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Ludwig Institute for Cancer Research, Box 595, S-75124 Uppsala, Sweden
1Correspondence and current address: Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: ptdijke{at}nki.nl
Transforming growth factor-ß (TGF-ß) superfamily members are multifunctional cell–cell signaling proteins that play pivotal roles in tissue homeostasis and development of multicellular animals. They mediate their pleiotropic effects from membrane to nucleus through distinct combinations of type I and type II serine/threonine kinase receptors and their downstream effectors, known as Smad proteins. Certain Smads, termed receptor-regulated Smads, become phosphorylated by activated type I receptors and form heteromeric complexes with a common-partner Smad4, which translocates into the nucleus to control gene transcription. In addition to these signal transducing Smads, inhibitory Smads have been identified that inhibit the activation of receptor-regulated Smads. In contrast to the still growing TGF-ß superfamily (with ~30 members in mammals), relatively few type I and type II receptors as well as Smads have been identified. We will focus on recent insights into the molecular mechanisms by which signaling specificity between different TGF-ß superfamily members is achieved and regulated, and how a single family member can elicit a broad scala of biological responses.—Piek, E., Heldin, C.-H., ten Dijke, P. Specificity, diversity, and regulation in TGF-ß superfamily signaling.
Key Words: activin • bone morphogenetic protein • signal transduction • Smad • transforming growth factor-ß
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 U. Bartram and C. P. Speer The Role of Transforming Growth Factor {beta} in Lung Development and Disease Chest, February 1, 2004; 125(2): 754 - 765. [Abstract] [Full Text] [PDF]
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C. E. Runyan, H. W. Schnaper, and A.-C. Poncelet The Phosphatidylinositol 3-Kinase/Akt Pathway Enhances Smad3-stimulated Mesangial Cell Collagen I Expression in Response to Transforming Growth Factor-{beta}1 J. Biol. Chem., January 23, 2004; 279(4): 2632 - 2639. [Abstract] [Full Text] [PDF]
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 J. C. Langer, E. Henckaerts, J. Orenstein, and H.-W. Snoeck Quantitative Trait Analysis Reveals Transforming Growth Factor-{beta}2 as a Positive Regulator of Early Hematopoietic Progenitor and Stem Cell Function J. Exp. Med., January 5, 2004; 199(1): 5 - 14. [Abstract] [Full Text] [PDF]
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S. Saika, Y. Okada, T. Miyamoto, O. Yamanaka, Y. Ohnishi, A. Ooshima, C.-Y. Liu, D. Weng, and W. W.-Y. Kao Role of p38 MAP Kinase in Regulation of Cell Migration and Proliferation in Healing Corneal Epithelium Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 100 - 109. [Abstract] [Full Text] [PDF]
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W. Li, W. Qiao, L. Chen, X. Xu, X. Yang, D. Li, C. Li, S. G. Brodie, M. M. Meguid, L. Hennighausen, et al. Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice Development, December 15, 2003; 130(24): 6143 - 6153. [Abstract] [Full Text] [PDF]
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T. G. Hofmann, N. Stollberg, M. L. Schmitz, and H. Will HIPK2 Regulates Transforming Growth Factor-{beta}-Induced c-Jun NH2-Terminal Kinase Activation and Apoptosis in Human Hepatoma Cells Cancer Res., December 1, 2003; 63(23): 8271 - 8277. [Abstract] [Full Text] [PDF]
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 A. Moustakas and C.-H. Heldin Ecsit-ement on the crossroads of Toll and BMP signal transduction Genes & Dev., December 1, 2003; 17(23): 2855 - 2859. [Full Text] [PDF]
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J. Yang, X. Zhang, Y. Li, and Y. Liu Downregulation of Smad Transcriptional Corepressors SnoN and Ski in the Fibrotic Kidney: An Amplification Mechanism for TGF-{beta}1 Signaling J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3167 - 3177. [Abstract] [Full Text] [PDF]
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H. Takahashi, T. Shintani, H. Sakuta, and M. Noda CBF1 controls the retinotectal topographical map along the anteroposterior axis through multiple mechanisms Development, November 1, 2003; 130(21): 5203 - 5215. [Abstract] [Full Text] [PDF]
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N. Wright, T. L. de Lera, C. Garcia-Moruja, R. Lillo, F. Garcia-Sanchez, A. Caruz, and J. Teixido Transforming growth factor-{beta}1 down-regulates expression of chemokine stromal cell-derived factor-1: functional consequences in cell migration and adhesion Blood, September 15, 2003; 102(6): 1978 - 1984. [Abstract] [Full Text] [PDF]
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C. E. Runyan, H. W. Schnaper, and A.-C. Poncelet Smad3 and PKC{delta} mediate TGF-{beta}1-induced collagen I expression in human mesangial cells Am J Physiol Renal Physiol, September 1, 2003; 285(3): F413 - F422. [Abstract] [Full Text] [PDF]
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S. C. Hubchak, C. E. Runyan, J. I. Kreisberg, and H. W. Schnaper Cytoskeletal Rearrangement and Signal Transduction in TGF-{beta}1-Stimulated Mesangial Cell Collagen Accumulation J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1969 - 1980. [Abstract] [Full Text] [PDF]
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 C. Merrihew, S. Soeder, D. C. Rueger, K. E. Kuettner, and S. Chubinskaya Modulation of Endogenous Osteogenic Protein-1 (OP-1) by Interleukin-1 in Adult Human Articular Cartilage J. Bone Joint Surg. Am., August 1, 2003; 85(90003): 67 - 74. [Abstract] [Full Text] [PDF]
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 L. Tadlock, Y. Yamagiwa, J. Hawker, C. Marienfeld, and T. Patel Transforming growth factor-{beta} inhibition of proteasomal activity: a potential mechanism of growth arrest Am J Physiol Cell Physiol, August 1, 2003; 285(2): C277 - C285. [Abstract] [Full Text] [PDF]
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H. Jono, H. Xu, H. Kai, D. J. Lim, Y. S. Kim, X.-H. Feng, and J.-D. Li Transforming Growth Factor-{beta}-Smad Signaling Pathway Negatively Regulates Nontypeable Haemophilus influenzae-induced MUC5AC Mucin Transcription via Mitogen-activated Protein Kinase (MAPK) Phosphatase-1-dependent Inhibition of p38 MAPK J. Biol. Chem., July 18, 2003; 278(30): 27811 - 27819. [Abstract] [Full Text] [PDF]
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D. Haller, L. Holt, S. C. Kim, R. F. Schwabe, R. B. Sartor, and C. Jobin Transforming Growth Factor-{beta}1 Inhibits Non-pathogenic Gramnegative Bacteria-induced NF-{kappa}B Recruitment to the Interleukin-6 Gene Promoter in Intestinal Epithelial Cells through Modulation of Histone Acetylation J. Biol. Chem., June 20, 2003; 278(26): 23851 - 23860. [Abstract] [Full Text] [PDF]
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 S. Luckhart, A. L. Crampton, R. Zamora, M. J. Lieber, P. C. Dos Santos, T. M. L. Peterson, N. Emmith, J. Lim, D. A. Wink, and Y. Vodovotz Mammalian Transforming Growth Factor {beta}1 Activated after Ingestion by Anopheles stephensi Modulates Mosquito Immunity Infect. Immun., June 1, 2003; 71(6): 3000 - 3009. [Abstract] [Full Text] [PDF]
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G. M. Wildey, S. Patil, and P. H. Howe 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., May 9, 2003; 278(20): 18069 - 18077. [Abstract] [Full Text] [PDF]
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 T. Thyagarajan, S. Totey, M. J. S. Danton, and A. B. Kulkarni GENETICALLY ALTERED MOUSE MODELS: THE GOOD, THE BAD, AND THE UGLY Critical Reviews in Oral Biology & Medicine, May 1, 2003; 14(3): 154 - 174. [Abstract] [Full Text] [PDF]
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W.-y. Lui, W. M. Lee, and C. Y. Cheng Transforming Growth Factor {beta}3 Regulates the Dynamics of Sertoli Cell Tight Junctions Via the p38 Mitogen-Activated Protein Kinase Pathway Biol Reprod, May 1, 2003; 68(5): 1597 - 1612. [Abstract] [Full Text] [PDF]
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 P. C. Gray, C. A. Harrison, and W. Vale Cripto forms a complex with activin and type II activin receptors and can block activin signaling PNAS, April 29, 2003; 100(9): 5193 - 5198. [Abstract] [Full Text] [PDF]
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C. Mukasa, M. Nomura, T. Tanaka, K. Tanaka, Y. Nishi, T. Okabe, K. Goto, T. Yanase, and H. Nawata Activin Signaling through Type IB Activin Receptor Stimulates Aromatase Activity in the Ovarian Granulosa Cell-Like Human Granulosa (KGN) Cells Endocrinology, April 1, 2003; 144(4): 1603 - 1611. [Abstract] [Full Text] [PDF]
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C. Liu, M. D. A. Gaca, E. S. Swenson, V. F. Vellucci, M. Reiss, and R. G. Wells Smads 2 and 3 Are Differentially Activated by Transforming Growth Factor-beta (TGF-beta ) in Quiescent and Activated Hepatic Stellate Cells. CONSTITUTIVE NUCLEAR LOCALIZATION OF Smads IN ACTIVATED CELLS IS TGF-beta -INDEPENDENT J. Biol. Chem., March 21, 2003; 278(13): 11721 - 11728. [Abstract] [Full Text] [PDF]
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 J. Xu, A. R. Beyer, W. H. Walker, and E. A. McGee Developmental and Stage-Specific Expression of Smad2 and Smad3 in Rat Testis J Androl, March 1, 2003; 24(2): 192 - 200. [Abstract] [Full Text] [PDF]
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 S. Chen, M. Kulik, and R. J. Lechleider Smad proteins regulate transcriptional induction of the SM22{alpha} gene by TGF-{beta} Nucleic Acids Res., February 15, 2003; 31(4): 1302 - 1310. [Abstract] [Full Text] [PDF]
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H. W. Schnaper, T. Hayashida, S. C. Hubchak, and A.-C. Poncelet TGF-beta signal transduction and mesangial cell fibrogenesis Am J Physiol Renal Physiol, February 1, 2003; 284(2): F243 - F252. [Abstract] [Full Text] [PDF]
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B. Schmierer, M. K. Schuster, A. Shkumatava, and K. Kuchler Activin and Follicle-Stimulating Hormone Signaling Are Required for Long-Term Culture of Functionally Differentiated Primary Granulosa Cells from the Chicken Ovary Biol Reprod, February 1, 2003; 68(2): 620 - 627. [Abstract] [Full Text] [PDF]
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R. K. Moore, F. Otsuka, and S. Shimasaki Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells J. Biol. Chem., January 3, 2003; 278(1): 304 - 310. [Abstract] [Full Text] [PDF]
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H. Kim, X. Liu, T. Kobayashi, T. Kohyama, F.-Q. Wen, D. J. Romberger, H. Conner, P. S. Gilmour, K. Donaldson, W. MacNee, et al. Ultrafine Carbon Black Particles Inhibit Human Lung Fibroblast-Mediated Collagen Gel Contraction Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 111 - 121. [Abstract] [Full Text] [PDF]
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A. V. Biankin, A. L. Morey, C.-S. Lee, J. G. Kench, S. A. Biankin, H. C. Hook, D. R. Head, T. B. Hugh, R. L. Sutherland, and S. M. Henshall DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma J. Clin. Oncol., December 1, 2002; 20(23): 4531 - 4542. [Abstract] [Full Text] [PDF]
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