TGF-β signaling by Smad proteins

Advances in Immunology

Volumn 75, Issue , 2000, Pages 115-157

  Miyazono, Kohei ^a   Ten Dijke, Peter ^b   Heldin, Carl Henrik ^c  

^a CANCER INSTITUTE   (Japan)

^b NETHERLANDS CANCER INSTITUTE   (Netherlands)

^c LUDWIG INSTITUTE FOR CANCER RESEARCH   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

DNA BINDING PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; OLIGOMER; PROTEIN SERINE THREONINE KINASE; REPRESSOR PROTEIN; SMAD PROTEIN; TRANSCRIPTION FACTOR; TRANSFORMING GROWTH FACTOR BETA;

CARCINOGENESIS; CELL MEMBRANE; DNA BINDING; GENE TARGETING; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN PHOSPHORYLATION; REPRESSOR GENE; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION;

EID: 0033932667     PISSN: 00652776     EISSN: None     Source Type: Book Series    
DOI: 10.1016/s0065-2776(00)75003-6     Document Type: Review

References (211)

1. 467 is required for Smad2-Smad4 complex formation and signaling. J. Biol. Chem. 272, 27678-27685.
2. Adachi-Yamada, T., Nakamura, M., Irie, K., Tomoyasu, Y., Sano, Y., Mori, E., Goto, S., Ueno, N., Nishida, Y., and Matsumoto, K. (1999). p38 mitogen-activated protein kinase can be involved in transforming growth factor β superfamily signal transduction in Drosophila wing morphogenesis. Mol. Cell. Biol. 19, 2322-2329.
3. Afrakhte, M., Morén, A., Jossan, S., Itoh, S., Sampath, K., Westermark, B., Heldin, C.-H., Heldin, N.-E., and ten Dijke, P. (1998). Induction of inhibitory Smad6 and Smad7 mRNA by TGF-/3 family members. Bochem. Bophys. Res. Commun. 249, 505-511.
4. Akimaru, H., Chen, Y., Dai, P., Hou, D. X., Nonaka, M., Smolik, S. M., Armstrong, S., Goodman, R. H., and Ishii, S. (1997). Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling. Nature 386, 735-738.
5. Armes, N. A., Neal, K. A., and Smith, J. C. (1999). A short loop on the ALK-2 and ALK-4 activin receptors regulates signaling specificity but cannot account for all their effects on early Xenopus development. J. Biol. Chem. 274, 7929-7935.
6. Arora, K., Dai, H., Kazuko, S. G., Jamal, J., O'Connor, M. B., Letsou, A., and Warrior, R. (1995). The Drosophila schnurri gene acts in the Dpp/TGFβ signaling pathway and encodes a transcription factor homologous to the human MBP family. Cell 81, 781-790.
7. Atfi, A., Buisine, M., Mazars, A., and Gespach, C. (1997a). Induction of apoptosis by DPC4, a transcriptional factor regulated by transforming growth factor-β through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling pathway. J. Biol. Chem. 272, 24731-24734.
8. Atfi, A., Djelloul, S., Chastre, E., Davis, R., and Gespach, C. (1997b). Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/ JNK) in transforming growth factor β-mediated signaling. J. Biol. Chem. 272, 1429-1432.
9. Attisano, L., Cárcamo, J., Ventura, F., Weis, F. M. B., Massagué, J., and Wrana, J. L. (1993). Identification of human activin and TGFβ type I receptors that form heteromeric kinase complexes with type II receptors. Cell 75, 671-680.
10. Attisano, L., and Wrana, J. L. (1998). Mads and Smads in TGFβ signalling. Curr. Opin. Cell Biol. 10, 188-194.
11. 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.
12. Beckmann, H., Su, L. K., and Kadesch, T. (1990). TFE3: A helix-loop-helix protein that activates transcription through the immunoglobulin enhancer μE3 motif. Genes Dev. 4, 167-179.
13. Bhatia, M., Bonnet, D., Wu, D., Murdoch, B., Wrana, J., Gallacher, L., and Dick, J. E. (1999). Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J. Exp. Med. 189, 1139-1148.
14. Bhushan, A., Chen, Y., and Vale, W. (1998). Smad7 inhibits mesoderm formation and promotes neural cell fate in Xenopus embryos. Dev. Biol. 200, 260-268.
15. Brown, J. D., DiChiara, M. R., Anderson, K. R., Gimbrone, M. A., Jr., and Topper, J. N. (1999). MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J. Biol. Chem. 274, 8797-8805.
16. Brummel, T., Abdollah, S., Haerry, T. E., Shimell, J. M., Merriam, J., Raftery, L., Wrana, J. L., and O'Connor, M. B. (1999). The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. Genes Dev. 13, 98-111.
17. Bruno, E., Horrigan, S. K., Van Den Berg, D., Rozler, E., Fitting, P. R., Moss, S. T., Westbrook, C., and Hoffman, R. (1998). The Smad5 gene is involved in the intracellular signaling pathways that mediate the inhibitory effects of transforming growth factor-β on human hematopoiesis. Blood 91, 1917-1923.
18. Campbell, G., and Tomlinson, A. (1999). Transducing the Dpp morphogen gradient in the wing of Drosophila: Regulation of Dpp targets by brinker. Cell 96, 553-562.
19. Candia, A. F., Watabe, T., Hawley, S. H., Onichtchouk, D., Zhang, Y., Derynck, R., Niehrs, C., and Cho, K. W. (1997). Cellular interpretation of multiple TGF-β signals: Intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. Development 124, 4467-4480.
20. Casellas, R., and Hemmati-Brivanlou, A. H. (1998). Xenopus Smad7 inhibits both the activin and BMP pathways and acts as a neural inducer. Dev. Biol. 198, 1-12.
21. Chang, H., Huylebroeck, D., Verschueren, K., Guo, Q., Matzuk, M. M., and Zwijsen, A. (1999). Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development 126, 1631-1642.
22. Chen, X., Rubock, M. J., and Whitman, M. (1996). A transcriptional partner for MAD proteins in TGF-β signalling. Nature 383, 691-696.
23. Chen, X., Weisberg, E., Fridmacher, V., Watanabe, M., Naco, G., and Whitman, M. (1997). Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85-89.
24. Chen, Y., Bhushan, A., and Vale, W. (1997). Smad8 mediates the signaling of the ALK-2 receptor serine kinase. Proc. Natl. Acad. Sci. USA 94, 12938-12943.
25. Chen, Y. G., Liu, F., and Massagué, J. (1997). Mechanism of TGFβ receptor inhibition by FKBP12. EMBO J. 16, 3866-3876.
26. Chen, Y. G., Hata, A., Lo, R. S., Wotton, D., Shi, Y., Pavletich, N., and Massagué, J. (1998). Determinants of specificity in TGF-β signal transduction. Genes Dev. 12, 2144-2152.
27. Chen, Y. G., and Massagué, J. (1999). Smad1 recognition and activation by the ALK1 group of transforming growth factor-β family receptors. J. Biol. Chem. 274, 3672-3677.
28. Chrivia, J. C., Kwok, R. P., Lamb, N., Hagiwara, M., Montminy, M. R., and Goodman, R. H. (1993). Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855-859.
29. Coffman, R. L., Lebman, D. A., and Shrader, B. (1989). Transforming growth factor β specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J. Exp. Med. 170, 1039-1044.
30. Conlon, F. L., Lyons, K. M., Takaesu, N., Barth, K. S., Kispert, A., Herrmann, B., and Robertson, E. J. (1994). A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120, 1919-1928.
31. Das, P., Maduzia, L. L., Wang, H., Finelli, A. L., Cho, S. H., Smith, M. M., and Padgett, R. W. (1998). The Drosophila gene Medea demonstrates the requirement for different classes of Smads in dpp signaling. Development 125, 1519-1528.
32. Das, P., Inoue, H., Baker, J. C., Beppu, H., Kawabata, M., Harland, K. M., Miyazono, K., and Padgett, R. W. (1999). Drosophila dSmad2 and Atr-I transmit activin/TGFβ signals. Genes Cells 4, 123-134.
33. Datto, M. B., Yu, Y., and Wang, X.-F. (1995). Functional analysis of the transforming growth factor β responsive elements in the WAF1/Cip1/p21 promoter. J. Biol. Chem. 270, 28623-28628.
34. Datto, M. B., Frederick, J. P., Pan, L., Borton, A. J., Zhuang, Y., and Wang, X.-F. (1999). Targeted disruption of smadS reveals an essential role in transforming growth factor β-mediated signal transduction. Mol. Cell. Biol. 19, 2495-2504.
35. de Caestecker, M. P., Hemmati, P., Larisch-Bloch, S., Ajmera, R., Roberts, A. B., and Lechleider, R. J. (1997). Characterization of functional domains within Smad4/DPC4. J. Biol. Chem. 272, 13690-13696.
36. 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.
37. Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., and Gauthier, J. M. (1998). Direct binding of Smad3 and Smad4 to critical TGFβ-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 17, 3091-3100.
38. Dennler, S., Huet, S., and Gauthier, J. M. (1999). A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and SmadS. Oncogene 18, 1643-1648.
39. Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson, S., and Akhurst, R. J. (1995). Defective haematopoiesis and vasculogenesis in transforming growth factor-β1 knockout mice. Development 121, 1845-1854.
40. Diebold, R. J., Eis, M. J., Yin, M., Ormsby, I., Boivin, G. P., Darrow, B. J., Saffitz, J. E., and Doetschman, T. (1995). Early-onset multifocal inflammation in the transforming growth factor β1-null mouse is lymphocyte mediated. Proc. Natl. Acad. Sci. USA 92, 12215-12219.
41. Duff, E. K., and Clarke, A. R. (1998). Smad4 (DPC4) - A potent tumour suppressor? Br. J. Cancer 78, 1615-1619.
42. Eckner, R., Ewen, M. E., Newsome, D., Gerdes, M., DeCaprio, J. A., Lawrence, J. B., and Livingston, D. M. (1994). Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 8, 869-884.
43. 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 TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543-552.
44. Feng, X.-H., and Derynck, R. (1997). A kinase subdomain of transforming growth factor-β (TGF-β) type I receptor determines the TGF-β intracellular signaling specificity. EMBO J. 16, 3912-3923.
45. Feng, X.-H., Zhang, Y., Wu, R. Y., and Derynck, R. (1998). The tumor suppressor Smad4/ DPC4 and transcriptional adaptor CBP/p300 are coactivators for SmadS in TGF-β-induced transcriptional activation. Genes Dev. 12, 2153-2163.
46. Frey, R. S., and Mulder, K. M. (1997). Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase/Jun N-terminal kinase activation by transforming growth factor β in the negative growth control of breast cancer cells. Cancer Res. 57, 628-633.
47. Fujii, M., Takeda, K., Imamura, T., Aoki, H., Sampath, T. K., Enomoto, S., Kawabata, M., Kato, M., Ichijo, H., and Miyazono, K. (1999). Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol. Biol. Cell 10, 3801-3813.
48. Giles, R. H., Peters, D. J., and Breuning, M. H. (1998). Conjunction dysfunction: CBP/ p300 in human disease. Trends Genet. 14, 178-183.
49. Goto, D., Yagi, K., Inoue, H., Iwamoto, I., Kawabata, M., Miyazono, K., and Kato, M. (1998). A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3, and has a dominant negative effect on TGF-β signals. FEBS Lett. 430, 201-204.
50. Grieder, N. C., Nellen, D., Burke, R., Basler, K., and Affolter, M. (1995). Schnurri is required for Drosophila Dpp signaling and encodes a zinc finger protein similar to the mammalian transcription factor PRDII-BF1. Cell 81, 791-800.
51. Gu, Z., Nomura, M., Simpson, B. B., Lei, H., Feijen, A., van den Eijnden-van Raaij, J., Donahoe, P. K., and Li, E. (1998). The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes Dev. 12, 844-857.
52. Hahn, S. A., Schutte, M., Hoque, A. T. M. S., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., and Kern, S. E. (1996). DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350-353.
53. Hahn, S. A., Bartsch, D., Schroers, A., Galehdari, H., Becker, M., Ramaswamy, A., Schwarte-Waldhoff, I., Maschek, H., and Schmiegel, W. (1998). Mutations of the DPC4/Smad4 gene in biliary tract carcinoma. Cancer Res. 58, 1124-1126.
54. Hanai, J.-i., Chen, L. F., Kanno, T., Ohtari-Fujita, N., Kim, W. Y., Imamura, T., Ishidou, Y., Fukuchi, M., Shi, M.-J., Stavnezer, J., Kawabata, M., Miyazono, K., and Ito, Y. (1999). Interaction and functional cooperation of PEBP2/CBF with Smads. J. Biol. Chem. 274, 31577-31582.
55. mapk in proliferating cultures of epithelial cells. J. Biol. Chem. 270, 7117-7124.
56. Hata, A., Lo, R. S., Wotton, D., Lagna, G., and Massagué, J. (1997). Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature 388, 82-87.
57. Hata, A., Lagna, G., Massagué, J., and Hemmati-Brivanlou, A. (1998). Smad6 inhibits BMP/ Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 12, 186-197.
58. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y. Y., Grinnell, B. W., Richardson, M. A., Topper, J. N., Gimbrone, M. A., Jr., Wrana, J. L., and Falb, D. (1997). The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89, 1165-1173.
59. Hejlik, D. P., Kottickal, L. V., Liang, H., Fairman, J., Davis, T., Janecki, T., Sexton, D., Perry, W., Tavtigian, S. V., Teng, D. H., and Nagarajan, L. (1997). Localization of SMAD5 and its evaluation as a candidate myeloid tumor suppressor. Cancer Res. 57, 3779-3783.
60. Heldin, C.-H., Miyazono, K., and ten Dijke, P. (1997). TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471.
61. Hocevar, B. A., Brown, T. L., and Howe, P. H. (1999). TGF-β induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. 18, 1345-1356.
62. Hoodless, P. A., Tsukazaki, T., Nishimatsu, S., Attisano, L., Wrana, J. L., and Thomsen, G. H. (1999). Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus. Dev. Biol. 207, 364-379.
63. Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., and Aaltonen, L. A. (1998). Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086-1088.
64. Howell, M., Itoh, F., Pierreux, C. E., Valgeirsdottir, S., Itoh, S., ten Dijke, P., and Hill, C. S. (1999). Xenopus Smad4β is the Co-Smad component of developmentally regulated transcription factor complexes responsible for induction of early mesodermal genes. Dev. Biol. 214, 354-369.
65. Hua, X., Liu, X., Ansari, D. O., and Lodish, H. F. (1998). Synergistic cooperation of TFE3 and Smad proteins in TGF-β-induced transcription of the plasminogen activator inhibitor-1 gene. Genes Dev. 12, 3084-3095.
66. Hudson, J. B., Podos, S. D., Keith, K., Simpson, S. L., and Ferguson, E. L. (1998). The Drosophila Medea gene is required downstream of dpp and encodes a functional homolog of human Smad4. Development 125, 1407-1420.
67. waf1 expression and growth inhibition in human carcinoma cells. Cancer Res. 58, 5656-5661.
68. Huse, M., Chen, Y. G., Massagué, J., and Kuriyan, J. (1999). Crystal structure of the cytoplasmic domain of the type I TGFβ receptor in complex with FKBP12. Cell 96, 425-436.
69. Iavarone, A., and Massagué, J. (1997). Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-β in cells lacking the CDK inhibitor p15. Nature 387, 417-422.
70. Iavarone, A., and Massagué, J. (1999). E2F and histone deacetylase mediate transforming growth factor β repression of cdc25A during keratinocyte cell cycle arrest. Mol. Cell. Biol. 19, 916-922.
71. Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J.-i., Kawabata, M., and Miyazono, K. (1997). Smad6 inhibits signalling by the TGF-β superfamily. Nature 389, 622-626.
72. Inoue, H., Imamura, T., Ishidou, Y., Takase, M., Udagawa, Y., Oka, Y., Tsuneizumi, K., Tabata, T., Miyazono, K., and Kawabata, M. (1998). Interplay of signal mediators of decapentaplegic (Dpp): Molecular characterization of mothers against dpp, Medea, and daughters against dpp. Mol. Biol. Cell 9, 2145-2156.
73. Ishisaki, A., Yamato, K., Nakao, A., Nonaka, K., Ohguchi, M., ten Dijke, P., and Nishihara, T. (1998). Smad7 is an activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J. Biol. Chem. 273, 24293-24296.
74. Ishisaki, A., Yamato, K., Hashimoto, S., Nakao, A., Tamaki, K., Nonaka, K., ten Dijke, P., Sugino, H., and Nishihara, T. (1999). Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J. Biol. Chem. 274, 13637-13642.
75. Ito, Y., and Bae, S.-C. (1997). The Runt domain transcription factor, PEBP2/CBF, and its involvement in human leukemia. In "Oncogenes as Transcriptional Regulators, Vol. 2" (M. Yaniv and J. Ghysdael, eds.), pp. 107-132. Birkäuser Verlag, Basel, Switzerland.
76. Itoh, S., Landström, M., Hermansson, A., Itoh, F., Heldin, C.-H., Heldin, N.-E., and ten Dijke, P. (1998). Transforming growth factor β1 induces nuclear export of inhibitory Smad7. J. Biol Chem. 273, 29195-29201.
77. Janknecht, R., Wells, N. J., and Hunter, T. (1998). TGF-β-stimulated cooperation of Smad proteins with the coactivators CBP/p300. Genes Dev. 12, 2114-2119.
78. Jazwinska, A., Kirov, N., Wieschaus, E., Roth, S., and Rushlow, C. (1999). The Drosophila gene brinker reveals a novel mechanism of Dpp target gene regulation. Cell 96, 563-573.
79. Jonk, L. J., Itoh, S., Heldin, C.-H., ten Dijke, P., and Kruijer, W. (1998). Identification and functional characterization of a Smad binding element (SBE) in the JunB promoter that acts as a transforming growth factor-β, activin, and bone morphogenetic protein-inducible enhancer. J. Biol. Chem. 273, 21145-21152.
80. Jonson, T., Gorunova, L., Dawiskiba, S., Andren-Sandberg, A., Stenman, G., ten Dijke, P., Johansson, B., and Hoglund, M. (1999). Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer. Genes Chromosomes Cancer 24, 62-71.
81. Kawabata, M., Imamura, T., and Miyazono, K. (1998a). Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 9, 49-61.
82. Kawabata, M., Inoue, H., Hanyn, A., Imamura, T., and Miyazono, K. (1998b). Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors. EMBO J. 17, 4056-4065.
83. Kim, J., Johnson, K., Chen, H. J., Carroll, S., and Laughon, A. (1997). Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 388, 304-308.
84. Kingsley, D. M. (1994). The TGF-β superfamily: New members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 8, 133-146.
85. Kleeff, J., Maruyama, H., Friess, H., Buchler, M. W., Falb, D., and Korc, M. (1999). Smad6 suppresses TGF-β-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer. Biochem. Biophys. Res. Commun. 255, 268-273.
86. Kretzschmar, M., Liu, F., Hata, A., Doody, J., and Massagué, J. (1997a). The TGF-β family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev. 11, 984-995.
87. Kretzschmar, M., Doody, J., and Massagué, J. (1997b). Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618-622.
88. Kretzschmar, M., Doody, J., Timokhina, I., and Massagué, J. (1999). A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Genes Dev. 13, 804-816.
89. Krishna, S., Maduzia, L. L., and Padgett, R. W. (1999). Specificity of TGFβ signaling is conferred by distinct type I receptors and their associated SMAD proteins in Caenorhabditis elegans. Development 126, 251-260.
90. Kulkarni, A. B., Huh, C. G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., and Karlsson, S. (1993). Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770-774.
91. Kurokawa, M., Mitani, K., Irie, K., Matsuyama, T., Takahashi, T., Chiba, S., Yazaki, Y., Matsumoto, K., and Hirai, H. (1998a). The oncoprotein Evi-1 represses TGF-β signalling by inhibiting Smad3. Nature 394, 92-96.
92. Kurokawa, M., Mitani, K., Imai, Y., Ogawa, S., Yazaki, Y., and Hirai, H. (1998b). The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-β-mediated growth inhibition of myeloid cells. Blood 92, 4003-4012.
93. Labbé, E., Silvestri, C., Hoodless, P. A., Wrana, J. L., and Attisano, L. (1998). Smad2 and Smad3 positively and negatively regulate TGFβ-dependent transcription through the forkhead DNA-binding protein FAST2. Mol. Cell 2, 109-120.
94. Lagna, G., and Hemmati-Brivanlou, A. (1999). A molecular basis for Smad specificity. Dev. Dyn. 214, 269-277.
95. Le Dai, J., Bansal, R. K., and Kern, S. E. (1999). G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: Phenotypes reversed by a tumorigenic mutation. Proc. Natl. Acad. Sci. USA 96, 1427-1432.
96. Lebrun, J. J., Takabe, K., Chen, Y., and Vale, W. (1999). Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Mol. Endocrinol. 13, 15-23.
97. LeSueur, J. A., and Graff, J. M. (1999). Spemann organizer activity of Smad10. Development 126, 137-146.
98. INK4B through an Sp1 consensus site. J. Biol. Chem. 270, 26750-26753.
99. Li, M., Li, J., Hoodless, P. A., Tzukazaki, T., Wrana, J. L., Attisano, L., and Tsang, B. K. (1997). Mothers against decapentaplegic-related protein 2 expression in avian granulosa cells is up-regulated by transforming growth factor β during ovarian follicular development. Endocrinology 138, 3659-3665.
100. Li, J., Tsuji, K., Komori, T., Miyazono, K., Wrana, J. L., Ito, Y., Nifuji, A., and Noda, M. (1998). Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells. J. Biol. Chem. 273, 31009-31015.
101. Liberati, N. T., Datto, M. B., Frederick, J. P., Shen, X., Wong, C., Rougier-Chapman, E. M., and Wang, X.-F. (1999). Smads bind directly to the Jun family of AP-1 transcription factors. Proc. Natl. Acad. Sci. USA 96, 4844-4849.
102. Liu, F., Hata, A., Baker, J. C., Doody, J., Cárcamo, J., Harland, R. M., and Massagué, J. (1996). A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381, 620-623.
103. Liu, F., Pouponnot, C., and Massagué, J. (1997). Dual role of the Smad4/DPC4 tumor suppressor in TGFβ-inducible transcriptional complexes. Genes Dev. 11, 3157-3167.
104. Liu, F., Massagué, J., and Ruiz i Altaba, A. (1998). Carboxy-terminally truncated Gli3 proteins associate with Smads. Nat. Genet. 20, 325-326.
105. Liu, X., Yue, J., Frey, R. S., Zhu, Q., and Mulder, K. M. (1998). Transforming growth factor β signaling through Smad1 in human breast cancer cells. Cancer Res. 58, 4752-4757.
106. Liu, B., Dou, C. L., Prabhu, L., and Lai, E. (1999). FAST-2 is a mammalian winged-helix protein which mediates transforming growth factor β signals. Mol. Cell. Biol. 19, 424-430.
107. Lo, R. S., Chen, Y. G., Shi, Y., Pavletich, N. P., and Massagué, J. (1998). The L3 loop: A structural motif determining specific interactions between SMAD proteins and TGF-β receptors. EMBO J. 17, 996-1005.
108. Lux, A., Attisano, L., and Marchuk, D. A. (1999). Assignment of transforming growth factor β1 and β3 and a third new ligand to the type I receptor ALK-1. J. Biol. Chem. 274, 9984-9992.
109. Lyons, I., Parsons, L. M., Hartley, L., Li, R., Andrews, J. E., Robb, L., and Harvey, R. P. (1995). Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 9, 1654-1666.
110. Macías-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., and Wrana, J. L. (1996). MADR2 is a substrate of the TGFβ receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87, 1215-1224.
111. Macías-Silva, M., Hoodless, P. A., Tang, S. J., Buchwald, M., and Wrana, J. L. (1998). Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J. Biol. Chem. 273, 25628-25636.
112. Massagué, J. (1998). TGF-β signal transduction. Annu. Rev. Biochem. 67, 753-791.
113. Masuyama, N., Hanafusa, H., Kusakabe, M., Shibuya, H., and Nishida, E. (1999). Identification of two Smad4 proteins in Xenopus: Their common and distinct properties. J. Biol. Chem. 274, 12163-12170.
114. Mathews, L. S. (1994). Activin receptors and cellular signaling by the receptor serine kinase family. Endocr. Rev. 15, 310-325.
115. Meersseman, G., Verschueren, K., Nelles, L., Blumenstock, C., Kraft, H., Wuytens, G., Remacle, J., Kozak, C. A., Tylzanowski, P., Niehrs, C., and Huylebroeck, D. (1997). The C-terminal domain of Mad-like signal transducers is sufficient for biological activity in the Xenopus embryo and transcriptional activation. Mech. Dev. 61, 127-140.
116. Minami, M., Kinoshita, N., Kamoshida, Y., Tanimoto, H., and Tabata, T. (1999). brinker is a target of Dpp in Drosophila that negatively regulates Dpp-dependent genes. Nature 398, 242-246.
117. Mishina, Y., Suzuki, A., Ueno, N., and Behringer, R. R. (1995). Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev. 9, 3027-3037.
118. Miyazono, K., ten Dijke, P., Ichijo, H., and Heldin, C.-H. (1994). Receptors for transforming growth factor-β. Adv. Immunol. 55, 181-220.
119. 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.
120. Nakao, A., Afrakhte, M., Morén, A., Nakayama, T., Christian, J. L., Heuchel, R., Itoh, S., Kawabata, M., Heldin, N.-E., Heldin, C.-H., and ten Dijke, P. (1997a). Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389, 631-635.
121. 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. (1997b). TGF-β receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 16, 5353-5362.
122. Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., and Taga, T. (1999). Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284, 479-482.
123. Nakayama, T., Gardner, H., Berg, L. K., and Christian, J. L. (1998a). Smad6 functions as an intracellular antagonist of some TGF-β family members during Xenopus embryogenesis. Genes Cells 3, 387-394.
124. Nakayama, T., Snyder, M. A., Grewal, S. S., Tsuneizumi, K., Tabata, T., and Christian, J. L. (1998b). Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning. Development 125, 857-867.
125. Newfeld, S. J., Chartoff, E. H., Graff, J. M., Melton, D. A., and Gelbart, W. M. (1996). Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGF-β responsive cells. Development 122, 2099-2108.
126. Ninomiya-Tsuji, J., Kishimoto, K., Hiyama, A., Inoue, J., Cao, Z., and Matsumoto, K. (1999). The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252-256.
127. Nishihara, A., Hanai, J.-i., Okamoto, N., Yanagisawa, J., Kato, S., Miyazono, K., and Kawabata, M. (1998). Role of p300, a transcriptional coactivator, in signalling of TGF-β. Genes Cells 3, 613-623.
128. Nishihara, A., Hanai, J.-i., Imamura, T., Miyazono, K., and Kawabata, M. (1999). E1A inhibits transforming growth factor-β signaling through binding to Smad proteins. J. Biol. Chem. 274, 28716-28723.
129. Nishimura, R., Kato, Y., Chen, D., Harris, S. E., Mundy, G. R., and Yoneda, T. (1998). Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J. Biol. Chem. 273, 1872-1879.
130. Nomura, M., and Li, E. (1998). Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393, 786-790.
131. Oshima, M., Oshima, H., and Taketo, M. M. (1996). TGF-β receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev. Biol. 179, 297-302.
132. Pardali, E., Xie, X.-Q., Tsapogas, P., Itoh, S., Arvanitidis, K., Heldin, C.-H., ten Dijke, P., Grundström, T., and Sideras, P. (2000). Smad and AML proteins synergisticalry confer transforming growth factor β1 responsiveness to human germ-line IgA genes. J. Biol. Chem. 275, 3552-3560.
133. Patterson, G. I., Koweek, A., Wong, A., Liu, Y., and Ruvkun, G. (1997). The DAF-3 Smad protein antagonizes TGF-β-related receptor signaling in the Caenorhabditis elegans dauer pathway. Genes Dev. 11, 2679-2690.
134. Persson, U., Izumi, H., Souchelnytskyi, S., Itoh, S., Grimsby, S., Engström, U., Heldin, C.-H., Funa, K., and ten Dijke, P. (1998). The L45 loop in type I receptors for TGF-β family members is a critical determinant in specifying Smad isoform activation. FEBS Lett. 434, 83-87.
135. Pouponnot, C., Jayaraman, L., and Massagué, J. (1998). Physical and functional interaction of SMADs and p300/CBP. J. Biol. Chem. 273, 22865-22868.
136. 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.
137. 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). Madrelated genes in the human. Nat. Genet. 13, 347-349.
138. Roberts, A. B. and Sporn, M. B. (1990). The transforming growth factor-βs. In "Peptide Growth Factors and Their Receptors, Part I" (M. B. Sporn and A. B. Roberts, eds.), pp. 419-472. Springer-Verlag, Berlin, Germany.
139. Sakurai, H., Miyoshi, H., Toriumi, W., and Sugita, T. (1999). Functional interactions of transforming growth factor β-activated kinase 1 with IκB kinases to stimulate NF-κB activation. J. Biol. Chem. 274, 10641-10648.
140. Sano, Y., Harada, J., Tashiro, S., Gotoh-Mandeville, R., Maekawa, T., and Ishii, S. (1999). ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-β signaling. J. Biol. Chem. 274, 8949-8957.
141. 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 β pathway components. Proc. Natl. Acad. Sci. USA 93, 790-794.
142. Schultheiss, T. M., Burch, J. B., and Lassar, A. B. (1997). A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev. 11, 451-462.
143. Schutte, M., Hruban, R. H., Hedrick, L., Cho, K. R., Nadasdy, G. M., Weinstein, C. L., Bova, G. S., Isaacs, W. B., Cairns, P., Nawroz, H., Sidransky, D., Casero, R. A., Jr., Meltzer, P. S., Hahn, S. A., and Kern, S. E. (1996). DPC4 gene in various tumor types. Cancer Res. 56, 2527-2530.
144. 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.
145. Shen, X., Hu, P. P., Liberati, N. T., Datto, M. B., Frederick, J. P., and Wang, X.-F. (1998). TGF-β-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/ CREB-binding protein. Mol. Biol. Cell 9, 3309-3319.
146. Shi, Y., Hata, A., Lo, R. S., Massagué, J., and Pavletich, N. P. (1997). A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature 388, 87-93.
147. Shi, M. J., and Stavnezer, J. (1998). CBFαS (AML2) is induced by TGF-β1 to bind and activate the mouse germline Ig α promoter. J. Immunol. 161, 6751-6760.
148. Shi, Y., Wang, Y. F., Jayaraman, L., Yang, H., Massagué, J., and Pavletich, N. P. (1998). Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-β signaling. Cell 94, 585-594.
149. Shi, X., Yang, X., Chen, D., Chang, D., and Cao, X. (1999). Smad1 interacts with homeobox DNA-binding proteins in bone morphogenetic protein signaling. J. Biol. Chem. 274, 13711-13717.
150. Shimizu, A., Kato, M., Nakao, A., Imamura, T., ten Dijke, P., Heldin, C.-H., Kawabata, M., Shimada, S., and Miyazono, K. (1998). Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line. Genes Cells 3, 125-134.
151. Shioda, T., Lechleider, R. J., Dunwoodie, S. L., Li, H., Yahata, T., de Caestecker, M. P., Fenner, M. H., Roberts, A. B., and Isselbacher, K. J. (1998). Transcriptional activating activity of Smad4: Roles of SMAD hetero-oligomerization and enhancement by an associating transactivator. Proc. Natl. Acad. Sci. USA 95, 9785-9790.
152. Shull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., Allen, R., Sidman, C., Proetzel, G., Calvin, D., Annunziata, N., and Doetschman, T. (1992). Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693-699.
153. Sirard, C., de la Pompa, J. L., Elia, A., Itie, A., Mirtsos, C., Cheung, A., Hahn, S., Wakeham, A., Schwartz, L., Kern, S. E., Rossant, J., and Mak, T. W. (1998). The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and
154. Song, C. Z., Siok, T. E., and Gelehrter, T. D. (1998). Smad4/DPC4 and Smad3 mediate transforming growth factor-β (TGF-β) signaling through direct binding to a novel TGF-β-responsive element in the human plasminogen activator inhibitor-1 promoter. J. Biol. Chem. 273, 29287-29290.
155. Sonoda, E., Matsumoto, R., Hitoshi, Y., Ishii, T., Sugimoto, M., Araki, S., Tominaga, A., Yamaguchi, N., and Takatsu, K. (1989). Transforming growth factor β induces IgA production and acts additively with interleukin 5 for IgA production. J. Exp. Med. 170, 1415-1420.
156. 467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-β signaling. J. Biol. Chem. 272, 28107-28115.
157. Souchelnytskyi, S., Nakayama, T., Nakao, A., Morén, A., Heldin, C.-H., Christian, J. L., and ten Dijke, P. (1998). Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-β receptors. J. Biol. Chem. 273, 25364-25370.
158. Staehling-Hampton, K., Laughon, A. S., and Hoffmann, F. M. (1995). A Drosophila protein related to the human zinc finger transcription factor PRDII/MBPI/HIV-EP1 is required for dpp signaling. Development 121, 3393-3403.
159. Stroschein, S. L., Wang, W., and Luo, K. (1999). Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhibitor-1 promoter mediates transforming growth factor β-induced Smad-dependent transcriptional activation. J. Biol. Chem. 274, 9431-9441.
160. Struhl, K. (1998). Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599-606.
161. Takagi, Y., Koumura, H., Futamura, M., Aoki, S., Yamaguchi, K., Kida, H., Tanemura, H., Shimokawa, K., and Saji, S. (1998). Somatic alterations of the SMAD-2 gene in human colorectal cancers. Br. J. Cancer 78, 1152-1155.
162. Takaku, K., Oshima, M., Miyoshi, H., Matsui, M., Seldin, M. F., and Taketo, M. M. (1998). Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Ape genes. Cell 92, 645-656.
163. Takase, M., Imamura, T., Sampath, T. K., Takeda, K., Ichijo, H., Miyazono, K., and Kawabata, M. (1998). Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem. Biophys. Res. Commun. 244, 26-29.
164. Tamaki, K., Souchelnytskyi, S., Itoh, S., Nakao, A., Sampath, K., Heldin, C.-H., and ten Dijke, P. (1998). Intracellular signaling of osteogenic protein-1 through Smad5 activation. J. Cell. Physiol. 177, 355-363.
165. Tang S. J., Hoodless, P. A., Lu, Z., Breitman, M. L., McInnes, R. R., Wrana, J. L., and Buchwald, M. (1998). The Tlx-2 homeobox gene is a downstream target of BMP signalling and is required for mouse mesoderm development. Development 125, 1877-1887.
166. ten Dijke, P., Yamashita, H., Sampath, T. K., Reddi, A. H., Estevez, M., Riddle, D. L., Ichijo, H., Heidin, C.-H., and Miyazono, K. (1994a). Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J. Biol. Chem. 269, 16985-16988.
167. ten Dijke, P., Yamashita, H., Ichijo, H., Franzén, P., Laiho, M., Miyazono, K., and Heldin, C.-H. (1994b). Characterization of type I receptors for transforming growth factor-β and activin. Science 264, 101-104.
168. Thatcher, J. D., Haun, C., and Okkema, P. G. (1999). The DAF-3 Smad binds DNA and represses gene expression in the Caenorhabditis elegans pharynx. Development 126, 97-107.
169. Thiagalingam, S., Lengauer, C., Leach, F. S., Schutte, M., Hahn, S. A., Overhauser, J., Willson, J. K., Markowitz, S., Hamilton, S. R., Kern, S. E., Kinzler, K. W., and Vogelstein, B. (1996). Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat. Genet. 13, 343-346.
170. Topper, J. N., Cai, J., Qiu, Y., Anderson, K. R., Xu, Y. Y., Deeds, J. D., Feeley, R., Gimeno, C. J., Woolf, E. A., Tayber, O., Mays, G. G., Sampson, B. A., Schoen, F. J., Gimbrone, M. A., Jr., and Falb, D. (1997). Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc. Natl. Acad. Sci. USA 94, 9314-9319.
171. Topper, J. N., DiChiara, M. R., Brown, J. D., Williams, A. J., Falb, D., Collins, T., and Gimbrone, M. A., Jr. (1998). CREB binding protein is a required coactivator for Smad-dependent, transforming growth factor β transcriptional responses in endothelial cells. Proc. Natl. Acad. Sci. USA 95, 9506-9511.
172. Travers, A. (1999). How to put a HAT on the histones. Curr. Biol. 9, R23-R25.
173. 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 TGFβ receptor. Cell 11, 779-791.
174. Tsuneizumi, K., Nakayama, T., Kamoshida, Y., Kornberg, T. B., Christian, J. L., and Tabata, T. (1997). Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389, 627-631.
175. Uchida, K., Nagatake, M., Osada, H., Yatabe, Y., Kondo, M., Mitsudomi, T., Masuda, A., and Takahashi, T. (1996). Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers. Cancer Res. 56, 5583-5585.
176. Ulloa, L., Doody, J., and Massagué, J. (1999). Inhibition of transforming growth factor-β/ SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710-713.
177. Verschueren, K., Remacle, J. E., Collart, C., Kraft, H., Baker, B. S., Tylzanowski, P., Nelles, L., Wuytens, G., Su, M.-T., Bodmer, R., Smith, J. C., and Huylebroeck, D. (1999). SIP1, a novel zinc finger/homeodomain represser, interacts with Smad proteins and binds to 5′-CACCT sequences in candidate target genes. J. Biol. Chem., 274, 20489-20498.
178. Vindevoghel, L., Lechleider, R. J., Kon, A., de Caestecker, M. P., Uitto, J., Roberts, A. B., and Mauviel, A. (1998). SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor β. Proc. Natl. Acad. Sci. USA 95, 14769-14774.
179. Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L., and Robertson, E. J. (1998). Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92, 797-808.
180. Waltzer, L., and Bienz, M. (1999). A function of CBP as a transcriptional co-activator during Dpp signalling. EMBO J. 18, 1630-1641.
181. Wang, T., Donahoe, P. K., and Zervos, A. S. (1994). Specific interaction of type I receptors of the TGF-β family with the immunophihn FKBP-12. Science 265, 674-676.
182. Wang, T., Li, B. Y., Danielson, P. D., Shah, P. C., Rockwell, S., Lechleider, R. J., Martin, J., Manganaro, T., and Donahoe, P. K. (1996). The immunophilin FKBP12 functions as a common inhibitor of the TGFβ family type I receptors. Cell 86, 435-444.
183. Watanabe, T. K., Suzuki, M., Omori, Y., Hishigaki, H., Horie, M., Kanemoto, N., Fujiwara, T., Nakamura, Y., and Takahashi, E. (1997). Cloning and characterization of a novel member of the human Mad gene family (MADH6). Genomics 42, 446-451.
184. Weinstein, M., Yang, X., Li, C., Xu, X., Gotay, J., and Deng C. X. (1998). Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. Proc. Natl. Acad. Sci. USA 95, 9378-9383.
185. Winnier, G., Blessing, M., Labosky, P. A., and Hogan, B. L. (1995). Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105-2116.
186. Wisotzkey, R. G., Mehra, A., Sutherland, D. J., Dobens, L. L., Liu, X., Dohrmann, C., Attisano, L., and Raftery, L. A. (1998). Medea is a Drosophila Smad4 homolog that is differentially required to potentiate DPP responses. Development 125, 1433-1445.
187. Wong, C., Rougier-Chapman, E. M., Frederick, J. P., Datto, M. B., Liberati, N. T., Li, J. M., and Wang, X.-F. (1999). Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the C-J un promoter by transforming growth factor β. Mol. Cell. Biol. 19,1821-1830.
188. Wotton, D., Lo, R. S., Lee, S., and Massagué, J. (1999). A Smad transcriptional corepressor. Cell 97, 29-39.
189. Xie, X. Q., Pardali, E., Holm, M., Sideras, P., and Grundstrom, T. (1999). AML and Ets proteins regulate the Iα 1 germ-line promoter. Eur. J. Immunol. 29, 488-498.
190. Xu, X., Yin, Z., Hudson, J. B., Ferguson, E. L., and Frasch, M. (1998). Smad proteins act in combination with synergistic and antagonistic regulators to target Dpp responses to the Drosophila mesoderm. Genes Dev. 12, 2354-2370.
191. Yagi, K., Goto, D., Hamamoto, T., Takenoshita, S., Kato, M., and Miyazono, K. (1999). Alternatively spliced variant of Smad2 lacking exon 3: Comparison with wild-type Smad2 and Smad3. J. Biol. Chem. 274, 703-709.
192. Yamaguchi, K., Shirakabe, K., Shibuya, H., Irie, K., Oishi, I, Ueno, N., Taniguchi, T., Nishida, E., and Matsumoto, K. (1995). Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270, 2008-2011.
193. Yamamoto, N., Akiyama, S., Katagiri, T., Namiki, M., Kurokawa, T., and Suda, T. (1997). Smad1 and Smad5 act downstream of intracellular signalings of BMP-2 that inhibits myogenic differentiation and induces osteoblast differentiation in C2C12 myoblasts. Biochem. Biophys. Res. Commun. 238, 574-580.
194. Yanagi, Y., Suzawa, M., Kawabata, M., Miyazono, K., Yanagisawa, J., and Kato, S. (1999). Positive and negative modulation of vitamin D receptor function by TGF-β signaling through Smad proteins. J. Biol. Chem. 274, 12971-12974.
195. Yanagisawa, K., Osada, H., Masuda, A., Kondo, M., Saito, T., Yatabe, Y., Takagi, K., and Takahashi, T. (1998). Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells. Oncogene 17, 1743-1747.
196. Yanagisawa, J., Yanagi, Y., Masuhiro, Y., Suzawa, M., Watanabe, M., Kashiwagi, K., Toriyabe, T., Kawabata, M., Miyazono, K., and Kato, S. (1999). Convergence of transforming growth factor-β and vitamin D signaling pathways on SMAD transcriptional coactivators. Science 283, 1317-1321.
197. Yang, X., Li, C., Xu, X., and Deng, C. (1998). The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc. Natl. Acad. Sci. USA 95, 3667-3672.
198. Yang, X., Castilla, L. H., Xu, X., Li, C., Gotay, J., Weinstein, M., Liu, P. P., and Deng, C. X. (1999a). Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development 126, 1571-1580.
199. Yang, X., Letterio, J. J., Lechleider, R. J., Chen, L., Hayman, R., Gu, H., Roberts, A. B., and Deng, C. (1999b). Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J. 18, 1280-1291.
200. Yue, J., Hartsough, M. T., Frey, R. S., Frielle, T., and Mulder, K. M. (1999a). Cloning and expression of a rat Smad1: Regulation by TGFβ and modulation by the Ras/MEK pathway. J. Cell. Physiol. 178, 387-396.
201. Yue, J., Frey, R. S., and Mulder, K. M. (1999b). Cross-talk between the Smad1 and Ras/ MEK signaling pathways for TGFβ. Oncogene 18, 2033-2037.
202. Zavadil, J., Brezinova, J., Svoboda, P., Zemanova, Z., and Michalova, K. (1997). Smad5, a tumor suppressor candidate at 5q31.1, is hemizygously lost and not mutated in the retained allele in human leukemia cell line HL60. Leukemia 11, 1187-1192.
203. Zawel, L., Le Dai, J., Buckhaults, P., Zhou, S., Kinzler, K. W., Vogelstein, B., and Kern, S. E. (1998). Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1, 611-617.
204. Zhang, Y., Musci, T., and Derynck, R. (1997). The tumor suppressor Smad4/DPC4 as a central mediator of Smad function. Curr. Biol. 7, 270-276.
205. Zhang, Y., Feng, X.-H., and Derynck, R. (1998). Smad3 and Smad4 cooperate with c-Jun/ c-Fos to mediate TGF-β-induced transcription. Nature 394, 909-913.
206. Zhou, S., Buckhaults, P., Zawel, L., Bunz, F., Riggins, G., Le Dai, J., Kern, S. E., Kinzler, K. W., and Vogelstein, B. (1998a). Targeted deletion of Smad4 shows it is required for transforming growth factor β and activin signaling in colorectal cancer cells. Proc. Natl. Acad. Sci. USA 95, 2412-2416.
207. Zhou, S., Zawel, L., Lengauer, C., Kinzler, K. W., and Vogelstein, B. (1998b). Characterization of human FAST-1, a TGFβ and activin signal transducer. Mol. Cell 2, 121-127.
208. Zhou, G., Lee, S. C., Yao, Z., and Tan, T.-H. (1999). Hematopoietic progenitor kinase 1 is a component of transforming growth factor β-induced c-Jun N-terminal kinase signaling cascade. J. Biol. Chem. 274, 13133-13138.
209. Zhu, H., Kavsak, P., Abdollah, S., Wrana, J. L., and Thomsen, G. H. (1999). A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687-693.
210. Zhu, Y., Richardson, J. A., Parada, L. F., and Graff, J. M. (1998). Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703-714.
211. Zimmerman, C. M., Kariapper, M. S., and Mathews, L. S. (1998). Smad proteins physically interact with calmodulin. J. Biol. Chem. 273, 677-680.