. Proc. Natl. Acad. Sci. USA 80, 3676-3680.
8. Roberts, A. B., Anzano, M. A., Meyers, C. A., Wideman, J., Blacher, R., Pan, Y. C., Stein, S., Lehrman, S. R., and Smith, J. M. (1983) Purification and properties of a type beta transforming growth factor from bovine kidney. Biochemistry 22, 5692-5698. (Pubitemid 14224613)
9. Kingsley, D. M. (1994) The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 8, 133-146. (Pubitemid 2044355)
10. Massague, J. (1998) TGF-beta signal transduction. Annu. Rev. Biochem. 67, 753-791.
11. Shi, Y. and Massague, J. (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685-700. (Pubitemid 36724933)
12. Tucker, R. F., Shipley, G. D., Moses, H. L., and Holley, R. W. (1984) Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226, 705-707.
13. Moses, H. L., Tucker, R. F., Leof, E. B., Coffey, R. J., Jr., Halper, J., and Shipley, G. D. (1985) Type β transforming growth factor is a growth stimulator and a growth inhibitor. In Growth Factors and Transformation. Cancer Cells, Vol. 3. (Feramisco, J., Ozanne, B., and Stiles, C. eds.). pp. 65-71, Cold Spring Harbor Press, Cold Spring Harbor, NY.
14. Pepper, M. S. (1997) Transforming growth factor-beta: vasculogeneis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8, 21-43.
15. Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L., and Arteaga, C. L. (2000) Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem. 275, 36803-36810.
16. Akhurst, R. J. and Derynck, R. (2001) TGF-beta signaling in cancera double-edged sword. Trends Cell Biol. 11, S44-S51. (Pubitemid 33001443)
17. Derynck, R., Akhurst, R. J., and Balmain, A. (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 29, 117-129.
18. Moustakas, A., Pardali, K., Gaal, A., and Heldin, C. H. (2002) Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol. Lett. 82, 85-91.
19. Roberts, A. B. and Wakefield, L. M. (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc. Natl. Acad. Sci. USA 100, 8621-8623.
20. Lamouille, S. and Derynck, R. (2007) Cell size and invasion in TGFbeta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J. Cell Biol. 178, 437-451. (Pubitemid 47196152)
21. Massague, J. (2008) TGF-beta in Cancer. Cell 134, 215-230.
22. Xu, J., Lamouille, S., and Derynck, R. (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19, 156-172.
23. Yamashita, H., Ten Dijke, P., Franzen, P., Miyazono, K., and Heldin, C. H. (1994) Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J. Biol. Chem. 269, 20172-20178.
24. Wrana, J. L., Attisano, L., Wieser, R., Ventura, F., and Massague, J. (1994) Mechanism of activation of the TGF-beta receptor. Nature 370, 341-347.
25. Wrana, J. L., Tran, H., Attisano, L., Arora, K., Childs, S. R., Massague, J., and O'Connor, M. B. (1994) Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol. Cell. Biol. 14, 944-950.
26. Wieser, R., Wrana, J. L., and Massague, J. (1995) GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 14, 2199-2208.
27. Groppe, J., Hinck, C. S., Samavarchi-Tehrani, P., Zubieta, C., Schuermann, J. P., Taylor, A. B., Schwarz, P. M., Wrana, J. L., and Hinck, A. P. (2008) Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol. Cell 29, 157-168. (Pubitemid 351172827)
28. Hart, P. J., Deep, S., Taylor, A. B., Shu, Z., Hinck, C. S., and Hinck, A. P. (2002) Crystal structure of the human TbetaR2 ectodomain-TGF-beta3 complex. Nat. Struct. Biol. 9, 203-208.
29. Massague, J. (2008) A very private TGF-beta receptor embrace. Mol. Cell 29, 149-150.
30. Raftery, L. A., Twombly, V., Wharton, K., and Gelbart, W. M. (1995) Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila. Genetics 139, 241-254.
31. Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H., and Gelbart, W. M. (1995) Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347-1358.
32. Savage, C., Das, P., Finelli, A. L., Townsend, S. R., Sun, C. Y., Baird, S. E., and Padgett, R. W. (1996) Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components. Proc. Natl. Acad. Sci. USA 93, 790-794.
33. Baker, J. C. and Harland, R. M. (1996) A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway. Genes Dev. 10, 1880-1889.
34. Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L. C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., and Attisano, L. (1996) MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543-552. (Pubitemid 26299486)
35. Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C. H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., and Wang, X. F. (1996) Nomenclature: vertebrate mediators of TGFbeta family signals. Cell 87, 173.
36. Macias-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., and Wrana, J. L. (1996) MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87, 1215-1224. (Pubitemid 27010105)
37. Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K., Markowitz, S. D., Kinzler, K. W., and Vogelstein, B. (1996) Mad-related genes in the human. Nat. Genet. 13, 347-349.
38. Yingling, J. M., Das, P., Savage, C., Zhang, M., Padgett, R. W., and Wang, X. F. (1996) Mammalian dwarfins are phosphorylated in response to transforming growth factor beta and are implicated in control of cell growth. Proc. Natl. Acad. Sci. USA 93, 8940-8944.
39. Zhang, Y., Feng, X., We, R., and Derynck, R. (1996) Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383, 168-172. (Pubitemid 26303979)
40. Nakao, A., Imamura, T., Souchelnytskyi, S., Kawabata, M., Ishisaki, A., Oeda, E., Tamaki, K., Hanai, J., Heldin, C. H., Miyazono, K., and Ten Dijke, P. (1997) TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 16, 5353-5362.
41. Liu, I. M., Schilling, S. H., Knouse, K. A., Choy, L., Derynck, R., and Wang, X.-F. (2008) TGFβ-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFb switch. EMBO J. 28, 88-98.
42. Xiao, Z., Liu, X., Henis, Y. I., and Lodish, H. F. (2000) A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation. Proc. Natl. Acad. Sci. USA 97, 7853-7858.
43. Kurisaki, A., Kose, S., Yoneda, Y., Heldin, C. H., and Moustakas, A. (2001) Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner. Mol. Biol. Cell 12, 1079-1091.
44. Xiao, Z., Brownawell, A. M., Macara, I. G., and Lodish, H. F. (2003) A novel nuclear export signal in Smad1 is essential for its signaling activity. J. Biol. Chem. 278, 34245-34252.
45. Prokova, V., Mavridou, S., Papakosta, P., and Kardassis, D. (2005) Characterization of a novel transcriptionally active domain in the transforming growth factor beta-regulated Smad3 protein. Nucleic Acids Res. 33, 3708-3721. (Pubitemid 41418540)
46. Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L., and Wrana, J. L. (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95, 779-791. (Pubitemid 29014458)
47. Miura, S., Takeshita, T., Asao, H., Kimura, Y., Murata, K., Sasaki, Y., Hanai, J. I., Beppu, H., Tsukazaki, T., Wrana, J. L., Miyazono, K., and Sugamura, K. (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol. Cell. Biol. 20, 9346-9355.
48. Qin, L., Ding, Y., and Bromberg, J. S. (1996) Gene transfer of transforming growth factor-beta 1 prolongs murine cardiac allograft survival by inhibiting cell-mediated immunity. Hum. Gene Ther. 7, 1981-1988.
49. Burd, C. G. and Emr, S. D. (1998) Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domains. Mol. Cell 2, 157-162.
50. Gaullier, J.M., Simonsen,A., D'Arrigo,A., Bremnes, B., Stenmark, H., and Aasland, R. (1998) FYVE fingers bind PtdIns(3)P. Nature 394, 432-433.
51. Patki, V., Lawe, D. C., Corvera, S., Virbasius, J. V., and Chawla, A. (1998) A functional PtdIns(3)P-binding motif. Nature 394, 433-434.
52. Hocevar, B. A., Smine, A., Xu, X. X., and Howe, P. H. (2001) The adaptor molecule disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J. 20, 2789-2801. (Pubitemid 32938562)
53. Prunier, C. and Howe, P. H. (2005) Disabled-2 (Dab2) is required for transforming growth factor beta-induced epithelial to mesenchymal transition (EMT). J. Biol. Chem. 280, 17540-17548. (Pubitemid 41389228)
54. Charng, M. J., Zhang, D., Kinnunen, P., and Schneider, M. D. (1998) A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor. J. Biol. Chem. 273, 9365-9368.
55. Mishra, B., Tang, Y., Katuri, V., Fleury, T., Said, A. H., Rashid, A., Jogunoori, W., and Mishra, L. (2004) Loss of cooperative function of transforming growth factor-beta signaling proteins, smad3 with embryonic liver fodrin, a beta-spectrin, in primary biliary cirrhosis. Liver Int. 24, 637-645. (Pubitemid 40028618)
56. Hayes, S., Chawla, A., and Corvera, S. (2002) TGF beta receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2. J. Cell Biol. 158, 1239-1249.
57. Penheiter, S. G., Mitchell, H., Garamszegi, N., Edens, M., Dore, J. J., Jr., and Leof, E. B. (2002) Internalization-dependent and -independent requirements for transforming growth factor beta receptor signaling via the Smad pathway. Mol. Cell. Biol. 22, 4750-4759.
58. Hartsough, M. T. and Mulder, K. M. (1995) Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J. Biol. Chem. 270, 7117-7124.
59. Atfi, A., Djelloul, S., Chastre, E., Davis, R., and Gespach, C. (1997) Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in transforming growth factor beta-mediated signaling. J. Biol. Chem. 272, 1429-1432.
60. Engel, M. E., McDonnell, M. A., Law, B. K., and Moses, H. L. (1999) Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J. Biol. Chem. 274, 37413-37420.
61. Hocevar, B. A., Brown, T. L., and Howe, P. H. (1999) TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. 18, 1345-1356.
62. Bakin, A. V., Rinehart, C., Tomlinson, A. K., and Arteaga, C. L. (2002) p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J. Cell. Sci. 115 (Part 15), 3193-3206.
63. Engel, M. E., Datta, P. K., and Moses, H. L. (1998) Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation. J. Cell Biochem. Suppl. 30-31, 111-122.
64. Yamashita, M., Fatyol, K., Jin, C., Wang, X., Liu, Z., and Zhang, Y. E. (2008) TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol. Cell 31, 918-924.
65. Bhowmick, N. A., Ghiassi, M., Bakin, A., Aakre, M., Lundquist, C. A., Engel, M. E., Arteaga, C. L., and Moses, H. L. (2001) Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell 12, 27-36.
66. Edlund, S., Landstrom, M., Heldin, C. H., and Aspenstrom, P. (2002) Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol. Biol. Cell 13, 902-914.
67. Vardouli, L., Moustakas, A., and Stournaras, C. (2005) LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-beta. J. Biol. Chem. 280, 11448-11457.
68. Kattla, J. J., Carew, R. M., Heljic, M., Godson, C., and Brazil, D. P. (2008) Protein kinase B/Akt activity is involved in renal TGF-beta1-driven epithelial-mesenchymal transition in vitro and in vivo. Am. J. Physiol. Renal Physiol. 295,F215-F225.
69. Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H. R., Zhang, Y., and Wrana, J. L. (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307, 1603-1609.
70. Kretzschmar, M., Doody, J., and Massague, J. (1997) Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389, 618-622.
71. Kretzschmar, M., Doody, J., Timokhina, I., and Massague, J. (1999) A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 13, 804-816.
72. de Caestecker, M. P., Parks, W. T., Frank, C. J., Castagnino, P., Bottaro, D. P., Roberts, A. B., and Lechleider, R. J. (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev. 12, 1587-1592.
73. Ulloa, L., Doody, J., and Massague, J. (1999) Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397, 710-713.
74. Yakymovych, I., Ten Dijke, P., Heldin, C. H., and Souchelnytskyi, S. (2001) Regulation of Smad signaling by protein kinase C. FASEB J. 15, 553-555.
75. Jenkins, B. J., Grail, D., Nheu, T., Najdovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R. M., Jones, S. A., Topley, N., Baumann, H., Judd, L. M., Giraud, A. S., Boussioutas, A., Zhu, H. J., and Ernst, M. (2005) Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat. Med. 11, 845-852.
76. Cordenonsi, M., Dupont, S., Maretto, S., Insinga, A., Imbriano, C., and Piccolo, S. (2003) Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell 113, 301-314.
77. Wilkinson, D. S., Ogden, S. K., Stratton, S. A., Piechan, J. L., Nguyen, T. T., Smulian, G. A., and Barton, M. C. (2005) A direct intersection between p53 and transforming growth factor beta path-ways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol. Cell. Biol. 25, 1200-1212.
78. Jiang, Y., Prunier, C., and Howe, P. H. (2008) The inhibitory effects of disabled-2 (Dab2) on Wnt signaling are mediated through axin. Oncogene 27, 1865-1875.
79. Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., Solari, A., Bobisse, S., Rondina, M. B., Guzzardo, V., Parenti, A. R., Rosato, A., Bicciato, S., Balmain, A., and Piccolo, S. (2009) A mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 137, 87-98.
80. Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J., Kawabata, M., and Miyazono, K. (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389, 622-626.
81. Hata, A., Shi, Y., and Massague, J. (1998) TGF-beta signaling and cancer: structural and functional consequences of mutations in Smads. Mol. Med. Today 4, 257-262.
82. Nakao, A., Afrakhte, M., Moren, A., Nakayama, T., Christian, J. L., Heuchel, R., Itoh, S., Kawabata, M., Heldin, N. E., Heldin, C. H., and Ten Dijke, P. (1997). Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389, 631-635.
83. Ebisawa, T., Fukuchi, M., Murakami, G., Chiba, T., Tanaka, K., Imamura, T., and Miyazono, K. (2001) Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J. Biol. Chem. 276, 12477-12480.
84. Shi, W., Sun, C., He, B., Xiong, W., Shi, X., Yao, D., and Cao, X. (2004) GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J. Cell Biol. 164, 291-300.
85. Lin, X., Liang, M., and Feng, X. H. (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J. Biol. Chem. 275, 36818-36822.
86. Di Guglielmo, G. M., Le Roy, C., Goodfellow, A. F., and Wrana, J. L. (2003) Distinct endocytic pathways regulate TGF-beta receptor signaling and turnover. Nat. Cell Biol. 5, 410-421.
87. McDonough, H. and Patterson, C. (2003) CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8, 303-308.
88. Xin, H., Xu, X., Li, L., Ning, H., Rong, Y., Shang, Y., Wang, Y., Fu, X. Y., and Chang, Z. (2005) CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J. Biol. Chem. 280, 20842-20850.
89. Bonni, S., Wang, H. R., Causing, C. G., Kavsak, P., Stroschein, S. L., Luo, K., and Wrana, J. L. (2001) TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat. Cell Biol. 3, 587-595.
90. Stroschein, S. L., Bonni, S., Wrana, J. L., and Luo, K. (2001) Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes Dev. 15, 2822-2836.
91. Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q., and Luo, K. (1999) Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286, 771-774.
92. Wu, J. W., Krawitz, A. R., Chai, J., Li, W., Zhang, F., Luo, K., and Shi, Y. (2002) Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGFbeta signaling. Cell 111, 357-367.
93. Lin, X., Duan, X., Liang, Y. Y., Su, Y., Wrighton, K. H., Long, J., Hu, M., Davis, C. M., Wang, J., Brunicardi, F. C., Shi, Y., Chen, Y. G., Meng, A., and Feng, X. H. (2006) PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 125, 915-928.
94. Bierie, B. and Moses, H. L. (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506-520.
95. Amendt, C., Schirmacher, P., Weber, H., and Blessing, M. (1998) Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development. Oncogene 17, 25-34.
96. Yanagisawa, K., Uchida, K., Nagatake, M., Masuda, A., Sugiyama, M., Saito, T., Yamaki, K., Takahashi, T., and Osada, H. (2000) Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers. Oncogene 19, 2305-2311.
97. Garrigue-Antar, L., Munoz-Antonia, T., Antonia, S. J., Gesmonde, J., Vellucci, V. F., and Reiss, M. (1995) Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells. Cancer Res. 55, 3982-3987.
98. Park, B. J., Park, J. I., Byun, D. S., Park, J. H., and Chi, S. G. (2000) Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer. Cancer Res. 60, 3031-3038.
99. Myeroff, L. L., Parsons, R., Kim, S. J., Hedrick, L., Cho, K. R., Orth, K., Mathis, M., Kinzler, K. W., Lutterbaugh, J., Park, K., et al. (1995) A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res. 55, 5545-5547.
100. Kang, S. H., Bang, Y. J., Im, Y. H., Yang, H. K., Lee, D. A., Lee, H. Y., Lee, H. S., Kim, N. K., and Kim, S. J. (1999) Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer. Oncogene 18, 7280-7286.
101. Markowitz, S. (2000) TGF-beta receptors and DNA repair genes, coupled targets in a pathway of human colon carcinogenesis. Biochim. Biophys. Acta 1470, M13-M20.
102. Goggins, M., Shekher, M., Turnacioglu, K., Yeo, C. J., Hruban, R. H., and Kern, S. E. (1998) Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 58, 5329-5332.
103. Lucke, C. D., Philpott, A., Metcalfe, J. C., Thompson, A. M., Hughes-Davies, L., Kemp, P. R., and Hesketh, R. (2001) Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res. 61, 482-485.
104. Wilkes, M. C., Repellin, C. E., Hong, M., Bracamonte, M., Penheiter, S. G., Borg, J. P., and Leof, E. B. (2009) Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta. Dev. Cell 16, 433-444.
105. de Caestecker, M. P., Piek, E., and Roberts, A. B. (2000) Role of transforming growth factor-beta signaling in cancer. J. Natl. Cancer Inst. 92, 1388-1402.
106. Mulder, K. M. and Brattain, M. G. (1988) Alterations in c-myc expression in relation to maturational status of human colon carcinoma cells. Int. J. Cancer 42, 64-70.
107. Zentella, A. and Massague, J. (1992) Transforming growth factor beta induces myoblast differentiation in the presence of mitogens. Proc. Natl. Acad. Sci. USA 89, 5176-5180.
108. Mulder, K. M., Levine, A. E., Hernandez, X., McKnight, M. K., Brattain, D. E., and Brattain, M. G. (1988) Modulation of c-myc by transforming growth factor-beta in human colon carcinoma cells. Biochem. Biophys. Res. Commun. 150, 711-716.
109. Alexandrow, M. G. and Moses, H. L. (1995) Transforming growth factor beta 1 inhibits mouse keratinocytes late in G1 independent of effects on gene transcription. Cancer Res. 55, 3928-3932.
110. Facchini, L. M. and Penn, L. Z. (1998) The molecular role of Myc in growth and transformation: recent discoveries lead to new insights. FASEB J. 12, 633-651.
111. Dang, C. V. (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell. Biol. 19, 1-11.
112. Alexandrow, M. G. and Moses, H. L. (1995) Transforming growth factor beta and cell cycle regulation. Cancer Res. 55, 1452-1457.
113. Yagi, K., Furuhashi, M., Aoki, H., Goto, D., Kuwano, H., Sugamura, K., Miyazono, K., and Kato, M. (2002) c-myc is a downstream target of the Smad pathway. J. Biol. Chem. 277, 854-861.
114. Datto, M. B., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y., and Wang, X. F. (1995) Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl. Acad. Sci. USA 92, 5545-5549.
115. Reynisdottir, I. and Massague, J. (1997) The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 11, 492-503.
116. Iavarone, A. and Massague, J. (1997) Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 387, 417-422.
117. Moustakas, A. and Kardassis, D. (1998) Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc. Natl. Acad. Sci. USA 95, 6733-6738.
118. Sandhu, C., Garbe, J., Bhattacharya, N., Daksis, J., Pan, C. H., Yaswen, P., Koh, J., Slingerland, J. M., and Stampfer, M. R. (1997) Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells. Mol. Cell. Biol. 17, 2458-2467.
119. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K., and Elledge, S. J. (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805-816.
120. Howe, P. H., Draetta, G., and Leof, E. B. (1991) Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest. Mol. Cell. Biol. 11, 1185-1194.
121. Nakayama, K., Ishida, N., Shirane, M., Inomata, A., Inoue, T., Shishido, N., Horii, I., Loh, D. Y., and Nakayama, K. (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707-720.
122. Nagahara, H., Ezhevsky, S. A., Vocero-Akbani, A. M., Kaldis, P., Solomon, M. J., and Dowdy, S. F. (1999) Transforming growth factor beta targeted inactivation of cyclin E: cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating kinase activity. Proc. Natl. Acad. Sci. USA 96, 14961-14966.
123. Bhowmick, N. A., Ghiassi, M., Aakre, M., Brown, K., Singh, V., and Moses, H. L. (2003) TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc. Natl. Acad. Sci. USA 100, 15548-15553.
124. Sanchez-Capelo, A. (2005) Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev. 16, 15-34.
125. Herzer, K., Grosse-Wilde, A., Krammer, P. H., Galle, P. R., and Kanzler, S. (2008) Transforming growth factor-beta-mediated tumor necrosis factor-related apoptosis-inducing ligand expression and apoptosis in hepatoma cells requires functional cooperation between Smad proteins and activator protein-1. Mol. Cancer Res. 6, 1169-1177.
126. Perlman, R., Schiemann, W. P., Brooks, M. W., Lodish, H. F., and Weinberg, R. A. (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat. Cell Biol. 3, 708-714.
127. Jang, C. W., Chen, C. H., Chen, C. C., Chen, J. Y., Su, Y. H., and Chen, R. H. (2002) TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat. Cell Biol. 4, 51-58.
128. Yoo, J., Ghiassi, M., Jirmanova, L., Balliet, A. G., Hoffman, B., Fornace, A. J., Jr., Liebermann, D. A., Bottinger, E. P., and Roberts, A. B. (2003) Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J. Biol. Chem. 278, 43001-43007.
129. Gottfried, Y., Voldavsky, E., Yodko, L., Sabo, E., Ben-Itzhak, O., and Larisch, S. (2004) Expression of the pro-apoptotic protein ARTS in astrocytic tumors: correlation with malignancy grade and survival rate. Cancer 101, 2614-2621.
130. Wildey, G. M., Patil, S., and Howe, P. H. (2003) Smad3 potentiates transforming growth factor beta (TGFbeta )-induced apoptosis and expression of the BH3-only protein Bim in WEHI 231 B lymphocytes. J. Biol. Chem. 278, 18069-18077.
131. Patil, S., Wildey, G. M., Brown, T. L., Choy, L., Derynck, R., and Howe, P. H. (2000) Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta -induced growth inhibition and apoptosis. J. Biol. Chem. 275, 38363-38370.
132. Ohgushi, M., Kuroki, S., Fukamachi, H., O'Reilly, L. A., Kuida, K., Strasser, A., and Yonehara, S. (2005) Transforming growth factor beta-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Mol. Cell. Biol. 25, 10017-10028.
133. Ramesh, S., Wildey, G. M., and Howe, P. H. (2009) Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise and fall of Bim. Cell Cycle 8, 11-17.
134. Zavadil, J. and Bottinger, E. P. (2005) TGF-beta and epithelial- tomesenchymal transitions. Oncogene 24, 5764-5774.
135. Thiery, J. P. and Sleeman, J. P. (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell. Biol. 7, 131-142.
136. Trelstad, R. L., Hay, E. D., and Revel, J. D. (1967) Cell contact during early morphogenesis in the chick embryo. Dev. Biol. 16, 78-106.
137. Larue, L. and Bellacosa, A. (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 24, 7443-7454.
138. Bhowmick, N. A., Zent, R., Ghiassi, M., McDonnell, M., and Moses, H. L. (2001) Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J. Biol. Chem. 276, 46707-46713.
139. Gotzmann, J., Huber, H., Thallinger, C., Wolschek, M., Jansen, B., Schulte-Hermann, R., Beug, H., and Mikulits, W. (2002) Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. J. Cell Sci. 115 (Part 6), 1189-1202.
140. Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., Downward, J., Beug, H., and Grunert, S. (2002) Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 156, 299-313.
141. Zavadil, J., Cermak, L., Soto-Nieves, N., and Bottinger, E. P. (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 23, 1155-1165.
142. Huber, M. A., Azoitei, N., Baumann, B., Grunert, S., Sommer, A., Pehamberger, H., Kraut, N., Beug, H., and Wirth, T. (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569-581.
143. Xie, L., Law, B. K., Chytil, A. M., Brown, K. A., Aakre, M. E., and Moses, H. L. (2004) Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia 6, 603-610.
144. Pradet-Balade, B., Boulme, F., Beug, H., Mullner, E. W., and Garcia-Sanz, J. A. (2001) Translation control: bridging the gap between genomics and proteomics? Trends Biochem. Sci. 26, 225-229.
145. Jechlinger, M., Grunert, S., Tamir, I. H., Janda, E., Ludemann, S., Waerner, T., Seither, P., Weith, A., Beug, H., and Kraut, N. (2003) Expression profiling of epithelial plasticity in tumor progression. Oncogene 22, 7155-7169.
146. Waerner, T., Alacakaptan, M., Tamir, I., Oberauer, R., Gal, A., Brabletz, T., Schreiber, M., Jechlinger, M., and Beug, H. (2006) ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10, 227-239.
147. Oft, M., Peli, J., Rudaz, C., Schwarz, H., Beug, H., and Reichmann, E. (1996) TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 10, 2462-2477.
148. Oft, M., Heider, K. H., and Beug, H. (1998) TGF beta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol. 8, 1243-1252.
149. Davies, M., Robinson, M., Smith, E., Huntley, S., Prime, S., and Paterson, I. (2005) Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. J. Cell Biochem. 95, 918-931.
150. Zavadil, J., Bitzer, M., Liang, D., Yang, Y. C., Massimi, A., Kneitz, S., Piek, E., and Bottinger, E. P. (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc. Natl. Acad. Sci. USA 98, 6686-6691.
151. Saika, S., Ikeda, K., Yamanaka, O., Sato, M., Muragaki, Y., Ohnishi, Y., Ooshima, A., Nakajima, Y., Namikawa, K., Kiyama, H., Flanders, K. C., and Roberts, A. B. (2004) Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Lab. Invest. 84, 1259-1270.
152. Giannelli, G., Bergamini, C., Fransvea, E., Sgarra, C., and Antonaci, S. (2005) Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129, 1375-1383.
153. Oft, M., Akhurst, R. J., and Balmain, A. (2002) Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat. Cell Biol. 4, 487-494.
154. Valcourt, U., Kowanetz, M., Niimi, H., Heldin, C. H., and Moustakas, A. (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol. Biol. Cell 16, 1987-2002.
155. Ju, W., Ogawa, A., Heyer, J., Nierhof, D., Yu, L., Kucherlapati, R., Shafritz, D. A., and Bottinger, E. P. (2006) Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol. Cell. Biol. 26, 654-667.